NON HODGKIN LYMPHOMA

Dr Vijay Shankar S

LEARNING OBJECTIVES Introduction Classification systems B cell lymphomas Burkitt lymphoma

Classification Systems

Recognized as neoplasms in early 1900 Chaotic terminology Descriptive vs cell lineage classification

systems

Classification based on: Morphology (H&E) Clinical Outcomes Morphology + markers + Molecular

techniques

Lymphoma Classification

Morphology Morphology + Clinical outcomes + ? Markers Morphology + Immunophenotype + Chromosome

data Morphology + IPX + Molecular studies + Chr

(biologic subgroups) Morphology + Clinical + IPX + Mol. Sty + Gene

arrays

+Proteomics

1900 2010

Reticulum Cell

Tumors & HD

Lymphoma Rappaport1950

WF / NCI1982

REAL -

WHO

Morphology

MarkersCD1, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11, CD14, CD15, CD19, CD20, CD21, CD25, CD30, CD33, CD79A, CD99, CD117 etc.

Molecular

T & B cell gene rearrangement studiesIn-situ (FISH etc.), HUMARA, Gene/tissue arrays, CGH, Proteomics etc.

Classification Criteria - WF-NCI Classification (1982)

Criteria

Pattern of Growth

Cells & Cellular Features

Prognostic Categories

Classification

Low Grade

Intermediate Grade

High Grade

Pathology - 1180 cases independently reviewed by panel of hematopathologists (US, Europe and Japan)

Clinical data – Survival/response analyzed by statisticians

NCI funded study, 1982

Small Cells Intermediate

Large Cells

Pathologic / Morphologic Criteria – WF/NCI Classification, 1982

Nodular / Follicular Diffuse

Small Cells Intermediate Large Cells

Lymphoma Classification Working Formulation (WF-NCI)

Classification Pattern of Growth

Follicular or Diffuse Cells

Cell size - Small, medium & large

Lymphocytes, plasma cells, immunoblasts

Prognostic Categories Low grade Intermediate &

High grade

Low Grade A. Small cell B. Follicular small cell

cleaved C. Follicular mixed small

and large Intermediate Grade

D. Follicular large cell E. Diffuse small cell

cleaved F. Diffuse mixed small &

large cell G. Diffuse large cell

High Grade H. Immunoblastic I. Lymphoblastic J. Small cell non-cleaved

WF-NCI Classification (1982) Limitations

Works well for B-cell lymphomas Mixed small and large cell

lymphomas ? IPX, Flow & molecular data not

applicable Marginal zone (MALT) and mantle

types not classifiable Newer subtypes (T, NK cell etc.)

cannot be adequately classified under WF-NCI system

Strengths Grading system and high clinical

acceptance Many Rx protocols are based on WF-

NCI

Revised European & American Lymphoma Classification

(1996) WF-NCI system enhanced by Ancillary studies ? IHC Flow, cytogenetic

Several sub-categories All neoplastic entities of reticuloendothelial

system Includes tissue based, BM and peripheral

blood neoplasms Grading system not used

Currently modified by Society of Hematopathology, European association of Hematopathology

Recent WHO publication (2001)

Criteria for WF-NCI and REAL/WHO

REAL-WHO Cells

Pattern

Immunophenotype

Grade (not graded*) *grading is under

development

WF-NCI

Pattern

Cells

Grade

REAL-WHO, 2001Cells and Cellular

Features Cell size (S, M & L),

cleaved Lymphoblasts,

large/small lymphocytes, mantle cells, monocytoid B-cells (marginal zone), immunoblasts, lymph-plasma cells

Pattern of Growth Follicular or diffuse

Immunophenotype IHC, Flow & Genotype Lymphoid (B, T, NK),

histocyte, myeloid and macrophages

Several Categories

B-cell Neoplasms T-cell Neoplasms Hodgkin’s disease Histiocytic/

Dendritic cell neoplasms

Acute leukemia Lymphoid or

myeloid Myelodysplasia Chronic

myeloproliferative disorders

REAL-WHO – 2001: Classification – Biologic Groups ?

Precursor B-cell ALL / lymphoblastic

lymphoma Mature (peripheral) B-

cell CLL / SLL B-prolymphocytic

leukemia Lymphoplasmacytic

leukemia Splenic marginal zone

(SLVL) Hairy cell leukemia Plasma cell myeloma Extranodal MALT Nodal MALT Follicular lymphoma Diffuse large B-cell

lymphoma Burkitt

lymphoma/leukemia

Precursor T-cell ALL / lymphoblastic

lymphoma Blastoid NK-cell lymphoma

Mature (peripheral) T-cell T-cell prolymphocytic T-cell large granular

lymph Aggressive NK-cell leuk ATLL (HTLV1+) Extranodal NK/T-cell

lymphoma Enteropathy associate T

lymp Hepatosplenic lymphoma Subcutaneous panniculitis

T-cell lymphoma MF/SS Primary cutaneous large

lymph Angioimmunoblastic

lymphoma Primary systemic

anaplastic large cell lymphoma (ALCL)

Relative Frequency of Lymphomas REAL .. N.

Harris et al B-cell > 85% T-cell < 15%

Types

Diffuse large B-cell – 31% Follicular lymphoma – 22% MALT lymphoma 8% Mature T-cell lymphoma – 8% CLL/SLL – 7% Mantle cell lymphoma – 6% Mediastinal large B-cell lymphoma – 2% Anaplastic large cell lymphoma – 2% Burkitt lymphoma – 2% Nodal marginal zone lymphoma – 2% Precursor T lymphoblastic – 2% Lymphoplasmacytic lymphoma – 1% Other types – 7%

WHO Classification of Hematopoietic and Lymphoid Tumors: B-cell Neoplasms

Indolent Chronic lymphocytic

leukemia (CLL)/small lymphocytic lymphoma

Lymphoplasmacytic/Waldenstrom’s macroglobulinemia (WM)

Hairy cell leukemia Marginal zone

lymphoma Extranodal

mucosa-associated lymphoid tissue (MALT)

Nodal Splenic

Follicle center lymphoma, follicular, grade I-II

Aggressive Prolymphocytic

leukemia Plasmacytoma/

multiple myeloma Mantle cell Follicle center

lymphoma, follicular, grade III

Diffuse large B-cell lymphoma (DLBCL)

Primary mediastinal large B-cell lymphoma

Very Aggressive Precursor

B-lymphoblastic lymphoma/leukemia

Burkitt lymphoma/ B-cell acute leukemia

Plasma cell leukemia

Jaffe E, et al. IARC Press, World Health Organization, 2001.

B-Cell Lymphoma (85%) B-Cells help make antibodies, which are

proteins that attach to and help destroy antigens

Lymphomas are caused when a mutation arises during the B-cell life cycle

Various different lymphomas can occur during several different stages of the cycle Follicular lymphoma, which is a type of B-cell

lymphoma is caused by a gene translocation which results in an over expressed gene called BCL-2, which blocks apoptosis.

Precursor B or T Lymphoblastic Leukemia/lymphoma

High grade B or T cell neoplasm

Common in children Leukemic or

lymphomatous phase

CD19+, CD79a+, CD10+, CD24+, tDt+ (precursor B)

CD3+, CD5+, tDt+ (precursor T)

B-Cell Small Lymphocytic / CLL

Small lymphoid cells & “pseudo growth centers”

Immunophenotype CD20+ dim, CD19+,

CD5+, CD23+, k or l+ dim

Indolent process Prolymphocytes

(<30%) High grade B-cell

lymphoma (Richter’s transformation)

SLL

SLL

CLL

Follicular Lymphoma Most common form of NHL Middle age. M:F:: 1:1 Rare in Asian population Neoplastic cells resemble normal

Germinal center B cells

Follicular Lymphoma Predominantly

follicular, focal diffuse or pure diffuse

Small cleaved cells (centrocytes)

Larger cells ( centroblasts)

Mixed small and large cells

Grade I, II & III a/b Nodal or extranodal BM + (85%)

Small Cell Cleaved Follicular LymphomaGrade I

Follicular Lymphoma Histopathology

Centrocytes:Small cells with irregular / cleaved nuclear contours & scant cytoplasm

Centroblasts: larger cells with open nuclear chromatin, several nucleoli& moderate cytoplasm

Centrocytes

Centroblasts

• Bone marrow involvement occurs in 85 % of cases

• Characteristically takes the form of paratrabecular aggregates

bcl2 positivity of bone marrow neoplastic cells Paratrabecular bone marrow infiltration by Follicular lymphoma

Immunophenotype

CD19+, CD20+, CD10+, k or l +, CD 5-, CD23+/-

Also expresses bcl-2 protein in more than 90 % of cases.

Cytogenetics & Molecular Genetics

Hallmark of follicular lymphoma is a (14 ;18 ) translocation that juxtaposes the IgH locus on Chr 14 and the bcl-2 locus on Chr 18

Clinical features. Painless, generalised

lymphadenopathy Indolent waxing and waning course Incurable Median survival- 7-9 yrs Histologic transformation to DLBCL

in 30% - 50% of cases., rarely into burkitt like lymphoma.

Survival less than 1 yr after transformation

Diffuse large B-cell lymphoma

most common type of “aggressive” lymphoma

usually symptomatic,presents with rapidly enlarging, mass at a single nodal or extranodal site

extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40 – 50%.

Diffuse Large Cell Lymphoma (B-cell)

Diffuse pattern of growth.

Large cell size(4 -5 times the diameter of a small lymphocyte.

R-S like cells may be seen in more anaplastic variants.

Large cell Lymphoma

Immunoblastic Lymphoma

BURKITT LYMPHOMA Aggressive B- cell neoplasm Types 1. African ( Endemic) Burkitt lymphoma2. Sporadic ( Non Endemic) Burkitt

lymphoma3. Aggressive lymphomas in individuals

infected with HIV

EBV infection related. t(8;14)

Died 23 Mar 1993 (born 28 Feb 1911) Irish surgeon and medical researcher who first identifiedBurkitt's lymphoma. In 1957, in Uganda, Burkitt found several children suffering from fast-spreading tumours in the head and neck. When they died within weeks, Burkitt recognised this was a previously undescribed cancer disease. He showed that these and all cases were characterized by infiltration of the affected tissues by lymphocytes. With colleagues Edward Williams and Clifford Nelson, he plotted the geographical incidence of the disease, and found it in the same areas endemic with malaria. This survey is regarded as one of the pioneering studies of geographical pathology. Burkitt helped to develop chemotherapy for the disease. Later, he championed high fibre diets.

Dr Denis (Parsons) Burkitt

A group of Burkitt's Lymphoma cases in Dr Burkitt's care.Mulago Hospital, Kampala, Uganda, in 1960

Clinical featuresBoth endemic & sporadic are found in children and young adults.

Endemic Burkitt lymphoma : often present as a mass involving mandibleUnusual prediliction for abdominal viscera(kidneys, ovaries, adrenals).

Sporadic Burkitt lymphoma: Most often presents as an abdominal mass involving the ileocecum and peritoneum

Morphology

Immunophenotype: Mature B cell markers – Surface IgM, CD19, CD20,CD10.

Cytogenetic Features

In most of the cases of Burkitt's lymphoma, a reciprocal translocation has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancers of the antibody heavy chain genes on chromosome 14.

T(8;14)

prognosis Very aggressive , but responds well

to short-term, high dose chemotherapy.

Most children and young adults can be cured.

Outcome guarded in older adults.

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