1. Week 6 BGD: Discussion on Hodgkin’s Lymphoma (Etiology, Immunology, Clinical Features, Staging Evluation, Treatment) Presented to the Department of Medicine University of Santo Tomas Faculty of Medicine and Surgery Medicine 3 Module I (Hematology/ Oncology and Gastroenterology) Presented by Group 4 (Palacpac, K.- Phoa, T. et al)

2. Epidemiology Whites> black; males> females Whites> black; males> females Bimodal age distribution: twenties and eighties Bimodal age distribution: twenties and eighties –late age peak may be due to entities with similar appearance (e.g. anaplastic large cell lymphoma, T cell–rich, B cell lymphoma) younger age groups (US) largely have the nodular sclerosing subtype of Hodgkin's disease younger age groups (US) largely have the nodular sclerosing subtype of Hodgkin's disease Occurs in 8,000 patients/ year in the US; incidence projection in the Philippines is at 2,200 (1) Occurs in 8,000 patients/ year in the US; incidence projection in the Philippines is at 2,200 (1) Elderly, HIV infected patients, 3 rd world countries commonly have mixed-cellularity Hodgkin's disease or lymphocyte-depleted Hodgkin's disease Elderly, HIV infected patients, 3 rd world countries commonly have mixed-cellularity Hodgkin's disease or lymphocyte-depleted Hodgkin's disease

3. Etiology and Immunology Commitment to B cell line when it begins to rearrange its immunoglobulin genes; Evidence suggests that Hodgkin's disease is of B cell origin Commitment to B cell line when it begins to rearrange its immunoglobulin genes; Evidence suggests that Hodgkin's disease is of B cell origin Viruses associated: HIV and most especially EBV Viruses associated: HIV and most especially EBV Normal B Cell Line Formation + EBV infection Mutation in IkB EBV DNA Episome Expression of LMP 1 ↑ NFkB (Lymphocyte activator) Rearrangement and hypermutation of Ig genes/ “gene crippling” Prevention of surface Ig expression death Further mutation R-S Cell CD40, C- MET, CD 30 GM- CSF, IL- 10, IL- 6

4. Reed- Sternberg (R-S) Cell The Reed-Sternberg cell is a neoplastic giant cell (15–45 μm in diameter) with multiple or multilobulated nuclei The Reed-Sternberg cell is a neoplastic giant cell (15–45 μm in diameter) with multiple or multilobulated nuclei This cell type is considered the hallmark of HD This cell type is considered the hallmark of HD It causes the accumulation of reactive lymphocytes, histiocytes (macrophages), and granulocytes It causes the accumulation of reactive lymphocytes, histiocytes (macrophages), and granulocytes Comprises 1-5% of the total tumor cell mass Comprises 1-5% of the total tumor cell mass

5. Immunology and Reed- Sternberg Cell ?

6. Classification of HL SubtypeMorphologyCompositionImmunologyFeatures Nodular sclerosis R-S and Lacunar cells T lymphocytes, eosinophils, macrophages, plasma cells CD 15, 30 (+); EBV (-) Common in stage 1 and 2 Mixed Cellularity R-S and Frequent Mononuclears CD 15, 30 (+); EBV (+) at 70% Common in stage 3 and 4 Lymphocyte Rich T lymphocytes CD 15, 30 (+); EBV (+) at 40% Uncommon, common in males Lymphocyte Depleted Reticular Variant: R-S and variants Decreased fibrillar background CD 15, 30 (+); most EBV (+) Lymphocyte Predominant Frequent L & H Popcorn Cell Variant Follicular dendritic cells and reactive B cells CD 15, 30 (-); CD 20 (+); EBV (-)

7. Clinical Features HL Spread: nodal  splenic  hepatic  marrow and extra nodal HL Spread: nodal  splenic  hepatic  marrow and extra nodal Mediastinal Lymphadenopathy (initial manifestation) Mediastinal Lymphadenopathy (initial manifestation) Palpable Non- tender lymphadenopathy (neck, supraclavicular area and axilla) Palpable Non- tender lymphadenopathy (neck, supraclavicular area and axilla) B Symptoms (fever, night sweats, weight loss) B Symptoms (fever, night sweats, weight loss) May present as fever of unknown origin May present as fever of unknown origin –Common in older patients with mixed-cellularity Hodgkin’s disease in an abdominal site –May follow Pel- Ebstein fever pattern (Persistent fever for days to weeks  Afebrile  recurrence)

8. Ann Arbor Staging System STAGEDEFINITION I Involvement of a single lymph node region or lymphoid structure (e.g. spleen, thymus, Waldeyer’s ring) II Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is a single site; hilar lymph nodes should be considered “lateralized” and, when involved on both sides, constitute stage II disease) III III 1 III 1 III 2 III 2 Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III 1 IV Involvement of extranodal site(s) beyond that designated as “E” More than one extranodal deposit at any location More than one extranodal deposit at any location Any involvement of liver or bone marrow Any involvement of liver or bone marrow

9. Ann Arbor Staging System A No symptom B Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation Unexplained, persistent, or recurrent fever with temperatures >38 ◦ C during the previous month Recurrent drenching night sweats during the previous month C Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow

10. Additional Evaluation Tools History and PE History and PE CBC CBC Erythrocyte Sedimentation Rate Erythrocyte Sedimentation Rate Serum chemistry studies Serum chemistry studies - LDH Chest Radiograph Chest Radiograph CT Scan CT Scan - chest, abdomen, pelvis Bone Marrow biopsy Bone Marrow biopsy PET and Gallium scans PET and Gallium scans

11. Other Manifestations Severe and unexplained itching Severe and unexplained itching Cutaneous disorders Cutaneous disorders - Erythema Nodosum - Ichthyosiform atrophy Paraneoplastic Cerebellar Degeneration Paraneoplastic Cerebellar Degeneration Other distant effects Other distant effects - CNS - nephrotic syndrome - immune hemolytic anemia & thrombocytopenia - hypercalcemia - pain in lymph nodes on alcohol ingestion

12. Treatment ABVD- Doxorubicin, Bleomycin, Vinblastine, Dacarbazine Sanford V- Doxorubicin, Bleomycin, Vincristine/ Vinblastine, Mechlorethamine, Etoposide, Prednisone BEACOPP- Doxorubicin, Bleomycin, Vincristine, Cyclophosphamide/ Procarbazine, Etoposide, Prednisone Gold standard for treatment; usually 6-8 months or more; Regimen combinations with MOPP- Mechlorethamine, vincristine, procarbazine and prednisone Half as long as ABVD but more intesive schedule; incorporates radiation therapy; inferior to ABVD in RCTs For stages > II; superior to ABVD in later stages - Complications may include secondary malignancies (most likely secondary to radiation), cardiac injury, infertility - BEACOPP is quite expensive because of the required GCSF and is now testing dose- cost relationship with the drug

13. Difference between HL and NHL Hodgkin Hodgkin –More localized to a singel axial group of nodes (cervical, mediastinal, para- aortic) –Orderly spread by contiguity –Mesenteric nodes and Ring of Walderyer is rarely involved –Extranodal involvement is uncommon –Pain post alcohol drink Non- Hodgkin Non- Hodgkin –More frequent involvement of peripheral nodes –Non- contiguous spread –Involvement of mesenteric nodes and Ring of Waldeyer –Extranodel involvement is common