EHA-TSH Haematology Tutorial on Lymphoma

Session 1 The History of Lymphoma Classification and 2016 WHO revision

lsquoLearn from the past look to the future but live

in the presentrsquo Classification of Lymphoid

neoplasms WHO 2016 Update

SpeakerAyşeguumll Uumlner

Hacettepe University School of Medicine

‒ No disclosures

Learning objectives

‒ Learn about the history of lymphoma classification

‒ To learn what is new in the WHO 2016 classification of lymphoid neoplasms

Why Classify

‒ Classification is essential for medicine ndash diseases can be described defined and named

‒ Disease entities should be distinct with non-overlapping features

‒ Consensus on definitions and terminology is necessary so that pathogenetic mechanisms behind diseases are better understood clinical trials could be carried out and comparisons are feasible

‒ Any proposed classification should be biologically rational

‒ It should be clinically useful

Although pathologists took the primary responsibility for

developing the classification of Hematological

Malignancies the advise of clinicians was obtained to

ensure its usefulness and acceptance in practice

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

‒ No disclosures

Learning objectives

‒ Learn about the history of lymphoma classification

‒ To learn what is new in the WHO 2016 classification of lymphoid neoplasms

Why Classify

‒ Classification is essential for medicine ndash diseases can be described defined and named

‒ Disease entities should be distinct with non-overlapping features

‒ Consensus on definitions and terminology is necessary so that pathogenetic mechanisms behind diseases are better understood clinical trials could be carried out and comparisons are feasible

‒ Any proposed classification should be biologically rational

‒ It should be clinically useful

Although pathologists took the primary responsibility for

developing the classification of Hematological

Malignancies the advise of clinicians was obtained to

ensure its usefulness and acceptance in practice

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Learning objectives

‒ Learn about the history of lymphoma classification

‒ To learn what is new in the WHO 2016 classification of lymphoid neoplasms

Why Classify

‒ Classification is essential for medicine ndash diseases can be described defined and named

‒ Disease entities should be distinct with non-overlapping features

‒ Consensus on definitions and terminology is necessary so that pathogenetic mechanisms behind diseases are better understood clinical trials could be carried out and comparisons are feasible

‒ Any proposed classification should be biologically rational

‒ It should be clinically useful

Although pathologists took the primary responsibility for

developing the classification of Hematological

Malignancies the advise of clinicians was obtained to

ensure its usefulness and acceptance in practice

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Why Classify

‒ Classification is essential for medicine ndash diseases can be described defined and named

‒ Disease entities should be distinct with non-overlapping features

‒ Consensus on definitions and terminology is necessary so that pathogenetic mechanisms behind diseases are better understood clinical trials could be carried out and comparisons are feasible

‒ Any proposed classification should be biologically rational

‒ It should be clinically useful

Although pathologists took the primary responsibility for

developing the classification of Hematological

Malignancies the advise of clinicians was obtained to

ensure its usefulness and acceptance in practice

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

‒ Any proposed classification should be biologically rational

‒ It should be clinically useful

Although pathologists took the primary responsibility for

developing the classification of Hematological

Malignancies the advise of clinicians was obtained to

ensure its usefulness and acceptance in practice

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Lymphoid neoplasms

NHLHodgkinrsquos Lymphoma

NLPHL

Classical HL

NSHL

MCHL

Lymphocyte-rich

Lymphocyte depleted

TNK-cell neoplasmsB-cell neoplasms

Precursor B-

cell

neoplasms

Mature B-

cell

neoplasms

Precursor T-

cell

neoplasms

Mature T-

cell

neoplasms

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

SAGeller amp CR Taylor

Virchows Arch (2013)

Thomas Hodgkin was the first lecturer in Morbid anatomy and curator of its museum at Guyrsquos Hospital

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

1832 19781966

19741940 1982Kiel Classification

Concept of tumor grading

introduced low grade lsquo-

cyticrsquo and higher grade lsquo-

blasticrsquo

Lennert

Report of 7 lymphoma

cases

Samuel Wilks used the

term lsquoHodgkinrsquos Disease in

1865

Thomas Hodgkin

Armed Forces Institute of

Pathology fascicle

published-based on

morphology architecture

and cell size

Rappaport

NCI-lymphomas divided

into low intermediate

and high grade groups

WF

Classification of malignant

lymphomas

Gall amp Mallory

LampC Included presumed

cell of origin (B T and

histiocytic) and

morphology

BNLI-Bennett et al

Lukes amp Collins

BNLI

Macroscopic

features

Microscopic

features

Cell of origin-

immunology

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

lsquoNowhere in pathology has a chaos of names so clouded clear concepts as in the subject lymphoid tumorsrsquo

RA Willis

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

1994 2008

20162001ILSG brought together

experts from around the

globe

Defined lsquorealrsquo disease

entities based on clinical

features morphology

immunophenotype and

genetic information

REAL Classification

Revised classification

WHO Classification of Hematopoietic and

Lymphoid Tissue

Based on REAL

Classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Revision of the 4th

edition of the

classification

WHO Classification

of Hematopoietic and

Lymphoid Tissue

Clinical morphologic phenotypic and genetic features

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

1975 20101985

2000rsquo

s

1980rsquo

s

2010rsquo

s

NGS

Monoclonal

Antibody

Technology

PCR and

Sequencing

WGS

WES in

hematopoetic

malignancies

Development

of numerous

antibodies

used in

immunophenotyping

GEP

chemotherapyImmuno-

chemotherapy

Targeted-

therapies

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

WHO Classification 2016

bull New genomic technologies clinical and morphologic observations has provided new insights into the biology of lymphomas

bull Data from multicenter clinical trials

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

WHO Classification- 2016bull Recommendations for handling patients with early

lesions

bull New definite and provisional entities defined

bull Modifications and renaming of some former entities

Nomenclature influenced by clinical behaviour

bull Refinement of diagnostic criteria Molecular changes

Diagnostic prognostic and therapeutic implications

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Early lesions of malignant lymphomas

‒ Can we apply the multistep carcinogenesis model to lymphomas

‒ Is there a benign lymphoma

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Monoclonal B-cell Lymphocytosis

bull Precursor to CLL

bull lt5x109L monoclonal B cells without LAP organomegaly or extramedullary disease

bull CLL-type-75 of the cases

bull Atypical CLL-type

bull Non-CLL-type

bull Minority of the patients will progress to overt lymphoid malignancy

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Rawstron AC et al Cytometry Part B (Clinical Cytometry) 78B (Suppl 1)S19 2010

WHO 2016bull Low-count MBL

(lt05x109L) vs High-count MBL

Low count MBL ndash no specific follow-up recommended as it has very limited potential for progression to CLL

Patients with high- count MBL require periodic evaluation

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

CLLbull No disease defining

mutations

bull Number of mutations have been identified-at low frequency

bull Some mutations are associated with poor prognosisTP53

NOTCH1

SF3B1

BIRC3

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

In Situ Follicular Neoplasia (WHO 2016)(Follicular Lymphoma in situ WHO 2008)

bull Incidental finding Intrafollicular BCL-2 positive centrocytes and centroblasts in an otherwise normal lymph node

bull Must be differentiated from partial involvement by FL

bull Staging work-up is necessary to exclude systemic FL

bull Few (lt5) patients progress to disseminated FL-markers to predict progression are not well defined

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

What is new in Follicular lymphoma-WHO 2016

bull Intestinal follicular lymphomabull Duodenal-type

bull Testicular FLbull Childhood

bull Cytologically grade 3a FL

bull Bcl-2 negative

bull Diffuse FLbull Pediatric-type FL

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Diffuse (appearing) FL

bull Frequently presents as a localised inguinal mass

bull Grade 1-23 morphology

bull BCL2 gene rearrangement negative

bull 1p36 deletion (not specific can be also seen in conventional FL)

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

bull It became a definite entity in WHO 2016 (was a provisional entity in WHO 2008)

bull Similar lymphoma can be seen in adult age group

bull Median age 15-18

bull MF 101

Pediatric-type Follicular Lymphoma

(WHO 2016)

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

bull Large expansilefollicles

bull No-diffuse areas

bull ldquoBlastoidrdquo morphology

bull Usually Grade 3 exceptionally Grade 1-2

bull No BM involvement

Pediatric-type Follicular Lymphoma

(WHO 2016)

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Pediatric-type Follicular Lymphoma (WHO 2016)

‒ Differential diagnosis from grade 3 FL is necessary

‒ BCL 2 BCL6 or MYC rearrangements are not seen although Bcl-2 protein expression can be seen

‒ Usually involves headneck region

‒ Stage 1 disease

‒ Excision alone can be curative

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

IRF4-associated Large B-cell Lymphomabull Rare -005 of LBCL bull Headampneck region and GISbull Wide age range (4-79)

median age of 12 bull FM (911)bull Usually stage I-II (84)bull Excellent prognosis (5 year

survival 100)bull Nodular-diffuse growth of

medium-large cellsbull BCL-6 and MUM-1

expression is a clue for the diagnosis

Salaveria et al Blood 2011

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Mantle Cell Lymphoma

bull In-situ mantle cell neoplasia

bull Should be differentiated from mantle zone pattern of MCL

bull Leukemic non-nodal MCL

bull Indolent

bull IGHV-mutated SOX11- B cells

Swerdlow S et al Blood 1272381 2016

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Molecular alterations are included in the diagnostic algorithm

Lymphoplasmacytic lymphomaMYD88 L265P mutation

bull İdentified in 90 of LPL Waldenstrom makroglobulinemi-

bull IgM MGUS

bull Not present in plasma cell myeloma

bull Can be seen in some othe NHLndash Some of the other low grade B cell lymphomas

ndash DLBCL non-GC (30) leg-type (50) cases involving immune-priviliged such as testis CNS etc

CXCR4 mutationsbull LPL (30) amp IgM MGUS (20)

bull Not seen in IgG or IgA MGUS

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Hairy cell leukemia

bull BRAF V600E mutation

bull Non present in Hairy cell

leukemia-variant

bull MAP2K1 (MEK1) mutation

bull In cases which do not

carry BRAF mutation and

those which use IGHV4-

34

bull 50 of Hairy cell

leukemia-variant

Molecular alterations are included in the diagnostic algorithm

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Changes in Low grade B-cell Neoplasms-WHO 2016

CLLEven if there is cytopeniasgt5x109L CLL cells necessary for diagnosis

Proliferation centersrsquo importance

Clinically relevant mutations identified

MBLLow-counthigh-count

MCLGenetic profile better delineated

İndolent types

In situ lesions-changed from lymphoma to neoplasia

HCLBRAF V600E and MAP2K1

LPLMYD88 L265P

FCLMutations better defined

In situ lesions-changed from lymphoma to neoplasia

Localized forms and diffuse forms defined

Pediatric-type FLBecame a definite entity broader age

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Rosenwald A et al NEJM 3461937 2002

Diffuse Large B cell Lymphoma

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

COOCD10

Bcl-6GC

Non-

GCMUM1

Non-

GC

GC

(+)

(+)

(+)

(-)

(-)

Hans CP Blood 103275-282 2004

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Scott et al JCO 2015

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

COO-WHO 2016

bull Identification of the COO subtype is requiredbull pathogenesis of GC and ABC subtypes are

different

bull Requiring different therapeutic approaches

bull IHC surrogates can be used (ease and expense) until gene-expression technology can be implemented in clinical practice

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

lsquoDouble expressorrsquo DLBCL

bull 19-34 of cases

bull Neoplastic cells

MYC gt40 and

BCL-2 gt50 of

bull Prognostically relevant but DE is not considered a separate entity

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

High Grade B cell LymphomasWHO 2016

bull Aggressive High Grade B cell cases which should not be classified as BL or DLBCL

bull Two subcategories

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

bull No evidence of DH or TH by genetic analysis

bull Should appear blastoid or Burkitt-like

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

DHLTHLBCL2MYC DHL

Majority show GC-phenotype (CD10+)

Proliferation index generally high (gt80) However in about 20 of the cases it is low

BCL6MYC DHL

ABC phenotype more frequent

Immunoblasticmorphology

Frequent extranodalinvolvement

Bcl-2 expression can be seen

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

FISH

BCL-2 BCL-6 MYC

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Burkitt-like lymphoma with 11q aberration

(WHO 2016 provisional)

‒ Resembles Burkitt lymphoma morphologically and phenotypically

‒ 11q alteration instead of MYC rearrangement

‒ More complex karyotypes higher degree of cytological pleomorphism

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Swerdlow SH et al Blood 127 2375 2016

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

EBV positive diffuse large B-cell lymphoma of the elderly-WHO 2008

bull lsquoEBV+ clonal B-cell lymphoid proliferation that occurs in patients gt50 years and without any known immunodeficiency or prior lymphomarsquo

bull Rare cases of similar lymphoma may occur in younger individuals

bull Well-defined disorders that may be EBV+ are excluded from this category

Nakamura S Jaffe E Swerdlow S EBV positive diffuse large B-cell of the elderly In S Swerdlow et al edsWHO Classification of Tumours of Haematopoieticand Lymphoid Tissues Lyon France IARC 2008243ndash244

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

EBV+ DLBCL NOSWHO 2016

bull EBV+ DLBCL is recognized in younger patients with a broader morphological spectrum and better survival than initially thought

bull lsquoNOSrsquo is to differentiate this from more specific entities such as LG etc

bull EBV+ mucocutaneous ulcer has been segragated from EBV+ DLBCL as a provisional entity due to its self limited growth potential and response to conservative management

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

EBV+ Mucocutaneous Ulcer

Am J Surg Pathol 1113106 Volume 34 2010

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

EBV+ mucocutaneous ulcerbull lsquoEBV+ circumscribed ulcerative

lesions involving oropharyngealmucosa skin and gastrointestinal tract associated with various types of ISrsquo

bull Self-limited indolent course generally responding well to conservative management

bull Patients with age-related or iatrogenic immunosuppression

Dojcinov et al Am J Surg Pathol 2010

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

DLBCL

COO

lsquoDouble-expressorrsquo

Genetic landscape better delineated

EBV+ DLBCL NOS

Can be seen at any age

Should be differentiated from EBV-related specific entitites

EBV+ mucocutaneousulcer

İatrogenic IS or age related ımmune senecense

Burkitt Lymphoma

TCF3 and ID3 mutations in 70

Burkitt-like lymphoma with 11q aberration

Changes in High grade B-cell Neoplasms-WHO 2016

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Changes in High grade B-cell Neoplasms-WHO 2016

HGBCL with MYC and BCL2 and or BCL6rearrangements (so-called DH and TH)

HGBCL NOS

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Mature TNK cell lymphomas

Account for 10-15 of lymphomas

Diagnosis not easy

Morphologic and phenotypic variability

Frequent extranodal presentation

Neoplastic cells are frequently accompanied by reactive cell population

Genetic tests are necessary for demonstration of clonality and neoplastic nature of the proliferation

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

What is new in T- NK- cell neoplasms

bull ALCL- a new definite and a provisional entity

bull Lymphomas derived from follicular TH cells better defined

bull New genetic information for PTCLNOS

bull Better understanding of EBV-associated lymphoproliferative disorders

bull Name changes for some previously defined entities

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

CD 30+ mature T cell lymphomas

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Savage KJ et al Blood 111 2008

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Anaplastic Large Cell Lymphoma

WHO 2008

Anaplastic Large Cell Lymphoma

ALCL ALK+

ALCL ALK-

WHO 2016

ALCL ALK+

ALCL ALK-

Breast implant associated ALCL

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Anaplastic Large Cell Lymphoma ALK-

bull Provisionel entity in WHO 2008 Classification became a real entity in the WHO 2016 update

bull lsquoCD30-positive mature T cell neoplasm which is morphologically similarto ALK-positive ALCL but with no ALK expressionrsquo

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Savage KJ et al Blood 111 2008

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Parilla Castellar ER et al Blood 2014

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Breast implant associated ALCL

Thompson et al Haematologica 2010

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Nodal T cell Lymphomas with TFH

Phenotype

TFH markersCD279PD1 CD10

BCL6 CXCL13 ICOS

SAP and CXCR5

bull Angioimmunoblastic T cell Lymphoma

bull Follicular T cell Lymphoma

bull Peripheral T cell Lymphoma NOS with TFH Phenotype

GeneticsIDH2 TET2 DNMT3A

CD28 RHOA

t(59) ITK-SYK

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Follicular T-cell Lymphoma PTCL NOS Follicular variant

bull Derived from TFH cells

bull Follicularnodular growth pattern

bull Expansion of FDC arborising blood vessels and polymorphic cellular background characteristic for AITL is not observed

bull RS-like cells (EBV+-) can be present

bull Localised disease

bull ITK-SYK translocation t(59)(q33q22)

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Javeed Iqbal et al Blood 20141232915-2923

bull Unique gene expression signatures were identified for

major PTCL entities

bull 14 of PTCL NOS cases were re-classified as AİTLbull ALK(ndash) ALCL is a distinct entity bull Tumor microenvironment plays an important role in prognosis

of AITL

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

PTCL NOS molecular subgroups

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Intestinal T-cell Lymphomas

Enteropathy- associated TCL

EATL Type I (WHO 2008)

bull Associated with celiac disease

bull Seen in individuals of northern European origin

bull Morphology Polymorphic

bull Adjacent mucosa epitheliotropism villus atrophy crypt hyperplasia

Monomorphic epitheliotropicintestinal TCL (MEITL)

EATL Type II (WHO 2008)

bull No association with celiac disease

bull İncreased in incidence in Asians and Hispanic population

bull Morphology Monomorphic

bull Phenotype CD8 CD56 and MATK+ mostly derived form gd T-cells (STAT5B mutations)

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Indolent T-cell LPD of the GI Tractbull Most common in small

intestine and colon less often in stomach and oral mucosa

bull Morphology

bull Low proliferative index

bull No destruction of glands

bull No cytologic atypia

bull Mostly CD8+

bull Conservative management

Perry A et al Blood 2013

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Gastrointestinal indolent T-cell lymphoproliferative disorder

Ganapathi KA et al Haematologica 2014

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Cutaneous T-cell Lymphomasbull Primary cutaneous acral

CD8+ TCL Derived from CD8+ cytotoxic T cells

bull Primary cutaneous gd TCL

bull Primary cutaneous CD4+ small medium T-cell LPD (provisional entity in the 2008 classification) TFH phenotype

Recurrent mutations seen in nodal TFH lymphoma were not identified

Indolent clinical behavior

Conservative local management

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Mature T- and NK-cell neoplasms-New provisionel entities in WHO 2016

bull Indolent T-cell lymphoproliferative disorder (LPD) of the GI tract

bull Primary cutaneous acral CD8+ TCL

bull Follicular T-cell lymphoma

bull Peripheral T cell lymphoma with TFH phenotype

bull Breast implantndashassociated ALCL

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Name changes

WHO 2016

bull Systemic EBV+ T-cell lymphoma of childhood

bull Hydroa vacciniformendashlike lymphoproliferative disorder

bull Monomorphic epitheliotropicintestinal T-cell lymphoma

bull Primary cutaneous CD4+ smallmedium T-cell lymphoproliferative disorder

WHO 2008

bull Systemic EBV+ T-cell lymphoproliferative disorder of childhood

bull Hydroa vacciniforme-like lymphoma

bull EATCL type 2

bull Primary cutaneous CD4+ smallmedium T-cell lymphoma

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Summary

‒ Refinement of definitions diagnostic criteria and terminology

‒ Early lymphoid lesions and those with indolent clinical behavior better delineated

‒ Impact of location age of the patient and infectious agents

‒ Relevance of phenotypic and molecular information in subtyping of various entities

‒ Impact of NGS is reflected in classification

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip

Future

‒ Ongoing research is providing insights and also raising questions for future discovery

‒ Potential targets for new therapies will be better defined and implemented

‒ New Classifications updates incorporating newly acquired information is at the horizonhelliphellip