Patho - 4th Asessment - Lymphoproliferative Disorders Ii - 31 Jan 2007

Lymphoproliferative Disorders II: Hodgkin’s Lymphoma and NonHodgkin’s Lymphoma Dilip K. Das, MBBS, MD, PhD, DSc, FRCPath. Department of Pathology, Faculty of Medicine, Kuwait University

Hodgkin’s Lymphoma: History and Pathognomonic Cells

• In 1832, Thomas Hodgkin, an English physician (1798-1866),

described peculiar morbid anatomical appearance of lymph nodes in some autopsy cases. • In 1865, Wilks applied the eponymous term ‘Hodgkin’s disease’ to it. • Carl von Sternberg (1898) and Dorothy Reed (1902) independently described the pathognomonic cell of Hodgkin’s disease, presently called Hodgkin cell and Reed-Sternberg cell (R-S cell). • The Hodgkin cell is a large mononucleated cell and Reed-Strenberg cell is a binucleated, multilobated or mulinucleated cell with prominent eosinophilic nucleoli.

Hodgkin’s Lymphoma: Constituent Cells and the Origin of Neoplastic Cells • The malignant cell of Hodgkin’s lymphoma forms only a small percentage of the cellular population within the affected lymph nodes. The bulk of the tissue is made up of reactive lymphocytes, macrophages, plasma cells, and eosinophils, attracted into the cellular mileau by a variety of cytokines secreted by the Hodgkin’s and RS cells.

Classification of Hodgkin’s Lymphoma World Health Organization (WHO) Classification: 2. • • • • 7.

Classical Hodgkin’s lymphoma (HL) lymphocyte rich classical HL mixed cellularity Lymphocyte depleted Nodular sclerosis Nodular lymphocyte predominant Hodgkin’s lymphoma

Classical Hodgkin’s Lymphoma: Clinical and Gross Anatomical Features •

Peak incidence in 3rd and 4th decades. • Lymphadenopathy in upper half of the body (cervical, axillary, and mediastinal). Enlarged lymph nodes are typically rubbery, discrete and mobile. Mediastinal involvement common (40%). Disease starts in lymph node or thymus and spread via lymphatics in a contiguous fashion. Spleen appears key to hematogenous dissemination. • A third of patients have systemic symptoms (weight loss, fever, and night sweats). • Affected lymph nodes are enlarged with smooth surface and cut surface is homogeneously white.

Classical Hodgkin’s Lymphoma: Histopathology A.

B.

C. D.

Lymphocyte rich classical Hodgkin’s lymphoma (LRCHL): Scattered or scanty classical Hodgkin and R-S cells in a lymphocyte rich background. Mixed cellularity: An admixture of lymphocytes, histiocytes, plasma cells, Hodgkin’s cell and R-S cells, the latter are relatively abundant compared to classical LRCHL. Lymphocyte depleted: Numerous Hodgkin’s cells and R-S cells with depletion of lymphocytes. Nodular sclerosis: Cellular nodules, which are separated by bands of collagen. Within the nodules mixed infiltrate and special Hodgkin cell variants called laculnar cells (cells which appear to sit in a space or lacuna).

A

C

B

D

Nodular Lymphocyte Predominant Hodgkin’s Lymphoma • • •

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•

Differs markedly from clinical presentation of classical Hodgkin’s lymphoma. Peak age is a decade older and marked male predominance. Most patients (90%) have asymptomatic localized disease and unusual sites (e.g. inguinal LN) involved. Histologically: Nodular growth pattern but no collagen band formation, abundant lymphocytes, paucity of typical Hodgkin’s cells, and a distinct R-S cell variant called ‘popcorn’ cell. Overall survival is excellent and superior to that in classical Hodgkin’s lymphoma.

Immunophenotyping of Hodgkin’s Lymphoma

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• In vast majority of cases, Hodgkin’s and R-S cells show clonal immunoglobulin gene rearrangement, indicationg their B-lymphocyte origin. Further, somatic hypermutation of immunoglobulin gene indicate that the cells are of germinal center origin. Hence, the term Hodgkin’s disease is replaced with Hodgkin’s lymphoma. Neoplastic cells in classical Hodgkin’s lymphoma: CD45–, CD30+,CD15+. Neoplastic cells in nodular lymphocytic predominance Hodgkin’s lymphoma: CD45+, CD30–, CD15–, CD20+. CD30

CD15

Non-Hodgkin Lymphoma: Definition and Morphologic Basis. Definition: •

In histology, lymphomas constitute a homogeneous neoplastic cell population, due to multiplication of one or more elements normally present in the lymph node to the point of destruction of nodal architecture. The tumor growth pattern is either as cohesive cellular aggregates called follicular or nodular pattern or as diffuse infiltration. Other histologic and cytologic features: • The neoplatic cells tend to infiltrate the capsule of the lymphoid organ they involve. • Cytologically, the neoplastic cells are monotypic but have resemblance with their nonneoplastic counterpart. • One type of neoplastic cell can transform/differentiate morphologically different cell type.

Reactive Follicular Hyperplasia of the Lymph Node

Immunologic and Gednetic Basis of NHL Immunologic Basis: Immunologically, lymphomas are expanded clones of lymphocytic precursors or functional cell types (B- or T-cell), which appear to develop from a block or switch on (derepression) of lymphocytic transformation. B-cell neoplasms are sIg+ and or cIg+, and express panB-cell markers (CD19, CD20, CD22, and CD79α). T-cell neoplasms express T-cell markers such as CD2, CD3, CD5, CD7, CD4, and CD8, but CD3 is considered lineage specific.

Genetic Basis: Genetically in most lymphoid neoplasms antigen receptor gene rearrangement precedes transformation. As a result, the daughter cells derived from the malignant progenitor share same antigen receptor gene configuration and sequence and synthesize identical antigen receptor protein (either Ig or T-cell receptor).

Extracted from the WHO Classification of Neoplastic Diseases of the Lymphoid Tissues: 1997 (Summary of Main Entries) •

B-cell neoplasms:

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T-cell neoplasia:

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Precursor B-cell (B- lymphoblastic lymphoma/leukemia) Mature (peripheral) B-cell neoplasms

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Precursor T-cell (T-lymphoblastic) lymphoma/leukemia Mature (peripheral) T-cell neoplasms

• • • • • • • • • •

B-cell CLL/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Mantle cell lymphoma Follicular lymphoma Marginal zone lymphoma (extranodal or MALT, Nodal, and Splenic) Hairy cell leukemia Diffuse large B-cell lymphoma and its subtypes (Burkitt lymphoma, immunoblastic lymphoma) Plasmacytoma, and plasma cell myeloma

•

• T-prolymphocytic leukemia • T-cell granular lymphocytic leukemia • Aggressive NK cell leukemia • Mycosis fungoides and Sezary syndrome • Angioimmunoblastic T-cell lymphoma • Peripheral T-cell lymphoma: Lymphoepithelioid (Lennert’s), Immunoblastic • Adult T-cell leukemia/ lymphoma (HTLV 1+) • Anaplastic large cell lymphoma (ALCL) (T and Null celltypes) • Intestinal T-cell lymphoma

Non-Hodgkin Lymphoma: Selected Sub-Types 1. B-cell CLL/small lymphocytic lymphoma. 2. Follicular lymphoma. 3. Diffuse large B-cell lymphoma. 4. Marginal zone lymphoma (extranodal MALT). 5. Burkitt lymphoma. 6. Precursor T-lymphoblastic lymphoma/leukemia. 7. Anaplastic large cell lymphoma.

B-cell CLL/Small Lymphocytic Lymphoma •

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•

•

Exclusively a disease of adults and affected lymph nodes are enlarged with smooth surface and homogeneous white cut surface. Are tumors of immature small lymphocytes. Normal lymph nodal architecture is replaced by a monotonous infiltrate of small lymphocytes. Disease is almost invariable disseminated with liver, spleen and bone marrow infiltration. The cells are of B-cell lineage and tissue manifestation of Bcell CLL. B-cell associated antigens are expressed. Genetic features: Immunoglobulin heavy and light chain genes are rearranged. CD20

Follicular lymphoma •

•

Commonest type of NHL and a disease of late adult life. Lymph nodes are enlarged. Involvement of bone marrow, liver, and spleen is common. Derived from (or differentiated towards) germinal center B-cells. Pure follicular or mixed follicular and diffuse pattern. Contain an admixture of centroblasts and centrocytes (neoplastic B-cells). Centrocytes predominate in most cases. Nonneoplastic follicular dendritic cells, and T-cells are also present.

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Express pan B-cell associate antigens.

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Chromosomal translocation t(14;18) (q32;q21) involving the immunoglobulin heavy chain promoter region on chromosome 14 and the antiapoptotic gene bcl-2 on chromosome 18. This translocation causes constitutive over-expression of bcl-2 protein, rendering follicular lymphoma relatively resistant to apoptosis.

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CD20

Bcl 2

Diffuse large B-cell lymphoma. •

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Usually a disease of adults. Majority of patients present with rapidly progressive nodal disease but extra-nodal involvement is common. May arise de novo or as a result of the transformation of follicular lymphoma. Histology: Characterized by a diffuse outgrowth of large B-cells, which may display centroblastic or immunoblastic cytology. Express one or more B-cell associated antigens. Common cytogenetic abnormalities are t (14;18) translocation resulting in deregulation of bcl-2, and translocations involving the 3q27 breakpoint with overexpression and mutation of bcl-6 gene, which is associated with extra-nodal presentation and more favorable clinical course.

Ig λ

Extranodal Marginal Zone Lymphoma (MALT Lymphoma) •

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Most commonly occurs in gastrointestinal tract. Other sites are thyroid, salivary gland, skin and orbit. Remain localized for a long period and have an indolent natural history, often with very good prognosis. Histology: Reactive germinal center surrounded by a population of neoplastic B-cells, morphologically similar to lymph node marginal zone B-cells (centrocyte-like marginal zone B-cells, monocytoid B-cells, plasmacells). May show impressive degree of plasma cell differentiation. Express B-cell associated antigens. Novel karyotypic abnormalities, t(11;18) and t(1;14); the latter is associated with mutation and gain of function of bcl-10 gene.

CD20

Burkitt Lymphoma •

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Burkitt lymphoma may be endemic (para-equatorial Africa), non-endemic (American, Indian) and immunodeficiency associated. The disease affects mostly children and adolescents. Associated with Epstein-Barr (EB) virus infection and malaria. Commonly involves extranodal sites (jaw bone involvement more common in endemic type and GIT in nonendemic type). Histology: Tightly packed mediumsized lymphoid cells with round nuclei, multiple nucleoli, interspersed with phagocytic macrophages, which impart a ‘starry sky’ appearance. High proliferation rate with almost 100% cells in cycle. Smears show cytoplasmic lipid vacuoles. Express B-cell associated antigens, and CD10. A distinctive type of B-cell lymphoma, associated with specific chromosomal translocation t(8;14)(p24;q32) involving cmyc gene at 8p24 and Ig heavy chain gene locus at 14q32.

Precursor T-lymphoblastic lymphoma/leukemia •

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Precursor T-cell lymphoma/leukemia tend to involve the mediastinum in adolescent boys. Histology: Diffuse sheets of small to medium-sized lymphoid cells with high nucleo-cytoplasmic ratio, moderately condensed to dispersed chromatin and indistinct nucleoli. may have a distinct convoluted morphology. Express the nuclear antigen TdT. Tlymphoblasts variably express T-cell antigens. Rearrangement of antigen receptor genes variable. Bone marrow infiltration is frequent.

Anaplastic Large Cell Lymphoma (ALCL) • • •

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Most common in children and young adults. May be nodal but frequent extranodal disease as well. Histology: Wide spectrum of appearance including small cell, lymphohistiocytic, giant cell, and sarcomatoid. Characteristic Doughnut and R-S-like cells. CD45+, CD30+, CD15–. Often of T-cell lineage. Particular chromosomal translocation, t(2;5) (p23;q35), which leads to expression of a fusion protein containing tyrosine kinase called anaplastic lymphoma kinase (ALK). Despite aggressive histological appearance, ALCL has a good overall survival.

LCA

CD30

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