LYMPHOMA

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LYMPHOMA

• Masatoshi Kida, M.D.
• Dept. of Pathology
• University of Vermont

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Lymphocytic 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

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Lymphoma

• Non-Hodgkins Lymphoma (NHL)
• Hodgkin Disease (HD) (Hodgkins Lymphoma)

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Non-Hodgkin Lymphoma classification

• 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)

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Working Formulation

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

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B-cell transformation
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REAL 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

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WHO Classification

• Non-Hodgkin lymphoma
• B cell CD20, CD22, CD79a
• pre-B cell tumor
• peripheral B cell tumor
• T/NK cell CD45RO
• pre-T cell tumor
• peripheral T cell NK cell tumor
• Hodgkin lymphoma

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B cell lymphoma
WHO classification

• 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

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T/NK Cell Lymphoma
WHO classification

• 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

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common lymphoma/leukemia in adults

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

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Follicular Lymphoma

• Overview -peripheral B-cell neoplasm
• -most common NHL in U.S.
• -45 of adult lymphomas
• Morphology -resembling nl germinal ctr cells
• centrocytes
• centroblasts

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Follicular Lymphoma

• Immunophenotype
• Pos CD19, CD20, CD10 (CALLA), CD23 (/-)
• sIg
• bcl 2 (? nl germinal center cells)
• Neg CD5 (? CLL/SLL, mantle cell lymphoma),
  CD43
• Genetics t(1418) ?turning on bcl-2

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Follicular Lymphoma

• 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

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bcl-2
CD20
CD3
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Diffuse 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

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Diffuse Large B-cell Lymphoma

• Immunophenotype
• Pos CD19, CD20, CD22, CD79a, (CD10), sIg
• Neg TdT
• Genetics t(1418)( bcl-2 rearrangement)-- 30
  of cases
• various translocations --- 20 to 30 of cases
• bcl 6 rearrangement (CH3)
• extranodal lesions
• negative for bcl 2 rearrangement

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Diffuse Large B-cell Lymphoma

• 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
  chemoRx
• better prognosis limited Dz, small
  lesion bcl 6 rearrangement
• worse prognosis p53 mutation

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Diffuse Large B-cell Lymphoma

• 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

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

• Overview -peripheral B-cell neoplasm
• CLL 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)

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

• Morphology -frequent BM involvement
• -interstitial infiltrates
• -nonparatrabecular aggregates
• -spleen white and red pulp involvements
• -liver portal space involvement

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

• Immunophenotype
• Pos CD19, CD20, CD79a, CD5
• CD23 ( mantle cell lymphoma)
• sIg heavy chain --- low level
• sIg light chain
• Genetics trisomy 12 (30 of cases)
• del 13q12-14 (20-30 of cases)
• del 11q (20-30 of cases)
• t(1114) bcl-1

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

• Clinical -over 50 y/o
• -male dominant (MF 21)
• -often asymptomatic
• -generalized lymphadenopathy (50-60)
• -hepatosplenomegaly (50-60)
• -disruption of immune function
• hypogammaglobulinemia
• autoimmune disorders
• hemolytic anemia
• thrombocytopenia

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

• course and prognosis depend on clinical stage
• better prognosis minimal tumor mass
• worse prognosis trisomy 12
• del 11q
• terminal transformation to more
  aggressive tumors
• transformation
• 1. prolymphocytic transformation (15-30)
• 2. Richter syndrome (5-10)
• transformation to diffuse large B cell tumor

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Common Lymphoma/Leukemia in Children

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

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Acute Lymphoblastic 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)

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Acute Lymphoblastic Leukemia/Lymphoma (ALL)

• Immunophenotype TdT() --- gt95 of cases
• Genetics t(1221) --- preB-cell type
• t(922) ----- 3 of children, 25 of adults
• t(411)
• hyperdiploidy
• pseudodiploidy

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Burkitt Lymphoma

• Overview relatively mature B-cell tumor
• three(3) subtypes
• 1. African(endemic) Burkitt lymphoma
• 2. sporadic(nonendemic) Burkitt lymphoma
• 3. HIV-associated neoplasm

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Burkitt Lymphoma

• 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)

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Burkitt Lymphoma

• Immunophenotype
• sIgM, light chain
• CD19, CD20, CD10
• CD5 -, CD23 -
• Genetics
• translocation of c-myc gene
• t(814)
• t(28)
• t(822)
• EBV infection
• 100 of African Burkitt
• 25 of HIV-associated Burkitt

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Burkitt Lymphoma

• 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

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Mantle 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
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normal lymphnode
Rubin Farber Pathology, 2nd ed, Lippincott
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Mantle Cell Lymphoma

• Morphology -homogeneous population of small
  lymphocytes
• -absence of centroblast-like cells

nucleus round to irregular occasionally
cleaved condensed chromatic
inconspicuous nucleoli scant cytoplasm
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Mantle Cell Lymphoma

• Immunophenotype
• Pos CD19, CD20, CD5(aberrant), CD43
• sIgM, sIgD
• light chain (k or l)
• Neg CD10, CD23 ( B-CLL/SLL)
• Genetics t(1114) (?elevated cyclin D1) -- 70
  of cases
• involving bcl 1 gene ? loss of cell cycle
  control

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Mantle Cell Lymphoma

• Clinical -males in 40s, 50s 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

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Marginal 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

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Marginal Zone Lymphoma (MALToma)
L-26
UCHL-1
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Marginal Zone Lymphoma

• Immunophenotype
• Pos sIg, (cIg), CD19, CD20, CD22, CD79a
• Neg CD5 ( B-CLL/SLL, mantle cell lymphoma)
• CD10 ( follicular lymphoma)
• CD23
• Genetics trisomy 18
• t(1118)
• polyclonal-to-monoclonal transition over time

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Marginal Zone Lymphoma

• 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 time
• prognosis 50 behave as low-grade lymphoma
• may transform into diffuse large B-cell
  lymphoma

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Adult 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

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Adult T-Cell Leukemia/Lymphoma

• Immunophenotype CD2, CD3, CD5, but CD7 -
• CD4, CD25
• CD8 (rare)
• Genetics clonal HTLV-1 provirus in tumor cells

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Adult T-Cell Leukemia/Lymphoma

• 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
  manifestation
• 1. rapidly progressive disease
• 2. indolent cutaneous disease

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Mycosis Fungoides/Sëzary Syndrome

• Overview -indolent peripheral CD4() T-cell
  disorders
• -different manifestations of a single process
  (cutaneous T-cell lymphoid neoplasms)
• Morphology cerebriform nuclei

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Mycosis Fungoides/Sëzary Syndrome

• Immunophenotype CD4, T-cell receptor a/b
• CD3, CD2, CD5
• Genetics no specific chromosomal abnormality

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Mycosis Fungoides/Sëzary Syndrome

• Clinical
• mycosis fungoides
• -infiltration of neoplastic T-cells in
  epidermis and upper dermis
• -three(3) stages
• 1. inflammatory premycotic phase
• 2. plaque phase
• 3. tumor phase
• -extracutaneous spread (LN, BM)
• Sëzary syndrome
• -generalized exfoliative erythroderma
• -occasional terminal transformation to large
  T-cell lymphoma

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Hodgkin Disease
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Reed-Sternberg (RS) Cell

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

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Hodgkin Diseaseclassification

• 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)

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Hodgkin Diseaselymphocyte predominance

• large of mature lymphocyte admixed with
  variable of benign histiocytes
• effacement of LN architecture
• scarce RS cells
• males, lt35 y/o
• localized cervical or axillary lymphadenopathy
  (stage I or II)
• excellent prognosis

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Hodgkin Diseasenodular sclerosis

• lacunar cell variant of RS cell with fixation
  artifact large cell with hyperlobated
  nucleus multiple small nucleoli abundant
  pale cytoplasm
• bifringent collagen bands
• F gt M, teen-age young adults
• mediastinal, supraclavicular, lower cervical LNs
• excellent prognosis

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Hodgkin Diseasemixed cellularity

• diffuse infiltrate of eosinophils, PMNs, plasma
  cells and histiocytes
• plentiful RS cells
• M gt F
• biphasic age distribution
• 1. young adult
• 2. gt55 y/o
• more advanced stage (stage III or IV)
• intermediate prognosis

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Hodgkin Diseaselymphocyte depletion

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

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Hodgkin Diseasestaging

• 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)

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Hodgkin Diseaseprognosis

• 65 ten(10)-year survival with treatment
• better prognosis young age low stage

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