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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.
THANK YOU