Dr. Sumant presentation

1. NON HODGKINS LYMPHOMA
- B CELL VARIANTS
DR. SUMANT R GOSAVI
PG GENERAL MEDICINE

2. SYNOPSIS
• INTRODUCTION
• CLASSIFICATION
• TYPES OF NON-HODGKIN LYMPHOMA
• TREATMENT

3. • NON-HODGKIN’S LYMPHOMAS (NHL) ARE A HETEROGENEOUS GROUP OF
MALIGNANT LYMPHOMAS. THERE ARE MANY DIFFERENT SUBTYPES, EVERY
FEW YEARS THE CLASSIFICATION IS UPDATED. TODAY, MORPHOLOGY,
IMMUNOPHENOTYPE, MOLECULAR, CYTOGENETICS, AND OTHER TECHNIQUES
ARE USED FOR DIAGNOSIS.
• TREATMENT GENERALLY DEPENDS ON THE AGGRESSIVENESS OF THE
DISEASE (INDOLENT, AGGRESSIVE, OR VERY AGGRESSIVE)

4. • INDOLENT – THESE LYMPHOMAS GROW SLOWLY. THE MAJORITY OF NHLS ARE
CONSIDERED INDOLENT. INDOLENT LYMPHOMAS ARE GENERALLY
CONSIDERED INCURABLE WITH CHEMOTHERAPY AND/OR RADIATION THERAPY.
• AGGRESSIVE – THESE LYMPHOMAS HAVE A RAPID GROWTH PATTERN. THIS IS
THE SECOND MOST COMMON FORM OF NHL AND ARE CURABLE WITH
CHEMOTHERAPY.
• VERY AGGRESSIVE – THESE LYMPHOMAS GROW VERY RAPIDLY. THEY
ACCOUNT FOR A SMALL PROPORTION OF NHLS AND CAN BE TREATED WITH
CHEMOTHERAPY. UNLESS TREATED RAPIDLY, THESE LYMPHOMAS CAN BE
LIFE THREATENING.

5. 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
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.

6. RELATIVE FREQUENCIES OF LYMPHOID
MALIGNANCIES
HARRISONS PRINCIPLES OF INTERNAL MEDICINE, 19TH EDITION; 696

8. FOLLICULAR LYMPHOMA
• CONSTITUTES 22% OF NON HODGKIN’S LYMPHOMA
• MIDDLE AGE. M:F:: 1:1
• RARE IN ASIAN POPULATION
• NEOPLASTIC CELLS RESEMBLE NORMAL GERMINAL CENTER B CELLS

9. 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
Small Cell Cleaved Follicular Lymphoma
Grade I

10. 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

11. •Bone marrow involvement occurs in 85 % of cases
•Characteristically takes the form of paratrabecular
aggregates
bcl2 positivity of bone marrow neoplastic cellsParatrabecular bone marrow infiltration
by Follicular lymphoma

12. 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

13. 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

14. TREATMENT
• IN ASYMPTOMATIC PT. WATCHFUL MANAGEMENT.
• SINGLE AGENT CLORAMBUCIL OR CYCLOPHOSPHAMIDE OR COMBINATION
CHEMOTHERAPY WITH CVP OR CHOP
• R-CHOP OR BENDAMUSTINE +RITUXIMAB WITH INTERMITTANT RITUXIMAB
MAITAINANCE FOR 2 YRS.
• FLUDARABINE ,INF-ALFA,ALSO USED
• LYMPHOMA VACCINE MONOCLONAL ANTIBODY WITH OR WITHOUT
RADIONUCLEOTIDE.

15. BURKITT LYMPHOMA
• DEFN:
IT’S A NHL OF THE HIGH GRADE TYPE
SMALL NON-CLEAVED CELL LYMPHOMA, EXCLUSIVELY OF B-CELL ORIGIN
• BURKITT LYMPHOMA IS NAMED AFTER DENIS PARSONS BURKITT, 1958,WHO
MAPPED ITS PECULIAR GEOGRAPHIC DISTRIBUTION ACROSS AFRICA

16. EPIDEMIOLOGY:
2 EPIDEMIOLOGICAL TYPES:
 ENDEMIC BL - AFRICAN TYPE
 NON-ENDEMIC - SPORADIC BL
 *HIV ASSOCIATED BL*

17. …
• ENDEMIC BL (AFRICAN TYPE):
DISTRIBUTED BTN 15ON & 15OS OF THE EQUATOR (LYMPHOMA BELT)
THE AREA OF HIGHEST RISK FOR BL IN AFRICA (INCIDENCE 5 – 15 PER 100,000
CHILDREN)
WITHIN THIS BELT, THERE ARE POCKETS WHERE THE TUMOR IS EXTREMELY
RARE-IN HIGH ALTITUDE AREAS (NO KNOWN REASON)
RESTRICTED TO THOSE AREAS WITH ANNUAL RAINFALL >50CM & AN AVERAGE
TEMP IN THE COOLEST MONTH OF OVER 15.6OC

18. …
BL COMMONLY AFFECTS CHILDREN
PEAK AGE BTN 4-7YRS (6-7YR)
UNCOMMON BELOW 1YR OF AGE, AND <1% OF CHILDREN GET IT BELOW 2YRS.
LESS THAN 10% OF PATIENTS ARE DIAGNOSED AFTER THE AGE OF 15YRS
M:F =2:1

19. ETIOLOGY
NO KNOWN CAUSE
1 EBV: EPSTEIN-BARR VIRUS, A MEMBER OF THE FAMILY HERPESVIRIDAE, WHICH CAN BE ISOLATED FROM TUMOR
CELLS IN CULTURE, THERE IS A STRONG ASSOCIATION BTN ENDEMIC BL AND EBV.
FOUND IN 95% OF CASES.
2 MALARIA: CHRONIC SEVERE FALCIPARUM MALARIA INFN LEAD TO INTENSE
HOST RESPONSE WITH PROLIFERATION OF THE LYMPHORETICUCAR SYSTEM,
PARTICULARLY OF THE B-LYMPHOCYTES.
3 CHROMOSOMAL ABNORMALITIES:
 T(8;14)-80%, T(8;22)-15%, T(2;8)-5%, THIS LEADS TO ACTIVATION OF C-MYC
ONCOGENE

20. …
IN 1979, GEORGE KLEIN POSTULATED A THREE-STAGE PATHOGENIC STEP
REQUIRED FOR THE DEV’T OF ENDEMIC BL:
 EBV TRANSFORMS B CELLS & IMMORTALIZES THEM;
 AN ENV’TAL FACTOR, E.G HOLOENDEMIC MALARIA PROMOTES POLYCLONAL
PROLIFERATION OF B CELLS; AND
 A CYTOGENETIC ERROR EMERGES & ENDOWS THE CELLS WITH SURVIVAL
ADVANTAGE
4 ONCOGENES: THESE ARE GENES WHICH CAUSE CANCER
4 HIV INFECTION: IN HIV ASSOCIATED BURKITTS LYMPHOMA

21. CLINICAL FEATURES
• ENDEMIC BL
PRESENTS WITH JAW SWELLING IN 75%
MAXILLAE ARE AFFECTED MORE FREQUENTLY THAN THE MANDIBLES
MAXILLARY TUMOR OFTEN INVOLVES THE ORBIT AS WELL
THE FIRST CLINICAL EVIDENCE IS OFTEN LOOSENING OF TEETH
NON-JAW TUMORS PRESENT MAINLY AS ABDOMINAL MASS IN ~60%

22. …
VIRTUALLY ANY ABDOMINAL ORGAN CAN BE INVOLVED-LIVER, KIDNEYS,
OVARIES, SUPRARENAL & RETROPERITINEAL LNS, MAY HAVE ASCITES
CNS INVOLVEMENT- 3RD MOST COMMON MODE OF PRESENTATION
SEEN IN ~30% OF PTS
OFTEN PRESENTS AS CRANIAL NERVE PALSY WITH OR WITHOUT MALIGNANT
SPINAL FLUID PLEOCYTOSIS
PERIPHERAL NODE INVOLVEMENT IS RARE IN ENDEMIC CASES.

23. OTHER SITES INVOLVED
• PLEURA, ENDOCRINE GLANDS, TESTIS, SKIN MAY BE INVOLVED
• BONE MARROW ONLY 7-8% EVEN AFTER MULTIPLE RELAPSES
• PAROTID GLANDS

25. • IN NON-ENDEMIC AREAS;
THE MOST COMMON SITE OF PRESENTATION IS WITH
ABDOMINAL D’SE IN 90% (OFTEN OVARY & ILEOCAECAL)
PERIPHERAL NODE D’SE –IN 20% OF PTS
JAW INVOLVEMENT -10%
CNS INVOLVEMENT-5%
*JAW TUMOR MOST COMMON IN YOUNG CHILDREN WHILE
ABDOMINAL D’SE INCREASES IN FREQUENCY WITH AGE*
…

26. RECORGNITION
• JAW: DISFIGUREMENT, LOOSENING AND LOSS OF TEETH, HALITOSIS,
DIFFICULTY FEEDING AND SPEECH
• ABDOMEN: MASSES, DISTENTION, PAIN, CONSTIPATION, DIARRHEA,
DIFFICULTY BREATHING, OBSTRUCTIVE UROPATHY, IO, AND GI PERFORATION.
• ORBIT: PROPTOSIS, ALTERED VISION, DISFIGUREMENT
• CNS/PNS: LOC, CRANIAL NERVE PALSIES, SPHINCTER ABNORMALITIES
(RETENTION OR INCONTINENCE), PARAPLEGIA, ETC.
• FEVER, LOSS OF APPETITE, LOSS OF WEIGHT, FREQUENT MORBIDITY

27. TREATMENT
• TREATMENT SHOULD BEGIN WITHIN 48 HRS. OF DIAGNOSIS.
• COMBINATION CHEMO REGIMES WITH HIGH DOSES OF CYCLOPHOSPHAMIDE.

28. HAIRY CELL LEUKAEMIA
• HAIRY CELL LEUKEMIA IS A CHRONIC LYMPHOPROLIFRATIVE
DISORDER.
• IN 1958, BOURONCLE ET AL. USED “LEUKEMIC
RETICULOENDOTHELIOSIS” TO DESCRIBE THE CLINICAL ENTITY NOW
RECOGNIZABLE AS HCL.*
• EIGHT YEARS LATER (1966), SCHREK AND DONNELLY ALSO REPORTED
ON THE SAME DISEASE AND COMMENTED ON “PECULIAR CELLS” THAT
HAD NUMEROUS SHORT VILLI AND WERE ARBITRARILY CALLED “HAIRY
CELLS” ON PHASE CONTRAST MICROSCOPY. “HAIRY CELL LEUKEMIA”
GAINED POPULAR AND OFFICIAL RECOGNITION.**
Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood 1958.
Schrek R, Donnelly WJ. “Hairy” cells in blood in lymphoreticular neoplastic disease and “ flagellated” cells of normal lymph nodes. Blood 1966.

29. EPIDEMIOLOGY
• HCL CONSTITUTES APPROXIMATELY 2% OF ALL LYMPHOID
LEUKEMIAS.
• IT IS PREDOMINANTLY A MALE DISEASE, WITH THE MALE:FEMALE
RATIO RANGING FROM 4:1 TO 7:1.
• THE VAST MAJORITY OF AFFECTED PEOPLE ARE WHITE, WITH
ASHKENAZI JEWS BEING AN OVERREPRESENTED GROUP.
• THE MEDIAN AGE OF ONSET IS IN THE EARLY FIFTH DECADE

30. BIOLOGY:
• IN THE SCHEMA OF B-CELL ONTOGENY, THE HAIRY CELL CAN BE CONSIDERED
AN ACTIVATED, LATE-STAGE, PRE-PLASMA CELL B LYMPHOCYTE.
• HAIRY CELLS DISPLAY IMMUNOGLOBULINS THAT ARE LIGHT-CHAIN
RESTRICTED, BUT HAVE MULTIPLE HEAVY-CHAIN ISOTYPES (IGM, IGD, IGA, AND
IGG)
• HAIRY CELLS ALSO DISPLAYED THE PAN-B-CELL MARKERS CD19, CD20, AND
CD22.

31. MORPHOLOGY IN PERIPHERAL BLOOD fiLMS:
• APPROXIMATELY TWICE AS LARGE AS NORMAL LYMPHOCYTES
• MICROVILLI
• “FLUFFY”
• LIGHT BASOPHILIC
CYTOPLASM
• SPONGY CHROMATIN
• FOLDED OR OVAL NUCLEUS
• INCONSPICUOUS NUCLEOLI

32. CLINICAL FEATURES
• PATIENTS MAY BE ASYMPTOMATIC AND THE DISEASE IS IDENTIFIED BECAUSE A
FULL BLOOD COUNT IS TAKEN FOR AN UNRELATED REASON.
• SYMPTOMS RELATED TO CYTOPENIAS:
• SPLEEN, LIVER, AND LYMPH NODES

33. TREATMENT
• CHEMOTHERAPY WITH INF-ALFA ,PENTOSTATIN OR CLADIRABINE(PREFERRED)
• MANY OF TUMORS HAVE V600E,BRAF MUTATION AND ACCORDINGLY
RESPONSIVE TO BRAF-INHIBITORS LIKE VEMURAFENIB.

34. A distinct subtype of non-Hodgkin’s lymphoma (NHL)
t(11; 14)(q13; q32) chromosomal translocation
Bcl-1/PRAD-1 gene with over expression of cyclin D1
MCL is derived from CD5-positive B cells within the mantle zone (CD5+,
CD23-, cyclin D1+)
A typical CD20 + B cell lymphoma, with the poorest survival among all NHLs.
High response rate to initial treatment
Inevitable relapse.
Mantle Cell Lymphoma (MCL)

35. Biology of mantle cell lymphoma

36. HISTOPATHOLOGY

38. TREATMENT
• COMBINATION CHEMOTHERAPY FOLLOWED BY RADIOTHERAPY.
• FOR YOUNG PATIENT AGGRESSIVE CHEMOTHERAPY F/B BONE MARROW
TRANSPLANT.
• HYPER C-VAD WITH RITUXIMAB –GOOD RESPOSE IN YOUNG PATIENT.
• RITUXIMAB+HIGH DOSE METHOTREXATEAND CYTARABINE.

39. REFERANCES
• HARRISONS PRINCIPLES OF INTERNAL MEDICINE 19 EDITION
• WINTROBES TEXTBOOK OF PATHOLOGY.
• ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE 9 EDITION.