Malignant lymphomasMalignant lymphomas

Lymph nodes:Lymph nodes: Germinal center (GC) Germinal center (GC) and mantle B-cellsand mantle B-cells

Paracortical T-cells Paracortical T-cells and high endothelial and high endothelial venulesvenules

capsulecapsule

sinussinus

GCGC

mantlemantle

Lymphoma - incidence and mortalityLymphoma - incidence and mortality 3-5% of deaths in developed world3-5% of deaths in developed world

– higher in other areashigher in other areas 3-7 cases per 100,000 in USA3-7 cases per 100,000 in USA

– males greater than females, white males highestmales greater than females, white males highest increases with ageincreases with age

– histology varies with age, low grade frequent in adultshistology varies with age, low grade frequent in adults– high grade most frequent in childrenhigh grade most frequent in children

Classification of lymphomaClassification of lymphoma Hodgkin’s Hodgkin’s

– mixed cellularitymixed cellularity

– nodular sclerosisnodular sclerosis

– lymphocyte depletedlymphocyte depleted

– lymphocyte lymphocyte predominantpredominant

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma

– low grade B-celllow grade B-cell

» small lymphocyticsmall lymphocytic

» marginal zonemarginal zone

– mantle cell (B-cell)mantle cell (B-cell)

– follicular (B-cell)follicular (B-cell)

– large B-celllarge B-cell

– Burkitt’s (B-cell)Burkitt’s (B-cell)

– lymphoblastic (mostly T-cell)lymphoblastic (mostly T-cell)

– T/NK-cellT/NK-cell

– mycosis fungoides (cutaneous T-cell)mycosis fungoides (cutaneous T-cell)

ML types in POG 1998-2000ML types in POG 1998-2000

0

50

100

150

200

250

300L

MC

HD

NSH

D

LD

HD

LP

HD

HD

, NO

S

LB

SNC

DL

BC

AL

CL

cases reviewed

476 NHL

373 HD

Thomas HodgkinThomas Hodgkin

Hodgkin’s DiseaseHodgkin’s DiseaseMixed cellularity

Nodular sclerosis

Lymphocyte depleted

Lymphocyte predominant

Reed Sternberg CellReed Sternberg Cell

R-S cells:H&E

Wright stainCD30

Incidence of HDIncidence of HD 3-7 per 100,0003-7 per 100,000 BimodalBimodal

– 15-34 & > 5515-34 & > 55 NS increasing in NS increasing in

young patientsyoung patients– young womenyoung women

LD decreasing in LD decreasing in older patientsolder patients

57.7

23.4

6 3.89.1

0

10

20

30

40

50

60

NS

MC

LP

LD

uncl

ass

Medeiros, Cancer 75:357,1995

Hodgkin’s DiseaseHodgkin’s Disease Reed-Sternberg (RS) cell in immunoproliferative backgroundReed-Sternberg (RS) cell in immunoproliferative background

– RS cells minorityRS cells minority

– backgroundbackground

» lymphocytes, eosinophils, plasma cells, histiocyteslymphocytes, eosinophils, plasma cells, histiocytes

– RS cells B-cells (90%) or T-cells (10%)RS cells B-cells (90%) or T-cells (10%) cervical LN or mediastinum; spread to thoracic para-aortic LN, spleen, cervical LN or mediastinum; spread to thoracic para-aortic LN, spleen,

liver, abdominal Para-aortic nodesliver, abdominal Para-aortic nodes Association with EBV: 96% MC, 34% NS, 10% LPAssociation with EBV: 96% MC, 34% NS, 10% LP radiation for localized disease radiation for localized disease chemotherapy or chemo/RT for advanced diseasechemotherapy or chemo/RT for advanced disease

Mixed cellularity Hodgkin’s DiseaseMixed cellularity Hodgkin’s Disease

Diffuse infiltrate Diffuse infiltrate including relatively including relatively frequent RS cellsfrequent RS cells

CD15 and CD30 CD15 and CD30 antigen expressionantigen expression

classical HDclassical HD

Nodular Sclerosis Hodgkin’s DiseaseNodular Sclerosis Hodgkin’s Disease

RS cells and RS cells and “lacunar” cells in “lacunar” cells in clusters surrounded clusters surrounded by collagen fibrosisby collagen fibrosis

CD15 and CD30+CD15 and CD30+ Often mediastinal Often mediastinal

mass in young mass in young womenwomen

Lymphocyte depletion HDLymphocyte depletion HD Diffuse infiltrate Diffuse infiltrate

– numerous RS cells numerous RS cells and variants with and variants with relatively few relatively few lymphocyteslymphocytes

Often older men Often older men with advanced with advanced diseasedisease

Difficult to Difficult to distinguish from distinguish from large cell NHLlarge cell NHL

Lymphocyte predominant HDLymphocyte predominant HD Nodular or sometimes Nodular or sometimes

diffuse infiltrate diffuse infiltrate containing “L&H” containing “L&H” cells (for “lymphocytic cells (for “lymphocytic and histiocytic and histiocytic LPHD”)LPHD”)

label as polyclonal B-label as polyclonal B-cellscells

usually localized (often usually localized (often cervical LN)cervical LN)

indolent clinical courseindolent clinical course

Hodgkin’s diseaseHodgkin’s disease

Most cases derived from clonal B-cellsMost cases derived from clonal B-cells Heavy load of somatic mutationsHeavy load of somatic mutations Lack crippling mutations, but do not transcribe Lack crippling mutations, but do not transcribe

IgH due to functional regulatory defectsIgH due to functional regulatory defects HD and NHL have derived from same cloneHD and NHL have derived from same clone

Seitz, Blood. 2000 May 15;95(10):3020-4

Non-Hodgkin’s LymphomaNon-Hodgkin’s LymphomaSmall lymphocytic Mantle cell Burkitt Lymphoblastic

Follicular center cell Large B-cell Peripheral T-cell

Phenotype in diagnosis of NHLPhenotype in diagnosis of NHL

CD79a (B-cell)

CD45Ro (T-cell)

BCL-2

ALK-1

Incidence of NHL in US overallIncidence of NHL in US overall 7.4-17.1 per 100,0007.4-17.1 per 100,000 Males > femalesMales > females Racial differencesRacial differences

– whites more FLwhites more FL– blacks more PTCblacks more PTC

SL

FL

Dif B

HG

PTC

NOS

0

1

2

3

4

5

6

7

8

SL

Dif

B

PT

C

n per100K

Groves, JNCI, 92;1240-51, 2000

NHL in ChildrenNHL in Children 4.6-9.1 per million 4.6-9.1 per million

– white > blackwhite > black– male > femalemale > female

1/3-1/2 SNC, LB, LC1/3-1/2 SNC, LB, LC Geographic variationGeographic variation

– incidenceincidence– histologic typehistologic type– biology of Burkitt’sbiology of Burkitt’s

0

20

40

60

80

100

120

140

160

SNC

LB

DL

BC

AL

CL

n

Shad, Ped Clin NA 44:863-89, 1997

POG 1998-2000

Human B-cell lymphomasHuman B-cell lymphomas Sequencing of the variable region genes - Sequencing of the variable region genes -

somatically mutated in majority of non-somatically mutated in majority of non-Hodgkin’s and Hodgkin’s lymphomasHodgkin’s and Hodgkin’s lymphomas

this indicates germinal or post-germinal this indicates germinal or post-germinal center origincenter origin

unmutated variable region genes: mantle unmutated variable region genes: mantle lymphoma, some CLL’slymphoma, some CLL’s

Burkitt’s LymphomaBurkitt’s Lymphoma Medium size cellsMedium size cells

– nuclei same as histiocyte nucleinuclei same as histiocyte nuclei Oval nucleiOval nuclei

– 3-5 nucleoli, open chromatin3-5 nucleoli, open chromatin Basophilic (vacuolated) cytoplasm Basophilic (vacuolated) cytoplasm High mitotic rate, starry skyHigh mitotic rate, starry sky Mature B-cell, surface IG+, Mature B-cell, surface IG+,

analogous to L3 ALLanalogous to L3 ALL EBV in endemic areas and EBV in endemic areas and

immunosuppressionimmunosuppression

Large B-cell LymphomaLarge B-cell Lymphoma

Average nuclei larger than Average nuclei larger than histiocyte nucleihistiocyte nuclei

Mature B-lineage (CD20+)Mature B-lineage (CD20+) Morphologic heterogeneityMorphologic heterogeneity

– CentroblasticCentroblastic– Centroblastic/centrocyticCentroblastic/centrocytic– B-immunoblasticB-immunoblastic

BCL 6 or BCL2 BCL 6 or BCL2 overexpression in someoverexpression in some

Burkitt-Like LymphomaBurkitt-Like Lymphoma Mature B-cellMature B-cell Average cell medium size (like Average cell medium size (like

Burkitt)Burkitt) More variability than BurkittMore variability than Burkitt

– Nuclear sizeNuclear size

– Nuclear shapeNuclear shape

– Nucleolar prominenceNucleolar prominence

– Sometimes fine fibrosisSometimes fine fibrosis Interface between Burkitt & large Interface between Burkitt & large

B-cell lymphomaB-cell lymphoma

Small lymphocytic lymphoma/CLLSmall lymphocytic lymphoma/CLL slow growingslow growing diffuse infiltrate of diffuse infiltrate of

small lymphocytessmall lymphocytes admixed admixed

prolymphocytes; prolymphocytes; growth centersgrowth centers

often indolentoften indolent mature B-cell with mature B-cell with

CD5 expressionCD5 expression

SLL in childrenSLL in children Rare cases describedRare cases described t(2;14)(p13;q32) in severalt(2;14)(p13;q32) in several Citations:Citations:

– Fell, et al. Science 232:491-4, 1986Fell, et al. Science 232:491-4, 1986

– Yoffe, et al. J Pediatr 116:114-7, 1990Yoffe, et al. J Pediatr 116:114-7, 1990

– Ribeiro, et al. Leukemia 6:761-5, 1992Ribeiro, et al. Leukemia 6:761-5, 1992

Follicular lymphomasFollicular lymphomas One of the most One of the most

common NHLcommon NHL Mature B-cellMature B-cell Slow-growing, Slow-growing,

persistentpersistent t(14;18) with bcl-2 t(14;18) with bcl-2

overexpressionoverexpression graded by cell typegraded by cell type

Follicular Lymphoma in childrenFollicular Lymphoma in children 1% (17) of 1336 pediatric lymphomas1% (17) of 1336 pediatric lymphomas

– Ribeiro, et al. Leukemia 6:761-5, 1992Ribeiro, et al. Leukemia 6:761-5, 1992

usually mixed or large cell, usually mixed or large cell, lack bcl-2 or p52 abn; some testicularlack bcl-2 or p52 abn; some testicular generally good outcomegenerally good outcome

– those who fail progressed to DLBCLthose who fail progressed to DLBCL» Frizzera, Cancer 44:2218, 1979; Winberg, Cancer 48:2223, 1981Frizzera, Cancer 44:2218, 1979; Winberg, Cancer 48:2223, 1981» Pinto, Mod Pathol 3:308, 1990; Moertel, Cancer 75:182, 1995Pinto, Mod Pathol 3:308, 1990; Moertel, Cancer 75:182, 1995» Atra, Br J Haem 103:220, 1998; Finn, Cancer 85:1626, 1999Atra, Br J Haem 103:220, 1998; Finn, Cancer 85:1626, 1999

Marginal zone lymphomaMarginal zone lymphoma mature B-cellmature B-cell arises from splenic or arises from splenic or

mucosal mucosal (MALT)(MALT) marginal marginal zone cellszone cells– ““monocytoid” appearancemonocytoid” appearance

– Lymphoepithelial lesions Lymphoepithelial lesions in MALTin MALT

often indolentoften indolent– Gastric; H. pyloriGastric; H. pylori

Marginal Zone lymphoma in childrenMarginal Zone lymphoma in children Occasional (<1%) Occasional (<1%) GastricGastric

– associated with H. pyloriassociated with H. pylori– may resolve with tx of H. pylorimay resolve with tx of H. pylori

Many associated with HIVMany associated with HIV Salivary gland, lung, GISalivary gland, lung, GI

– Citations:Citations:» Teruya-Feldstein, AJSP 19:357, 1995; Blecker, Gastroent.109:973, 1995Teruya-Feldstein, AJSP 19:357, 1995; Blecker, Gastroent.109:973, 1995» Joshi, AJCP 107:592, 1997; Corr, J Ultrasound Med 16:615, 1997Joshi, AJCP 107:592, 1997; Corr, J Ultrasound Med 16:615, 1997» Berrebi, J Peds 133:290, 1998; Fukumoto Hihon Rinsho MGK 23:49, 2000Berrebi, J Peds 133:290, 1998; Fukumoto Hihon Rinsho MGK 23:49, 2000

Mantle cell lymphomaMantle cell lymphoma mature B-cellmature B-cell arises from follicular mantlearises from follicular mantle resembles SLL and MZLresembles SLL and MZL t(11;14) with cyclin-D1, CD5, t(11;14) with cyclin-D1, CD5,

(CD23-)(CD23-) expresses bcl-2 as do nl expresses bcl-2 as do nl

mantle cells; long-livedmantle cells; long-lived difficult to eradicate and difficult to eradicate and

aggressiveaggressiveResidual germinal center

Neoplastic mantle zone cells

T-cell lymphomasT-cell lymphomas Less common that B-cellLess common that B-cell Some associations with retrovirusesSome associations with retroviruses

– HTLV-1HTLV-1 Cytogenetic abnormalities variableCytogenetic abnormalities variable

– include chr. 14 abnormalitiesinclude chr. 14 abnormalities– t(2;5) and variants in ALCLt(2;5) and variants in ALCL

Generally difficult to eradicateGenerally difficult to eradicate

T-cell developmentT-cell development Maturation/selection in thymusMaturation/selection in thymus T-cell receptor gene rearrangementT-cell receptor gene rearrangement

– gamma/deltagamma/delta

– alpha/betaalpha/beta Tdt, CD7, CD5, CD2Tdt, CD7, CD5, CD2 CD1, CD4/CD8, CD3CD1, CD4/CD8, CD3 Mature cells CD4 or CD8 and CD3Mature cells CD4 or CD8 and CD3

Lymphoblastic LymphomaLymphoblastic Lymphoma Small cellsSmall cells

– nuclei smaller than histiocyte’snuclei smaller than histiocyte’s Diffuse chromatin, inconspicuous Diffuse chromatin, inconspicuous

nucleoli, often nuclear convolutionsnucleoli, often nuclear convolutions High mitotic rate, starry skyHigh mitotic rate, starry sky Precursor T-cellPrecursor T-cell

– T-zone distribution, infiltrativeT-zone distribution, infiltrative– Tdt, CD7, CD1, CD4/CD8Tdt, CD7, CD1, CD4/CD8

Rare precursor B-lineageRare precursor B-lineage

Anaplastic Large Cell LymphomaAnaplastic Large Cell Lymphoma Large cells with abundant Large cells with abundant

cytoplasmcytoplasm

– often indented or lobated often indented or lobated nucleinuclei

– LN sinus, paracortexLN sinus, paracortex CD30 expressionCD30 expression T or null phenotypeT or null phenotype t(2;5)t(2;5) ALK protein expressionALK protein expression

ALCL - CD30 and ALK expressionALCL - CD30 and ALK expression

CD30

ALK1

Most cases in children and young adults express ALK due to t(2;5) or variant translocation. Most cases over 35 are ALK negative

ALK-1 in recent LCLALK-1 in recent LCL

35

1

8

47

12

48

05

10

1520

2530

3540

4550

B-cell T/null CD30

ALK-ALK+

A majority of T or null LCL in children express CD30 and ALK

Non-anaplastic PTCLNon-anaplastic PTCL Diverse entitiesDiverse entities

– PTCL, NOS; angiocentric; nasal; T-PTCL, NOS; angiocentric; nasal; T-gamma; panniculitic; ATL; MF gamma; panniculitic; ATL; MF

Rare in childrenRare in children Likely worse than ALCLLikely worse than ALCL