Leukopenia, leukocytosis

Follicular hyperplasia

NEOPLASTIC PROLIFERATIONS OF WHITE CELLS Lymphoid neoplasms The phenotype of the tumor cells resembles that of normal counterparts Myeloid neoplasms Origin of hematopoietic stem cells that give rise to cells of the myeloid lineage Histiocytoses Proliferative lesions of macrophages and dendritic cells

Etiology and pathogenetic factors in white cell neoplasia Chromosomal translocations and oncogenes Inherited genetic factors Virus Environmental agents Iatrogenic factors

Definition of lymphoid neoplasms Lymphoma Lymphoid neoplasms present predominantly as solid masses Leukemia (lymphoid leukemia) Lymphoid neoplasms involve mainly in bone marrow and usually in peripheral blood

Histology of a lymph node

Secondary Lymphoid Follicle (B-cell) Interfollicular zone (T-cell) Mantle zone Germinal center Dark zone Light zone Centrocyte Centroblast

Development of Lymphocytes

Normal Counterpart of B-cell Neoplasms

Lymphoma Classification “Revised European-American Classification of Lymphoid Neoplasms” (REAL) proposed by ILSG in 1994 World Health Organization (WHO) classification Why classification?

Three major categories of lymphoid neoplasms B cell lymphomas Precursor vs. peripheral T and NK cell lymphomas Hodgkin lymphoma (HL) Lymphoma vs. leukemia Small lymphocyte, lymphoblast, Burkitt

The WHO Classification of the Lymphoid Neoplasms I. Precursor B-Cell Neoplasms Precursor-B lymphoblastic leukemia/lymphoma II. Peripheral B-Cell Neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma (LPL) Splenic and nodal marginal zone lymphomas Extranodal marginal zone lymphoma Mantle cell lymphoma (MCL) Follicular lymphoma (FL) Marginal zone lymphoma (MZL) Hairy cell leukemia Plasmacytoma/plasma cell myeloma Diffuse large B-cell lymphoma (DLBCL) Burkitt lymphoma (BL)

III. Precursor T-Cell Neoplasms Precursor-T lymphoblastic leukemia/lymphoma IV. Peripheral T-Cell and NK-Cell Neoplasms T-cell prolymphocytic leukemia Large granular lymphocytic leukemia Mycosis fungoides/Sézary syndrome Peripheral T-cell lymphoma, unspecified (PTCL, NOS) Anaplastic large cell lymphoma (ALCL) Angioimmunoblastic T-cell lymphoma Enteropathy-associated T-cell lymphoma Panniculitis-like T-cell lymphoma Hepatosplenic γ/δ T-cell lymphoma Adult T-cell leukemia/lymphoma NK/T-cell lymphoma, nasal type NK-cell leukemia

V. Hodgkin Lymphoma Classical subtypes Nodular sclerosis (NS) Mixed cellularity (MC) Lymphocyte-rich (LRC) Lymphocyte depletion (LD) Lymphocyte predominance (LP)

Summary of Major Types of Lymphoid Neoplasms Diagnosis Cell of Origin Genotype Salient Clinical Features BL Germinal center B-cell; CD10 expression usually seen Translocations involving c-myc and Ig loci; usually t(8;14), but also t(2;8) or t(8;22). African (endemic) cases latently infected with EBV Adolescents or young adults with jaw or extranodal abdominal masses; uncommonly presents as a "leukemia"; aggressive

SLL/CLL

Prolymphocyte

CLL

SLL/CLL

FL

Centrocyte & centroblast

FL (spleen)

Bcl-2 expression in reactive and neoplastic follicles

DLBCL

DLBCL (spleen)

BL

BL

LPL

MCL

MCL

Mucosa-associated lymphoid tissue (MALT) type-lymphoma Extranodal marginal zone lymphoma Postgerminal center memory B-cell Trisomy 18, t(11;18), t(1;14); latter create MALT1-IAP2 and BCL10-IgH fusion genes, respectively Arises at extranodal sites in adults with chronic inflammatory diseases; may remain localized; indolent

Mature B cell lymphomas Epidemiology Median age: 6th~7th decades Mediastinal large B-cell lymphoma: 37 Burkitt lymphoma: 30 In children Burkitt lymphoma (BL) Diffuse large B-cell lymphoma (DLBCL) M>F: mantle cell lymphoma F>M: mediastinal large B-cell lymphoma

Risk factors Abnormality of the immune system Immunodeficiency (HIV, recipient of transplantation) BL, DLBCL Autoimmune disease MALT lymphoma

Etiology-- Infectious agents EBV BL (100% in endemic, 40% in others) lymphomas in immunosuppressed patients HHV8 primary effusion lymphoma Hepatitis C virus lymphoplasmacytic lymphoma Bacteria MALT lymphoma (stomach, skin, intestine)

Genetics Mantle cell lymphoma (MCL) Follicular lymphoma (FL) t(11;14): Cyclin D1/Bcl-1 Follicular lymphoma (FL) t(14;18): Bcl-2 Burkitt lymphoma (BL) t(8;14), t(2;8), t(8;22): c-myc MALT lymphoma t(11;18): API-2

Clinical Presentations Predominantly disseminated (leukemia) SLL/CLL, LPL, hairy cell leukemia (HCL), splenic marginal zone lymphoma, myeloma Primary extranodal MALT lymphoma Predominantly nodal Follicular lymphoma, mantle cell lymphoma, nodal marginal zone lymphoma

Clinical features and survival Indolent & incurable SLL/CLL, FL: median survival > 5 yrs Indolent & curable MALT lymphoma Incurable & aggressive MCL: median survival 3 yrs Aggressive but curable DLBCL (40% cure rate), BL

Mature T- and NK-cell neoplasms Incidence 12% in the Western world Peripheral T-cell lymphoma, unspecified (PTCL-U) Anaplastic large cell lymphoma (ALCL) 39% in Taiwan Nasal and nasal-type NK/T-cell lymphoma Why? Lower B lymphoma, virus, racial predisposition

Etiology Virus unknown EBV NK/T-cell lymphoma NK/T-cell leukemia HTLV-1 Adult T-cell leukemia/lymphoma unknown

PTCL, unspecified

ALCL-hallmark (horseshoe) cells

ALK expression in ALCL

Nasal type NK/T-cell lymphoma Natural killer cell (common) or cytotoxic T-cell (rare) No specific chromosomal abnormality; uniformly EBV associated Adults with destructive extranodal masses, most commonly sinonasal; often accompanied by hemophagocytic syndrome; aggressive

Reed-Sternberg (RS) cell

Characteristics About 30% of all lymphomas Usually arise in cervical lymph nodes The majority in young adults Typically localized at presentation Scattered tumor cells in a background of inflammatory cells The tumor cells are usually ringed by T-cells in a rosette-like manner

Mononuclear variant of RS cell

Lacunar variant

Lymphohistiocytic (L&H) variant

Subclassification Nodular lymphocyte predominant (NLPHL) 5% of all HL 30~50 y/o male Most stage I/II Develop slowly Frequent relapses Responsive to Tx Rarely being fatal 10 yr survival rate >90% Classical (CHL) 95% of all HL 15~35 & late adult Neck, mediastinum 55% stage I/II 40% systemic symptoms EBV association Curable in the majority 5 yr survival >85%

NS type

MC type

NLP type

Signals mediate cross-talk between RS and surrounding normal cells

Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic) More frequent involvement of multiple peripheral nodes Orderly spread by contiguity Noncontiguous spread Mesenteric nodes and Waldeyer ring rarely involved Waldeyer ring and mesenteric nodes commonly involved Extranodal involvement uncommon Extranodal involvement common

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HCL

HCL