Management of Hodgkin’s Lymphoma: An Overview

1. Management of Hodgkin’s Lymphoma: An Overview Shahina Qureshi MD State University of New York Downstate Medical Centre

2. US Study Incidence %Children’s Hospital Relative Frequency Leukemias 30.1 Leukemias 38.5 CNS Tumours 19.1 CNS Tumours 22.1 Lymphomas 12.3 Lymphomas 8.7 Renal Tumours 6.5 Renal Tumours 5.8 Sympathetic Tumours 8.1 Sympathetic Tumours 4.8 Bone Tumours 4.8 Bone Tumours 4.8 Retinoblastoma 2.7 Retinoblastoma 6.7 Soft Tissue Tumours 6.3 Soft Tissue Tumours 3.8 Gonadal Germ Cell 2.0 Gonadal Germ Cell 2.9 Liver Tumours 1.1 Liver Tumours 1.9 Others 8.0 Major Cancers in Children under 14 Years

3. Hodgkin’s Disease Epidemiology • 5% of all malignancies • Bimodal distribution . • Three distinct forms, <14 yrs., 15-34 yrs, 55-74yrs • Peak late 20 and after 50 yrs. Rare under 5 yrs • Familial clustering,three fold in relatives to seven fold in siblings.4.5% of all cases • Greater in females M:F Age dependant 15-19 y =0.8 • 15 Y=1.3, ,5Y = 5.3

4. Epidemiology • Common in immunodeficiency diseases,e.g. HIV , Ataxia telagiectasia • Variation in incidence, age , sex seen in diff. geographic locations and socioeconomic status • Associated with viruses EBV , CMV, Herpes • 25-50% classical H.D in developing countries are EBV pos

5. EBV in Hodgkins Lymphoma • LMP 1&2 Seen in EBV +ve tumors • Virus in serum disappears in remission • Virus association different in diff geographic areas. • North America 25% • Honduras 100% • Islamabad 75% • Madras 75% • Median time of progression to HL after EBV infection is 4 yrs • Degree of association differs with age Pos in very young and older age groups.

6. W.H.O. Classification of Hodgkins Lymphoma • Classical 95% • Nodular Lymphocyte predominant 5%

7. Classical Hodgkins lymphoma Subtypes • Lymphocyte predominant [10-15%] • Nodular sclerosis [Most common-40% in younger pts, 70% in adolescents, effects lower cervical , supraclavicular, mediastinal lymph nodes] • Mixed cellularity [30% , common in >10yrs, advanced disease, developing countries • Lymphocyte depletion. More common in HIV .

9. Lymph Node Showing Reed-Sternberg Cell

10. HRS Cell • Constitute 1% cells in L.N. • Secrete Cytokines and chemokines • Originate from T or B Lymphocyte • Nodular sclerosing express B-cell markers CD 19, CD20. • Mixed cellularity express LeuM1[CD15], Ki-1[CD30]antigen • Lymphocyte predominant Bcell type express LCA[CD45],L26[CD20]

11. Cytokines Produced by HRS cells Relatable biological features in Hodgkin’s disease Cytokine Lymphoproliferation, fever, night sweats,immunodeficiency, fibrosis IL-1 IL-2 Similar to IL-1 IL-4 IL-5 Eosinophilic infiltration IL-6 IL-9 Lymphoproliferation TNF-Weight loss TNF-Weight loss IFN GM-CSF Leukocyte or eosinophil infiltration G-CSF Myeloproliferation TGF- Fibrosis

13. Clinical Presentation Painless ,rubbery lymphadenopathy • Axillary 10-20% • Cervical 60-80% • Inguinal 6-12% • Infradiaphragmatic ,10% • Mediastinal involvement in 17-40% [.Than 1/3 diameter of the chest] cough, superior vena cava syndrome • Systemic symptoms 30%, Weight loss>10% in 6 months, fever>38, night sweats • Splenomegaly in 30-40% • Hepatomegaly ,5% • Extranodal involvement, pulmonary parenchyma, pleura, chest wall,pericardium

14. Clinical presentation • Paraneoplastic syndrome • Cholestatic liver disease • Skin lesions, urticaria, erythema multiforme • Neurologic symptoms ,cerebellar degeneration Cerebral pontine myelionlysis • Nephrotic syndrome • Hypertrophic osteoarthropathy • Hematological, autoimmune hemolytic anemia, thrombocytopenia • Hypothermia due to disordered cytokine release with liver involvement

16. Radiograph

17. CT scan

18. Differential Diagnosis • NHL • Mycobacterial infection • Toxoplasmosis • Infectious mononucleosis • Metastasis • Enlarged thymus

19. Prognostic Factors in H.L • Mediastinal Disease • WBC >13,500 • Hemoglobin<11.0g/Dl • Disease stages 11B,111B OR IV • Fever • Night sweats • Weight loss

20. Diagnostic Workup • Physical exam • Chest x-ray • C.B.C with Sed rate, Ferritin • Renal, hepatic function tests, alkaline phosphatase • Lymph node biopsy • CT scan [lung] or MRI[ better for infradiaphragmatic LN] Abdomen, Pelvis • Bone marrow biopsy in stage 111, IV OR B- symptoms.4%+ve • Gallium –67 scan [for supradiaphragmatic], Bone Scan if 11B /bone pain, PET scan • Lymphangiogram [displays internal lypmh node architecture] • ECHO or MUGA

21. PET scan in HodgkinsLymphoma • Images whole body • Sensitivity depends on FDG activity [time of scan]100% specificity is 55.6% • More sensitive than gallium and CT scans . Shorter time 2 h CT may not diff between fibrosis and residual tumor. • Positive predictive value is 25-100% [ False positive can occur due to uptake in brown fat and muscles. Should not be done after radiation • False negative can occur, In stage 3 &4 MRD cannot be detected, should be confirmed by CT and clinical findings • Strong negative predictive value.81-100% Negative scan is a good predictor of survival [Mikhaeel Ann ofoncology 2002;13 2/26 neg PET relapsed] • Elstrom Blood may 15 2003;3875

23. Ann Arbor staging • Stage 1 involvement of a single lymph node region,or single extra lymphatic organ or site • Stage 11 involvement of two or more lymph node regions on the same side of the diaphragm, or localized involvement of an extra lymphatic organ or site and one or more lymph node regions on the same side of the diaphragm. • Stage 111 involvement of lymph node regions on both sides of the diaphragm with spleen involvement or localized involvement of an extra lymphatic site or both. • Stage 1V diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node involvement.

26. Treatment • Radiotherapy • Chemotherapy

27. Limited Stage DiseaseTreatment • 1990 suspected that surgical staging was unnecessary • MOPP based chemo was the standard • Extended field radiation was given • 2003 surgical staging not done • Different chemotherapeutic regimens used • Trials CT vs RT or CMT • JCO 1993

28. Progress in therapy [SEER]

29. Treatment Stage I and II A and II B – 90% DFS MOPP – 6 courses + 2000 GGY MOPP – 6 courses + 3500 – 4000 GGY Stage-III-B MOPP – 6 courses + full dose involved field radiation MOPP/ABVD 12 Courses Antiferritin labeled antibody with 131

30. ABVD Adriamycin 25mg/m² I.V day1 , 15 Bleomycin 10 units/m² I.V day 1 ,15 Vinblastine 6mg/m² I.V day 1 , 15 Dacarbazine 375 mg/m² 1 , 5 Repeat every 28 days

31. MOPP Nitrogen Mustard 6mg/m² I.V day 1 , 8 Vincristine 1.4mg/m² I.V day 1 , 8 Procarbazine 100mg/m² P.O 1-14 Prednisone 40mg/m² P.O 1-14

32. Therapy Options and Toxicity

33. Good Risk Localized/Favorable

34. Localized/ Favorable Treatment Results

35. Treatment Results • Stage 1,11A 70-86% 5yr DFS With involved field radiation,> 90% with radiation + chemotherapy • Stage 111B, IV, 70-90% DFS.

36. Intermediate Risk Localized Unfavorable

37. Localized/ Unfavorable Treatment Results

38. High-Risk Advanced/ Unfavorable

39. Advanced/ Unfavorable Treatment Results

40. Involved field regions • Mantle • Mini mantle • Hemi minimantle • Mediastinum • Para aortic and spleen • Spade • Pelvis • Hemi pelvis • Inverted Y

41. Acute Effects of Radiation • Alopecia • Skin Changes, erythema, hyperpigmentation • Infections, Herpes Zoster, Varicella in 35% • GI sypmtoms • Lhermitte Syndrome

42. Effects of chemotherapy • Nausea, vomiting • Cardiac toxicity[adriamycin] • Pulmonary toxicity [Bleomycin] • Neurotoxicity [vincristine] • Myelosuppression • Hyperpigmentation

43. Cardiac Complications After Anthracyclines

44. Factors Contributing to Morbidity

45. Pulmonary Toxicity

46. Late effects of radiotherapy • Soft tissue and bone growth alterations • Pulmonary sequelae 3.6% • Cardiac sequelae • Endocrine sequelae, thyroid dysfunction related to rad dose • Sterility [20%-30% with MOPP] • Second malignant tumours[NHL 4%, ANLL 1.2-13%, soft tissue ,osteogenic sarcoma, lungs ,GI]]

47. Growth Impairment After RT

48. Cardiac Complications After Radiation

49. Thyroid Nodules

50. Ovarian Failure