Follicular lymphoma

follicular lymphoma

1. FOLLICULAR LYMPHOMA

2. Definition Follicular lymphoma is a neoplasm of a follicle center B cell that is composed of a mixture of cleaved follicle center cells ( centrocytes ) and large non cleaved follicle center cells ( centroblasts ).

3. MC human B cell neoplasm. Primarily affecting adults, Rare in childrens . Median age of presentation is 59 years. male : female – 1:1.7 45% of all NHL, 80% of all Indolent Lymphomas. Stage I & II – 33% ( Low grade) Stage III & IV – 67% (High grade).

4. Clinical presentation New painless lymphadenopathy Non tender, firm, rubbery in consistancy Mostly involves retroauricular,cervical,supraclvicular,axillary,inguinal,popiletial rarely epitrochlear node. Extra nodal sites includes spleen,liver,bonemarrow . CNS disease is rare.

5. B symptoms, Fever >38˚ Night sweats Weight loss >10% of body weight in preceding month. Asthenia Anemia,leukopenia,thrombocytopenia due to BM suppression FL follows Waxing n Waning course.

6. CAUSES Genetics – chromosomal translocations Viruses- EBV, HTLT I, HHV 8. Immunodeficiency state : Congenital Acquired- hiv,immunosupprasant drugs Autoimmune disorders

7. Follicular Lymphoma Bcl2 Chromosome 18 Mbr (major breakpoint region, 150 bp) J H C  Double strand DNA break by RAG1/2 Chromosome 14 Bcl2 C  t(14;18) translocation bcl2 C  E  C  3’E Unregulation of Bcl2 expression by IgH enhancers Translocation takes place in B cell precursors. Transformation takes place during B cell activation in GC.

8. Bcl2 inhibits apoptosis cytochrome c Apaf-1 dATP or ATP mitochondrion Apaf-1 Pro-caspase-9 Caspase-9 Pro-caspase-3 Caspase-3 Apoptosis Bcl-2, Bcl-X L Bax, Bad Pro-survival oncogene

9. Over-expression of Bcl-2 may prevent the apoptosis of germinal center B cells activation Germinal center Germinal center apoptosis IgH-Bcl2 activation Germinal center Germinal center Plasma cells Memory cells follicular lymphoma Apoptosis inhibited Most follicular lymphoma Ig V regions contain somatic hypermutation.

10. Bcl 2 translocation rearrangements, 1) mcr ---- 95% 3year failure 2)MBR ---- 76% free survival 3)Germ line mutation ---57% rate.

11. Investigation Diagnostic confirmation-tissue biopsy,BMA , PS. Assessment of clonality Immunophenotype,cytogenetics,molecular study. Viral testing Laboratory assessment of organ function CD4,LDH,serum beta2 microglobulin,se.AFP / BetaHCG CXR,CT scan, PET scan

12. IMMUNOPHENOTYPE POSITVE Monoclonal surface Ig Bcl 2 CD10 CD 19 CD 20 CD 22 CD 79a NEGATIVE CD 5 CD 11 CD 23c CD 43

13. GRADING WHO Morphalogical grading, Grade I -- < 5 centroblasts /HPF Grade II -- 6-15 centroblasts /HPF Grade III -- >15 centroblasts /HPF. IIIa -- centrocyte still present IIIb --- fully contains centroblasts

14. Stage I Stage II Stage III Stage IV Staging of lymphoma A : absence of B symptoms B : fever, night sweats, weight loss

15. ANN ARBOR STAGING Stage I Involvement of a single lymph-node region (I) or a single extralymphatic organ or site (IE) Stage II Involvement of two or more lymph-node regions on the same side of the diaphragm (II) or localized involvement of an extra-lymphatic organ or site (IIE) Stage III Involvement of lymph-node regions on both sides of the diaphragm (III) or localized involvement of an extra-lymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE) Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph-node involvement; the organ(s) involved should be identified by a symbol: (P) pulmonary, (O) osseous, or (H) hepatic. (A) indicates an asymptomatic patient; (B) indicates the presence of fever, night sweats, or weight loss > 10% of body weight.

16. FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX (FLIPI) Age 60 or more Ann Arbor stage III & IV LDH level above the upper limit at the diagnosis. Hb < 12gms% at diagnosis. Presence of more than 4 nodal site involement

17. Treatments Indolent Aggressive

18. Treatment Waxing n waning course- wait n watch low grade (I, II) Most radio sensitive Radiotherapy uesd for localised disease Involved field or extended field RT ranging from 35 to 50Gy Achive remission in 50% patients

19. Single agent chemotherapy chlorambucil fludarabine rituximab idelasilib – phophoinositide 3 kinase delta inhibitor ( Pl3k)

20. Multi agent chemotherapy R-CVP R – CHOP FCR RFCM FR

21. HEMATOPOIETIC STEM TRANSPLANTATION Allogenic autologus

22. Targeted radio immuno therapy Radio sensitive tumor Iodine 131 labeled Tosutumomab . Yettrium 90 labeled Ibritumomab Tiuxetan .

23. Interferan alpha Interleukin 2 Anti idiotype therapy: murine monoclonal antiidiotype antibody combined with INF aplha or chlrambucil or antibody alone can be given. Vaccine therapy: Idiotypic protein coupled to keyhole limpet hemocyanin (KLH) and combined with an immunologic adjuvant Immuno toxin therapy: Monoclonal antibody specific for tumor-associated antigens conjugated toxins -- immunotoxins . Ricin is a heterodimeric protein- inhibits protein synthesis by the action of its cytotoxic A-chain.

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