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– Precursor vs. peripheral

• 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)

– 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– 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

Hodgkin Lymphoma Non-Hodgkin Lymphoma

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

THANK YOU

HCL

HCL