Hodgkin’S Lymphoma


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A presentation which discuss in detail regarding types, stage, and current management guidelines for hodgkin's lymphoma.

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Hodgkin’S Lymphoma

  2. 2. INTRODUCTION <ul><li>Hodgkin’s disease (HD) is potentially curable malignant lymphoma </li></ul><ul><li>Thomas Hodgkin 1852 described it </li></ul><ul><li>It is defined in terms of –microscopic appearance & expression of cell surface markers </li></ul><ul><li>WHO classified HD into five types- nodular sclerosis, mixed cellularity, lymphocyte depleted, lymphocyte rich HD {collectively called classic HD} & non lymphocyte predominant HD (NLPHD) </li></ul><ul><li>Neoplastic cell in HD is Reed-Sternberg (RS) cell: it comprises 1-2% of total tumor mass remainder are variety of mixed inflammatory cells </li></ul><ul><li>Most RS cells are of B-cell origin derived from lymph node germinal centre but no longer able to express antibodies, T-cell origin in 1-2% cases only </li></ul><ul><li>RS cell consistently express CD 30 (Ki-1) & CD 15 (Leu M1) antigens. CD 30 is a marker of lymphocyte activation, CD15 is a marker of late granulocyte, monocyte & activated T cell not normally expressed on B cell lineage </li></ul>
  3. 3. INTRODUCTION <ul><li>Nodular sclerosis HD: 60-80% of all cases, affects mainly adolescents & young adults, involves mediastinum and other supra diaphragmatic sites </li></ul><ul><li>MC HD: 15-30% of all cases, commonly affects abdominal lymph nodes and spleen, pt. usually presents in advanced stage, common in HIV pt. </li></ul><ul><li>LD HD: <1% of cases, affects mainly old age and HIV +VE pt., usually present with advanced stage, cells shows expression of EB virus protein </li></ul><ul><li>LR HD: 5% of cases, requires immunohistochemical diagnosis, clinically similar to MC HD </li></ul><ul><li>NLPHD: 5% of cases, RS cells are infrequent or absent, pop corn cells (nuclei like exposed kernel of corn) are seen, CD 19 & CD 20 +VE (B cell antigens), -ve for CD 15 & CD 30, diagnosis is immunohistochemical- express J chain and display CD 45 & ema (epithelial membrane antigen) </li></ul><ul><li>Frequency of HD: US-2.7 cases/100,000, internationally-rare in Japan and china. In developing countries incidence of MC HD & LD HD is higher in contrast NS HD in developed cpuntries. </li></ul>
  4. 4. STAGING <ul><li>Ann Arbor (1971) staging is used- it is a clinical staging and assessed by clinical examination, history and imaging, when staging laparotomies are used as part of staging disease extent is designated as pathologic staging- </li></ul><ul><ul><li>Stage1: denotes a single lymph node area or single extra nodal site </li></ul></ul><ul><ul><li>Stage2: denotes two or more lymph nodes area on same side of diaphragm </li></ul></ul><ul><ul><li>Stage3: lymph node areas on both sides of diaphragm </li></ul></ul><ul><ul><li>Stage4: denotes disseminated or multiple involvement of extra nodal organs. Involvement of liver or bone marrow is stage4 </li></ul></ul><ul><li>For staging classification spleen is considered to be a lymph node area and involvement of spleen is denoted with suffix S </li></ul><ul><li>A or B designations denotes presence or absence of B symptoms </li></ul><ul><li>B designation includes presence of one or more of : fever (>38°C), drenching night sweats & unexplained loss of >10% of body weight within preceding 6 mths. A designation is absence of these. An X designation indicates bulky disease </li></ul><ul><li>Splenic involvement: 1/3 of all pts, 2/3 of MC HD pts, 1/3 of LD HD & NS HD pts </li></ul><ul><li>When liver or bone marrow involvement is present spleen is likely to be involved. </li></ul><ul><li>Spread of HD takes place via: lymphatic, hematogenous & direct extension </li></ul>
  5. 5. INTRODUCTION <ul><li>Morbidity & Mortality: 5 yrs disease specific survival rate- stage1 & 2 (90%), stage 3 (84%), stage 4 (65%). </li></ul><ul><li>HD more common in males than females & in males particularly in children </li></ul><ul><li>Age incidence is bimodal peaking in 15-34 yrs & >55 yrs. NS HD in 15-34 yrs & MC HD in old & children </li></ul>
  6. 6. CLINICAL DIFFERENCES B/W HD & NHL HD NHL 1.Cellular derivation unresolved 90% B – cell, 10% T- cell, rarely monocytic 2.Localised to a single group of LN Involvement of multiple peripheral LN 3.Spreads by contiguity Non contiguous spread 4.Mesnteric LN & Waldeyer's ring rarely involved Commonly involved 5.Exta nodal involvement uncommon Common 6.BM involvement uncommon Common 7.Chromosomal translocation yet to be described Common 8. Curability >75% <30-40%
  7. 7. CLINICAL PRESENTATION <ul><li>Most common is asymptomatic LAP (80% cases), above diaphragm, non tender. >1/2 have mediastinal LAP at diagnosis & this is sometimes the initial manifestation. Sub diaphragmatic presentation of HD is unusual & more common in older males </li></ul><ul><li>Constitutional symptoms: fever, unexplained wt loss, night sweats- 40% cases. PUO seen occasionally in MC HD older pt with abdominal site of disease. Intermittent fever in 35% cases, infrequently Pel – Ebstein fever is seen (1-2 weeks of high fever f/b afebrile period of 1-2 weeks) </li></ul><ul><li>Unusual presentations: unexplained itching, cutaneous disorders such as erythema nodosum & itchthyosiform atrophy, paraneoplastic cerebellar degeneration , nephrotic syndrome, immune hemolytic anemia & thrombocytopenia, hypercalcemia & pain in lymph node region on alcohol ingestion (is specific for HD but is seen in <10% of pts) </li></ul><ul><li>Back/bone pain is rare. </li></ul><ul><li>Physical examination: palpable painless LAP, rubbery consistency- cervical (60-80%),axillae (6-20%), inguinal (6-20%). Waldeyer’s ring or occipital/ epitrochlear LAP rare. Splenomegaly, hepatomegaly, SVC syndrome due to mediastinal LAP, CNS symptoms ( multi focal leukoencephalopathy) </li></ul>
  8. 8. ETIOLOGY <ul><li>Epstein- Barr virus in 50% cases- more in MC HD (60-70%) than NS HD (15-30%) </li></ul><ul><li>100% of HIV associated HD are EBV +ve </li></ul><ul><li>HIV infection is associated with higher incidence of HD, but HD is not a AIDS defining neoplasm </li></ul><ul><li>HLA-DP allele more common in HD </li></ul>
  9. 9. INVESTIGATIONS <ul><li>BIOCHEMICAL: ESR- elevated level poor prognosis, LDH- correlate with bulk of disease, CBC- anemia of chronic disease, lymphopenia, neutrophilia, eosinophilia. Serum creatinine – for nephrotic syndrome, ALP- liver/bone marrow involvement, elevated serum calcium and sodium, hypoglycemia (due to presence of insulin auto antibodies) </li></ul><ul><li>HIV test : as anti retroviral therapy can improve outcome in +ve pts </li></ul><ul><li>Serum cytokines: IL 6, IL 10 & soluble CD 25 (IL 2 receptor) </li></ul>
  10. 10. INVESTIGATIONS <ul><li>CECT- chest, abdomen & pelvis to look for LAP, splenomegaly with or without focal parenchymal abnormality, lung nodules or parenchymal infiltrates, mediastinal mass (LAP) </li></ul><ul><li>Mediastinal LAP is a very common finding in classic HD but uncommon in NLPHD </li></ul><ul><li>Gallium 67 scan/PET scan. PET scan is more sensitive than Ga 67 scan </li></ul><ul><li>A pretreatment scan is valuable as a baseline comparison for PET scan obtained to assess response to therapy </li></ul><ul><li>Staging laparotomies (biopsy of liver, splenectomy & biopsy from multiple lymph nodes i.e. para aortic, mesenteric, portal & splenic hilar region if enlarged) were once popular for most patients with HD but are now done rarely because of an increased reliance on systemic rather than local therapy. The procedure can be helpful in rare cases where radio therapy is considered as sole t/t of early stage HD </li></ul><ul><li>Other tests: pleural tap, lumbar puncture where indicated </li></ul><ul><li>A histological diagnosis is always required: excision LN Bx is required as LN architecture is important for histological classification </li></ul><ul><li>In neck LAP due to H&N cancer FNA is advised as initial diagnostic step f/b excisional biopsy if squamous cell histology is excluded </li></ul>
  11. 11. UNFAVORABLE FACTORS IN EARLY STAGE HD <ul><li>These helps in whether a pt has high or lo risk of proving resistant to therapy. following factors are considered unfavorable for pt with stage 1 or 2 disease & if present will increase the intensity of recommended initial therapy: </li></ul><ul><ul><ul><ul><ul><li>Bulky disease: defined as mediastinal mass >1/3 of intra thoracic diameter on CXRAY or >35% of thoracic diameter at vertebral level T5-6 or >10 cm in diameter on ct scan </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>ESR ≥ 50 if pt is otherwise asymptomatic </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>> 3 sites of HD involvement </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>The presence b symptoms </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>The presence of extra nodal disease </li></ul></ul></ul></ul></ul>
  12. 12. INTERNATIONAL PROGNOSTIC SCORE FOR ADVANCED HD <ul><li>It is a survey of characteristics at diagnosis & outcome of 5,141 HD pts with either advanced stage disease (stage 3 or 4) or earlier stage with systemic features or bulky disease. Of the following characteristics each contribute independently to an increased risk for HD progression despite therapy: </li></ul><ul><ul><ul><ul><ul><li>S. albumin <4g/dl </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hb <10.5g/dl </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Male sex </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Stage 4 disease </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Age ≥ 45 yrs </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>WBC count ≥ 15,000 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Lymphocytes count < 600/mm³ or < 8% of total count </li></ul></ul></ul></ul></ul><ul><li>IPS 0-1: 90% overall survival rates, ≥ 4 only 59% </li></ul>
  13. 13. PRINCIPAL OF THERAPY <ul><li>Advances in t/t have sought: minimize t/t given to pts with early stage low risk disease & safely maximize t/t for pts with disease refractory to standard therapies </li></ul><ul><li>Combined modality therapy (CMT): radio therapy (XRT) & chemotherapy is preferred approach in most pts </li></ul><ul><li>Early stage: CMT has synergistic effect limits total exposure to any on agent </li></ul><ul><li>Advanced stage: involved field XRT used for sites of persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a standard feature of Stanford V regimen </li></ul><ul><li>A +ve PET scan following therapy correlates strongly with high risk of relapse , an early attainment of -ve PET scan in ABVD therapy is a +ve prognostic indicator </li></ul><ul><li>PET/CT scans should be obtained at least 3 weeks & preferably 6-8 weeks following last therapy </li></ul>
  14. 14. GOAL OF THERAPY <ul><li>To induce a complete remission (CR) which is “disappearance of all evidence of disease” evaluated by PET/CT, physical examination & BM examination (if appropriate) </li></ul><ul><li>A partial response (PR) IS “regression of measurable disease & no new site of disease” </li></ul><ul><li>Despite high rate of cure many HD pts relapse: in these salvage chemotherapy f/b high dose chemotherapy with autologous stem cell support is indicated </li></ul><ul><li>NLPHD is clinically distinct from classic HD , presents at early stage which can be treated with local measures (surgery / radiation) or followed expectantly, some cases can transform into aggressive NHL </li></ul>
  15. 15. RADIATION THERAPY <ul><li>Classic HD: in combination with chemotherapy involved field RT (encompasses only areas of observed disease) is used, in regional field therapy adjacent lymph regions are also involved </li></ul><ul><li>Other fields of historical interests are: Mantle field – covering mediastinal cervical & axillary nodes. Inverted Y field – covering para aortic, pelvic & inguinal nodes. Sub-total nodal irradiation – mantle field + para aortic nodes </li></ul><ul><li>Doses in CMT are: 30-36 Gy for bulky disease 20-30 Gy for non bulky disease, when used alone doses are – 30-40 Gy </li></ul><ul><li>NLPHD: involved field radiotherapy is recommended for stage 1A & 2A </li></ul>
  16. 16. CHEMOTHERAPY <ul><li>Induction regimens are those which are given as initial HD t/t: </li></ul><ul><ul><ul><ul><ul><li>MOPP: (mechlorethamine, vincristine, procarbazine, prednisone) was first effective therapy developed by Vincent Devita at national cancer institute in mid 1960s & is primarily of historical importance </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>ABVD (adriamycin, bleomycin, vincristine, dacarbazine): designed in Italy by Gianni Bonadonna in early 1970s, now standard regimen for HD, superior to MOPP in terms of disease free survival & has lower incidence of sterility & secondary leukemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Stanford V: created at Stanford university by Sandra Honning, comprises: doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide & prednisone. Administered weekly alternating myelosuppressive & non myelosuppressive agents for two weeks. Involved field RT at the conclusion of 12 weeks regimen is an important part of this regimen. Advantages – broad spectrum of drugs, limits exposure & potential side effects of any single drug </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>BEACOPP ( bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone): developed in Germany by Valker Diehl. Dose intensified version of BEACOPP with higher doses of etoposide, adriamycin, and cyclophosphamide & addition of G-CSF for neutrophil support (called ESCALATED BEACOPP) is useful in unfavorable advanced HD but it is associated with greater hematologic toxicity & higher incidence of secondary malignancies including AML </li></ul></ul></ul></ul></ul>
  17. 17. SALVAGE CHEMOTHERAPY <ul><li>Pts who failed induction are candidate for this </li></ul><ul><li>Includes drugs complementary to those failed during induction </li></ul><ul><li>Commonly used regimens are: ICE (ifosfamide, carboplatin, etoposide) & ESHAP (etoposide, methylprednisolone, cytaarabine, cisplatin) </li></ul><ul><li>High dose chemotherapy with BM transplantation: HDC ablates BM then reinfusion of pts own hematopoietic stem cells (HSC) or donor’s stem cells is done, HSC are obtained by pheresis of peripheral blood lymphocytes </li></ul><ul><li>Conditioning regimen used is BEAM (BCNU, etoposide, cytaarabine, melphalan). HSC are administered on day 0 following BEAM. </li></ul>
  18. 18. STAGE WISE MANAGEMENT <ul><li>EARLY STAGE LOW RISK DISEASE: includes stage 1A or 2A classic HD without unfavorable factors – generally receives 4 cycles of ABVD or 8 cycles of Stanford V f/b involved field radiotherapy. If RT contraindicated or not possible then 2 additional cycles of chemotherapy to be given following attainment of CR </li></ul>
  19. 19. INTERMEDIATE STAGE <ul><li>EARLY STAGE WITH UNFAVOURABLE FACTORS: includes stage 1 or 2 with bulky disease with or without unfavorable factors – 4-6 cycles of ABVD or 12 weeks Stanford V f/b involved field RT </li></ul>
  20. 20. ADVANCED OR HIGH RISK DISEASE <ul><li>Include stage 1 or 2 with B symptoms or stage 3 or 4 </li></ul><ul><li>NCCN (national comprehensive cancer network) guidelines – either 4 cycles of ABVD or 12 weeks of Stanford V f/b restaging with PET/CT scan, if pt has +ve results following ABVD additional 2 cycles are given once CR achieved involved field RT is given. If after 12 weeks of Stanford V pt is in CR or PR then involved field RT is given </li></ul><ul><li>EMSO (European society for molecular oncology) recommends – 8 cycles of ABVD or standard dose BEACOPP with involved RT applied only to tumors initially >7.5 cm or to sites of residual disease following chemotherapy </li></ul>
  21. 21. NLPHD <ul><li>Early stage: local excision or involved field RT or expectant management. Advanced stage treated as NHL with regimen R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) </li></ul>
  22. 22. HD WITH HIV <ul><li>Treated simultaneously with HAART (2 NRTI+1PI+1NNRTI) </li></ul>
  23. 23. RELAPSED OR PRIMARY REFRACTORY DISEASE <ul><li>HD which has never entered CR or relapsed after CR – HDC with HSC transplantation is done </li></ul><ul><li>Steps: salvage chemotherapy -> CR (IF POSSIBIE) -> collect HSC from pts blood freeze them -> give myeloablative chemotherapy BEAM -> transfuse pt’s HSC into blood -> if HDC fails -> allogenic HSC tranplantation </li></ul>
  24. 24. FOLLOW UP OF PATIENTS <ul><li>Most relapse in first 3 yrs after therapy </li></ul><ul><li>Follow every 2-4 mths for first 1-2 years & every 3-6 mths for next 3-5 yrs </li></ul><ul><li>FU examinations: </li></ul><ul><ul><ul><ul><ul><li>History & physical examination </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>CBC, LDH, ESR, glucose, lipids </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>TSH: annually in pts of H&N RT </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>CXRay & CT scan of chest every 3-6 mths for first 2-3 yrs then at least annually up to 5 yrs </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Abdomen & pelvis CT every 3-12 mths (if indicated) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>PET scan not specifically recommended </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Spiral CT chest 5 yrs after for lung cancer </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Mammography in female pts annually from 40 yrs or 5-8 yrs after RT </li></ul></ul></ul></ul></ul>
  25. 25. LATE COMPLICATIONS OF THERAPY <ul><li>Treatment related causes exceeds HD as predominant causes of death at 15 yrs, these include: </li></ul><ul><ul><ul><ul><ul><li>Cardiac diseases </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pulmonary fibrosis </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Secondary cancer / leukemia: low risk with current regimen . MDS / acute leukemia seen in first 3-8 yrs following t/t </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Breast cancer: mantle radiation, MOPP </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Solid tumors: most common secondary malignancy following HD is lung cancer </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Infertility: MOPP – permanent, not permanent with ABVD & Stanford V </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>INFECTIONS </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hypothyroidism </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Lhermite syndrome </li></ul></ul></ul></ul></ul>
  26. 26. CURRENT CLINICAL RESEARCH <ul><li>Three current trials analyze combined modality protocols comparing ABVD with more intense regimens : EORTC, H9V & GHSD HD11. studies are comparing 4 cycles of ABVD with 4 cycles of BEACOPP & RT is limited to involved field at dose of 20-30 Gy </li></ul><ul><li>Milan trial sufficiently answered that radiation fields can be reduced to the involved sites after adequate chemotherapy </li></ul>
  27. 27. FUTURE STRATEGIES FOR ADVANCED STAGE HD <ul><li>The aim of any modern t/t in such cases is to: maintain good results with current therapies, reaching cure rates of >85% but reduce the still too high acute and lng term toxicity </li></ul>
  28. 28. DO WE NEED CONSOLIDATED RADIATION? <ul><li>EORTC trial demonstrated that after reaching a CR after 8 cycles of effective chemotherapy do not benefits from additive RT </li></ul><ul><li>80% of secondary AML/MDS in this study were seen in RT arm, PR pts however showed benefit from complimentary radiation & fared as good as primary CR pts </li></ul><ul><li>GHSG HD12 study demonstrated that after 8 cycles of chemotherapy there was no difference b/w RT or non RT arms </li></ul><ul><li>HD 15 trial of GHSG that only pts with PET +ve residual disease are treated with 30 Gy radiation </li></ul><ul><li>Therefore consolidated RT should only be given to HD pts that only reached a PR after 6-8 course of ABVD or have a minor response (<70%) with residual nodal lesion </li></ul><ul><li>Using an escalated BEACOPP for advanced HD only a minority (<20%) pts need RT to residual lesions <2.5 cm, PET imaging might help to distinguish b/w scar and vital tumor tissue in residual lesion </li></ul>
  29. 29. THANK YOU
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