lymphoma_06-07.ppt

LYMPHOMALYMPHOMA

Masatoshi Kida, M.D.Dept. of Pathology

University of Vermont

Lymphocytic Leukemia & LymphomaLymphocytic Leukemia & Lymphoma

• The line between lymphocytic leukemia and lymphoma is often unclear

• The terms merely describe the site of disease distribution

Leukemia: widespread involvement of BM and presence of large number of tumor cells in peripheral

blood

Lymphoma: lymphoid proliferations as discrete tissue masses

LymphomaLymphoma

Non-Hodgkin’s Lymphoma (NHL)

Hodgkin Disease (HD) (Hodgkin’s Lymphoma)

Cotran, Kumar, Collins: Robbins PATHOLOGIC BASIS OF DISEASE

Non-Hodgkin Lymphoma Non-Hodgkin Lymphoma classificationclassification

• Rappaport• Lukes-Collins• Working Formulation (1982)• Revised European-American Classification of Lymphoid

Neoplasms (REAL) (1994)• World Health Organization Classification of Neoplastic and

Lymphoid Tissues (WHO classification) (1999)

Working FormulationWorking Formulation

• Three(3) prognostic groups• pattern of tumor growth• size of tumor cells

B-cell transformationB-cell transformation

REAL ClassificationREAL Classification

B-cell neoplasms

1. Precursor B-cell neoplasms

2. Peripheral B-cell neoplasms

T-cell neoplasms

3. Precursor T-cell neoplasms

4. Peripheral T-cell neoplasms

Hodgkin Disease

WHO ClassificationWHO Classification

Non-Hodgkin lymphoma

B cell : CD20, CD22, CD79CD20, CD22, CD79aapre-B cell tumorperipheral B cell tumor

T/NK cell : CD45ROCD45ROpre-T cell tumorperipheral T cell & NK cell tumor

Hodgkin lymphoma

B cell lymphomaB cell lymphoma

• lymphoblastic leukemia/lymphoma• follicular lymphoma• chronic lymphocytic leukemia/small lymphocytic lymphoma• mantle cell lymphoma• prolymphocytic leukemia• hairy cell leukemia• lymphoplasmacytic lymphoma• marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT)-

type• nodal marginal zone B cell lymphoma• splenic marginal zone B cell lymphoma• Burkitt lymphoma• diffuse large B cell lymphoma• plasmacytoma• plasma cell myeloma

WHO classification

T/NK Cell LymphomaT/NK Cell Lymphoma

• lymphoblastic leukemia/lymphoma• T cell prolymphocytic leukemia• peripheral T cell lymphoma, unspecified• angioimmunoblastic T cell lymphoma• mycosis fungoides• Sezary syndrome• adult T cell leukemia/lymphoma• T cell large granular lymphocytic leukemia• anaplastic large cell lymphoma• primary cutaneous anaplastic large cell lymphoma• subcutaneous panniculitis-like T cell lymphoma• enteropathy-type intestinal T cell lymphoma• hepatosplenic gamma/delta T cell lymphoma• NK cell leukemia• nasal and nasal type NK/T cell lymphoma

WHO classification

common lymphoma/leukemia in adultscommon lymphoma/leukemia in adults

• follicular lymphoma• diffuse large B-cell lymphoma• chronic lymphocytic leukemia/small lymphocytic lymphoma

Follicular LymphomaFollicular Lymphoma

Overview: -peripheral B-cell neoplasm

-most common NHL in U.S.

-45% of adult lymphomas

Morphology: -resembling nl germinal ctr cellscentrocytescentroblasts


Immunophenotype:

Pos: CD19, CD20, CD10 (CALLA), CD23 (+/-)

sIg

bcl 2 ( nl germinal center cells)

Neg: CD5 ( CLL/SLL, mantle cell lymphoma), CD43

Genetics: t(14;18) turning “on” bcl-2


Clinical: -75 to 80% of indolent B-cell lymphomas-middle aged to older adults-M = F-generalized painless lymphadenopathy-indolent waxing and waning course

prognosis: -incurable (mean survival : 7-9 yrs)-aggressive therapy not effective-30-50% transformation to diffuse large cell

lymphoma

CD20

bcl-2

CD3

Diffuse Large B-cell LymphomaDiffuse Large B-cell Lymphoma

Overview: -heterogeneous peripheral B-cell tumor

-20% of all NHL

-60-70% of aggressive lymphoid tumors

Morphology: -diffuse growth pattern

-large tumor cells


Immunophenotype:

Pos: CD19, CD20, CD22, CD79a, (CD10), sIg

Neg: TdT

Genetics: t(14;18)(= bcl-2 rearrangement)-- 30% of cases

various translocations --- 20 to 30% of cases

bcl 6 rearrangement (CH3)

extranodal lesions

negative for bcl 2 rearrangement


Clinical: -wide age range (median age : 60 y/o)-slight male predominance-rapidly enlarging mass

(GI tract, skin, bone, brain, ORL lymphoid tissue, liver, spleen)

-aggressive behavior, but potentially curable

prognosis: responsive to intensive combination chemoRxbetter prognosis: limited Dz, small lesion

bcl 6 rearrangementworse prognosis: p53 mutation


Special Subtypes

1. Immunodeficiency-associated large B-cell lymphoma

-with latent EBV infection

2. body cavity large B-cell lymphoma

-mostly seen in advanced HIV(+) patients

-arises as malignant pleural or ascitic effusion

-infected with human herpes virus 8

Chronic Lymphocytic Leukemia (CLL) Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL)Small Lymphocytic Lymphoma (SLL)

Overview: -peripheral B-cell neoplasmCLL: most common leukemia in Western World

SLL: 4% of NHL

-less common in Asia

Morphology: -diffuse involvement of LN architecture

-two(2) cell types (small & large)


Morphology: -frequent BM involvement

-interstitial infiltrates

-nonparatrabecular aggregates

-spleen: white and red pulp involvements

-liver: portal space involvement


Immunophenotype:Pos: CD19, CD20, CD79a, CD5

CD23 ( mantle cell lymphoma)sIg heavy chain --- low levelsIg light chain

Genetics: trisomy 12 (~30% of cases)del 13q12-14 (20-30% of cases)del 11q (20-30% of cases)t(11;14) bcl-1


Clinical: -over 50 y/o-male dominant (M:F = 2:1)-often asymptomatic-generalized lymphadenopathy (50-60%)-hepatosplenomegaly (50-60%)-disruption of immune function

hypogammaglobulinemiaautoimmune disorders

hemolytic anemiathrombocytopenia


course and prognosis depend on clinical stagebetter prognosis: minimal tumor massworse prognosis: trisomy 12

del 11qterminal transformation to more aggressive tumors

transformation:1. prolymphocytic transformation (15-30%)2. Richter syndrome (5-10%)

transformation to diffuse large B cell tumor

Common Lymphoma/Leukemia in Common Lymphoma/Leukemia in ChildrenChildren

1. Acute Lymphoblastic Leukemia/Lymphoma (ALL)

2. Burkitt Lymphoma

Acute Lymphoblastic Acute Lymphoblastic Leukemia/Lymphoma (ALL)Leukemia/Lymphoma (ALL)

Overview: predominantly B-cell tumor (85%)

T-cell tumors tend to be seen in adolescent males with frequent thymic involvement

differential diagnosis from AML is important

Morphology: PAS(+) cytoplasmic granules

absence of peroxidase(+) granules ( AML)

Acute Lymphoblastic Acute Lymphoblastic Leukemia/Lymphoma (ALL)Leukemia/Lymphoma (ALL)

Immunophenotype: TdT(+) --- >95% of cases

Genetics: t(12;21) --- preB-cell type

t(9;22) ----- 3% of children, 25% of adults

t(4;11)

hyperdiploidy

pseudodiploidy

Burkitt LymphomaBurkitt Lymphoma

Overview: relatively mature B-cell tumor

three(3) subtypes:

1. African(endemic) Burkitt lymphoma

2. sporadic(nonendemic) Burkitt lymphoma

3. HIV-associated neoplasm


Morphology:

• diffuse infiltrate of intermediate-size tumor cells

• round to oval nucleus

• coarse chromatin

• several nucleoli

• moderate amount of basophilic cytoplasm with vacuoles

• high mitotic rate

• apoptotic tumor cell death

• numerous macrophages (‘starry sky” appearance)

Burkitt LymphomaBurkitt LymphomaImmunophenotype:

sIgM, light chainCD19, CD20, CD10CD5 -, CD23 -

Genetics:translocation of c-myc gene

t(8;14)t(2;8)t(8;22)

EBV infection100% of African Burkitt25% of HIV-associated Burkitt


Clinical: children and young adults

frequent extranodal involvement

African Burkitt: mandible

abdominal organs (kidneys, ovaries,

adrenal)

nonendemic Burkitt: ileocecum

peritoneum

prognosis: generally aggressive tumor, but responds well to therapy

Mantle Cell LymphomaMantle Cell Lymphoma

Overview: peripheral B-cell tumor

3% of NHL in U.S. (7-9% in Europe)

Morphology: two(2) patterns of LN involvement

1. mantle zone pattern

2. diffuse pattern

Normal


Morphology: -homogeneous population of small lymphocytes

-absence of centroblast-like cells

nucleus: round to irregular occasionally cleaved condensed chromatic inconspicuous nucleoli

scant cytoplasm


Immunophenotype:

Pos: CD19, CD20, CD5(aberrant), CD43

sIgM, sIgD

light chain ( or )

Neg: CD10, CD23 ( B-CLL/SLL)

Genetics: t(11;14) (elevated cyclin D1) -- 70% of cases

involving bcl 1 gene loss of cell cycle control


Clinical: -males in 40’s, 50’s and older

-generalized lymphadenopathy (widespread)

-BM: para- and non-trabecular aggregates

-extranodal involvement including liver & spleen

“lymphomatoid polyposis”

multifocal entero-colic mucosal involvement

prognosis: poor (median survival : 3-5 yrs)

not curable with conventional chemotherapy

death due to organ dysfunction

Marginal Zone LymphomaMarginal Zone Lymphoma

Overview: -peripheral B-cell tumor

-tumors of mucosa-associated lymphoid tissue (“MALToma”)

-association with autoimmune or infectious chronic inflammatory disorders

Morphology: -resembling marginal zone B-cells

-various stages of B lymphoid differentiation

-”lymphoepithelial lesion”

Marginal Zone Lymphoma (MALToma)Marginal Zone Lymphoma (MALToma)

L-26 UCHL-1


Immunophenotype:

Pos: sIg, (cIg), CD19, CD20, CD22, CD79a

Neg: CD5 ( B-CLL/SLL, mantle cell lymphoma)

CD10 ( follicular lymphoma)

CD23

Genetics: trisomy 18

t(11;18)

polyclonal-to-monoclonal transition over time


Clinical: -majority of low-grade gastric lymphomas-middle-aged adult-frequently arises at extranodal sites-within chronically inflamed tissue

salivary glands (Sjögren disease)thyroid (Hashimoto thyroiditis)stomach (Helicobacter gastritis)

-localized for long periods of timeprognosis: 50% behave as low-grade lymphoma

may transform into diffuse large B-cell lymphoma

Adult T-Cell Leukemia/LymphomaAdult T-Cell Leukemia/Lymphoma

Overview: CD4(+) T-cell neoplasm

infectious etiology (HTLV-1)

Morphology: multilobated nuclei (“clover leaf-” or “flower” cells)

multinucleated giant cells

mixture of

large cells

small cells


Immunophenotype: CD2, CD3, CD5, but CD7 -

CD4, CD25

CD8 (rare)

Genetics: clonal HTLV-1 provirus in tumor cells


Clinical: -most frequently seen in HTLV-1 endemic areas-adults-generalized lymphadenopathy-BM involvement-hepatosplenomegaly-peripheral blood lymphocytosis-hypercalcemia

prognosis: two(2) types of clinical manifestation1. rapidly progressive disease2. indolent cutaneous disease

Mycosis Fungoides/Sëzary SyndromeMycosis Fungoides/Sëzary Syndrome

Overview: -indolent peripheral CD4(+) T-cell disorders

-different manifestations of a single process (cutaneous T-cell lymphoid neoplasms)

Morphology: “cerebriform nuclei”


Immunophenotype: CD4, T-cell receptor /CD3, CD2, CD5

Genetics: no specific chromosomal abnormality


Clinical:mycosis fungoides

-infiltration of neoplastic T-cells in epidermis and upper dermis-three(3) stages

1. “inflammatory” premycotic phase2. plaque phase3. tumor phase

-extracutaneous spread (LN, BM)Sëzary syndrome

-generalized exfoliative erythroderma-occasional terminal transformation to large T-cell lymphoma

Hodgkin DiseaseHodgkin Disease

Reed-Sternberg (RS) CellReed-Sternberg (RS) Cell

• neoplastic, diagnostic cell of Hodgkin Disease• large cells with abundant eosinophilic cytoplasm• “owl’s eye” or multi-lobed nuclei• distinct, irregularly thickened nuclear membranes• prominent eosinophilic nucleoli

Hodgkin DiseaseHodgkin Diseaseclassificationclassification

1. lymphocyte predominance (15%)

2. nodular sclerosis (30-50%)

3. mixed cellularity (20-40%)

4. lymphocyte depletion (10-15%)

(5. lymphocyte-rich classic Hodgkin disease)

Hodgkin DiseaseHodgkin Diseaselymphocyte predominancelymphocyte predominance

• large # of mature lymphocyte admixed with variable # of benign histiocytes

• effacement of LN architecture• scarce RS cells• males, <35 y/o• localized cervical or axillary lymphadenopathy (stage I or II)• excellent prognosis

Hodgkin DiseaseHodgkin Diseasenodular sclerosisnodular sclerosis

• “lacunar cell” variant of RS cell with fixation artifactlarge cell with hyperlobated nucleus

multiple small nucleoliabundant pale cytoplasm

• bifringent collagen bands• F > M, teen-age & young adults• mediastinal, supraclavicular, lower cervical LNs• excellent prognosis

Hodgkin DiseaseHodgkin Diseasemixed cellularitymixed cellularity

• diffuse infiltrate of eosinophils, PMNs, plasma cells and histiocytes

• plentiful RS cells• M > F• biphasic age distribution

1. young adult

2. >55 y/o• more advanced stage (stage III or IV)• intermediate prognosis

Hodgkin DiseaseHodgkin Diseaselymphocyte depletionlymphocyte depletion

• older male• disseminated disease (stage III or IV)• also seen in HIV(+) patients• more aggressive clinical course

Hodgkin DiseaseHodgkin Diseasestagingstaging

Stage I : limited to one lymph node region

Stage II : limited to two lymph node regions, on same side of diaphragm

Stage III : limited to lymph nodes but on both sides of diaphragm

Stage IV : involving extranodal tissue

A: no systemic symptoms

B: with systemic symptoms (fever, night sweats, wt. loss, etc)

Hodgkin DiseaseHodgkin Diseaseprognosisprognosis

• 65% ten(10)-year survival with treatment• better prognosis: young age

low stage

lymphoma_06-07.ppt

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