follicular lymphoma: how many diseases? who classification ... · follicular lymphoma: how many...

Follicular Lymphoma: How many diseases ?

WHO classification – planned updates

Andreas Rosenwald Institute of Pathology, University of Würzburg, Germany

Schwabing, November 17

Follicular lymphoma: 7 diseases?

1. Precursor ‚disease‘

2. Cytological ‚diseases‘

3. Intestinal ‚disease‘

4. Other extranodal ‚disease‘

5. Pediatric ‚disease‘

6. Diffuse ‚disease‘

7. t(14;18)-negative ‚disease‘

FL in situ / FL partial involvement

Mamessier E et al. Haematologica 2014;99:802-810

A FL in situ / follicular lymphoma-like B-cells of undetermined significance (FLBUS):

reactive-appearing lymph node, architecture preserved, strong expression of CD10 and BCL2, carry BCL2 translocation, open sinuses, intact paracortex

B FL partial involvement:

architecture partially preserved, affected follicles expanded (crowded), attenuatedmantle zones, displacement of normal elements

FL in situ

Paucity of genetic alterations compared to overt FL (Mamessier et al., Haematologica 2014; Schmidt et al., Leukemia 2014)

EZH2 mutations

Risk of progression ~10% (Jegalian et al., Blood 2011)

in 15-20% in the context of another B-NHL (MCL, CLL, MZL) (Jegalian et al., Blood 2011, Montes-Moreno et al., Histopathology 2010; Pillaiet al., Haematologica 2013)

Clinical consequences:-staging work up to rule out concurrent lymphoma-if no lymphoma, conservative management-monitoring B-cells with t(14;18) in peripheral blood?

FL partial involvement/limited stage

Presence of preserved reactive follicles predicts limited clinical stage (stage I/II; 83% versus 17%)(Adam et al., AJSP 2005)

9/17 (53%) FL with partial involvement progressed tosystemic FL (Jegalian et al., Blood 2011)

Stage I/II FL show fewer chromosomal alterationscompared to disseminated FL by array CGH thusrepresenting an early stage of disseminated FL (Krijgsman et al., Haematologica 2013)

Topics








Follicular Lymphoma (grade 1 -3A)

• 20% to 30% of all NHL• Morphological, biological and clinical heterogeneity• Extremely variable clinical course

Follicular Lymphoma (grade 3B)

follicles composed entirely of blastspure FL3B very rare! many FL3B have component of DLBCL

Follicular lymphoma grade 3B Comparison with FL grade 1-3A:CD10 expression less frequent (50%)MUM1/IRF4 expression more frequentBCL2 expression less frequent

Genetics:rare presence of t(14;18)rare presence of 3q27/BCL6 rearrangements - morefrequent in FL3B + DLBCLmore similar to DLBCL?

Prognostic significance:unclear –studies use different inclusion criteria (e.g. +/- DLBCL), no uniform treatment recommendations (included in DLBCL trials)

Topics








CD10 Ki67 BCL-2

Follicular Lymphoma of the Duodenum

Follicular Lymphoma of the duodenum

• Involvement of second portion of the duodenum most common• Localized disease• Grade 1/2• Rare spread to lymph nodes (?)• Very rare transformation into diffuse large B-cell lymphoma• Presence of the t(14;18)• Immunohistochemical expression of CD10 and BCL2

• Lack of follicular dendritic cells (FDCs)• No AID expression• Gene expression profile has similarities to MALT lymphoma

Schmatz et al., JCO, 2011

Therapy No CRStable

LesionsDuodenal Relapse

Nodal Dissemi-

nation

Follow-Up(months)

Median Range

Watch andwait

24 7 17 0 2 55 6-137

Radiation 19 19 0 0 0 37 10-108

Rituximabmonotherapy

5 4 1 0 0 36 29-118

Chemotherapy with or without radiation *

8 8 0 3 0 44 15-95

To treat or not to treat?(63 patients)

Stage I/II follicular lymphoma of the duodenum

• watch and wait?

• radiotherapy?

• R mono?

• R-chemo?

Targeted mutational landscape of giFL vs. nFL

Weigert et al., unpublished

Topics








Primary extranodal follicular lymphoma

testicular (pediatric, adult)ovary thyroidskin

BCL2

• head/neck region• usually negative for CD10 and BCL2 • no t(14;18)

Primary cutaneous follicle center lymphoma

Topics








Pediatric FL

Liu et al., AJSP 2013

HE IgD

CD79a CD10

Pediatric FL

Oschlies et al., Haematologica 2010

Pediatric /Pediatric -type FLMorphology:Large, expansive, ill-defined folliclesLack of polarization, attenuated mantle zonesBack-to-back follicles, serpiginous configuration, frequently grade 3A/3B

Immunohistochemistry:Usually CD10-positive, more frequently BCL2-negative high Ki-67

Genetics:Almost always lack of t(14;18), rare breaks in IgH, BCL6 or IRF4

Clinical course:Good outcome

CAVE: Not all BCL2-negative FL in adults with high Ki-67 expression are‚pediatric-type‘ FL!!

Oschlies et al., Haematologica 2010; Liu et al., Am J Surg Pathol 2013; Louissant et al., Blood 2012

Topics








Predominantly diffuse follicular lymphoma

HE HE

Rosenwald, Ott et al., Blood 2009Katzenberger et al., Blood 2009

HE HE

t(14;18)-negative FL with predominantly diffuse growth pattern

Morphology:Atypical follicles in less than 25% of the infiltratePredominantly diffuse patternGrade 1/2

Immunohistochemistry:Frequent expression of CD10, BCL6 and CD23, variable expression of BCL2

Genetics:Usually lack the t(14;18), frequent deletions in 1p36Cave: 1p36 deletions frequent in t(14;18) positive FL!

Clinical course:Frequent inguinal localization, low stage

Katzenberger et al., Blood 2009

Topics








t(14;18)-negative follicular lymphomas

t(14;18)-positive90%

t(14;18)-negative10%

Horsman et al., Br J Haematol 2003Vaandrager et al., Genes Chrom Cancer 2000

Genetic similarities and differencesbetween FL with and without t(14;18)

t(14;18) -, n=13t(14;18) +, n=121

Leich et al., Blood 2009; Leich et al., Blood 2011

Features of nodal t(14;18)-negative FL

- atypical follicles, predominantly centrocytes- majority grade 1/2- no atypical proliferation in the marginal zones- all cases strongly BCL6 and IRF8 positive- expression of CD10 in ~70% of cases- ongoing somatic hypermutations in all cases- no occurence of trisomies 3, 7, and 18- gains/amplifications of the REL locus

in 2p16 in 5 of 17 cases

- Gene expression and miRNA profiles suggestlate germinal center B-cell phenotype

HE

BCL2

Leich et al., Blood 2009; Leich et al., Blood 2011

Clinical correlations: 540 FL

DNA

IHC

FISHFL 1-3A

M/F=259/281M-age: ~53y

German Low Grade Lymphoma Study Group (GLSG)Würzburg/Stuttgart, Kiel, Berlin, Lübeck, Frankfurt, Ulm

ClincalD

ata

Survival Therapy

BCL2-BAPBCL6-BAPMYC-BAP

CD20CD5Ki67BCL2 (Dako, E17)BCL6P53CD10MUM1

2 Study arms:CHOP +/- Anti-CD20/RituximabMCP vs CHOP

see Leich et al., Poster

P-value BCL2-FISHBCL2-

IHCP53-IHC CD10-IHC

KI67-IHC

MUM1-IHC

BCL6-FISH

BCL2-IHC

0,000008

P53-IHC 0,034 0,84

CD10-IHC 0,000007 0,164 0,171

KI67-IHC 0,639 0,019 0,137 0,246

MUM1-IHC

0,044 0,308 0,2780,003073

33450,306

BCL6-FISH

0,256 0,046 > 0,999 0,029 0,726 0,322

MYC-FISH

> 0,999 > 0,999 > 0,999 > 0,999 0,490 0,184 > 0,999

Correlation of the t(14;18) with IHC- and FISH markers


Time to treatment failure

t(14;18)-pos (n=351)

t(14;18)-neg (n=56)

p=0.466


p=0.466

t(14;18)-pos (n=351)

t(14;18)-neg (n=56)

p=0.116

Med overall survivalt(14;18)-pos: 9.4yt(14;18)-neg: 8.6y


Overall survival

Conclusions

HE BCL2

No good arguments to separate t(14;18)-negative FL from thespectrum of FL as defined in the current WHO classification

WHO Update: in Progress

• 4th Edition is now 6 years old and out of date• WHO Bureaucracy will not permit a 5 th edition until

all volumes of the 4 th are published• Update to 4 th edition will be allowed

– Available both online and in print and eBook– Anticipated in 2016

• Multiple meetings of editors (2012-2014)– Senior advisors added (genetics, myeloid)– Authors invited to update chapters

• Clinical Advisory Committees (Lymphoid and Myeloid)– March 2014, Chicago

WHO Update: What’s New?

• B-cell neoplasms– Small/indolent clonal lymphoid populations

• Pediatric-type follicular lymphoma– New genetic information for some entities– Large cell and borderline (grey zone)

categories• What to do with FL grade 3B?• DLBCL vs BL and “double hit”• THRLBCL vs NLPHL

Indolent Clonal Populations: WHO Update

• Intrafollicular neoplasia/Follicular lymphoma in-situ– “FL-like B-cells of undetermined significance” vs– “In situ follicular neoplasia”

• Avoid “undetermined significance” (patients hate thi s)• Avoid calling these “lymphoma”

• Mantle cell lymphoma “in situ”– “In-situ mantle cell neoplasia”

-----------------------------------------------------------------------

• MCL, leukemic non ‐‐‐‐nodal type

Follicular lymphomasWHO Update

• Pediatric FL -> “Pediatric-type FL”– Diagnostic criteria

• Nodal, Localized • Purely follicular• High Ki67, BCL2-• No rearrangement of BCL2/BCL6

– Not all FL in children are “pediatric type”– Cases may occur in adults

• Cases of DLBCL/FL with IRF4 translocations are excluded from “PTFL”

• Other genomic aberrations may identify FL in young people that are more likely to be disseminated

Follicular Lymphoma 3B +/-DLBCL

• Grade 3B FL+/- DLBCL with MUM1 expression– Should be separated from other FL– Maybe be closer to DLBCL

• Grade 3B FL/DLBCL with IG/IRF4 translocation– Distinct entity within both DLBCL (most)

and FL (some)– Younger patients, Waldeyer’s ring– Require treatment but good prognosis

Large B -cell Lymphomas

• Distinguishing GCB from non-GCB types now required– Any IHC algorithm accepted (state in report)– Morphologic subtypes optional (state in report)– Anatomic location still important (CNS, skin, etc)

• MYC and IHC coexpression– Not clinically actionable at present– May be done to decide whether to do MYC FISH

• EBV+ DLBCL-NOS (not “elderly”)– Vs EBV+ mucocutaneous ulcer - indolent

• THRLBCL vs NLPHL– Debate on whether diffuse areas/progression in

NLPHL=THRLBCL– Comment on variant patterns in NLPHL at diagnosis

“Double -Hit” B -cell LymphomasWHO Update

• Definition– MYC+ BCL2 and/or BCL6 rearrangements– Morphology: DLBCL or BL-like (BCL-U)

• Will be recognized– Either as a separate category, subdivided by

morphology– Or as separate categories within DLBCL and BCL-U

• Criteria for doing MYC FISH on DLBCL– All cases?– Immunophenotype (MYC&BCL2 expression)?

New genetic informationWHO Update

• BRAF mutations in HCL• MYD88 mutations in LPL• NOTCH1/2 mutations in CLL, MCL,

SMZL• ID3 mutations in BL, BCL -U• IG/IRF4 translocations in DLBCL/FL

Acknowledgements

Institute of Pathology, University of Würzburg, Germ anyEllen LeichMartin Wartenberg

Department of Clinical Pathology, Robert-Bosch-Krank enhaus Stuttgart, Germany Heike HornAnnette StaigerGerman Ott

Department of Internal Medicine III, University of Mu nich, GermanyMichael Unterhalt, Eva HosterO. WeigertMartin DreylingWolfgang Hiddemann

Centers for Reference Pathology, GermanyWolfram Klapper, Harald Stein, Martin Hansmann, Peter Möller, Alfred Feller

Institute of Human Genetics, Kiel, GermanyReiner Siebert

follicular lymphoma: how many diseases? who classification ... · follicular lymphoma: how many...

Documents