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Hodgkin's disease (Hodgkin's lymphoma)

Etiology: - currently thought that Hodgkin's disease may be a heterogenous disease derived from subpopulations of activated B-cells. activated T-cells & dendritic cells [3] Classification: - not a true lymphoma - malignant cells are not of lymphocytic origin Histology prevalence prognosis lymphocyte predominance 2-10% excellent nodular sclerosis 40-80% very good mixed cellularity 20-40% good lymphocyte depletion 2-15% poor Epidemiology: - seasonal variation in incidence & mortality - incidence in March is 15% higher than in September - seasonal variations more pronounced at high latitudes [22] Pathology: - lymph node biopsy - presence of Reed-Sternberg cells (RSC) is pathognomonic - number of infiltrating malignant macrophages (RSC) identified by CD68 immunohistochemistry correlates with treatment failure [6] - vitamin D may play a protective role [22] Genetics: - implicated genes: - CD302, LY75, CLIP1, LGALS9 Clinical manifestations: 1) palpable lymphadenopathy, generally painless a) most commonly involves neck b) cervical, supraclavicular, mediastinal lymphadenopathy 2) B symptoms - fever, night sweats (Pel-Epstein fever), weight loss 3) hepatomegaly 4) splenomegaly 5) malaise 6) persistent, non-productive cough 7) pruritus may be a presenting symptom [25] 8) pain associated with alcohol ingestion (may be due to eosinophil infiltration) [5] Laboratory: 1) complete blood count (CBC) 2) liver function tests (LFTs) 3) renal function tests (BUN & serum creatinine) 4) uric acid 5) C-reactive protein, erthrocyte sedimentation rate 6) screening for viral infections - screening for hepatitis B - screening for hepatitis C - screening for HIV1 6) tests which may be useful a) cell surface marker phenotype analysis b) gene rearrangement analysis c) delayed hypersensitivity status d) polymerase chain reaction (PCR) detects Epstein-Barr virus in 60-80% of patients Special laboratory: 1) surgical excisional lymph node biopsy to examine lymph node architecture (essential) 2) bone marrow biopsy, essential for a) B symptoms b) stage 3 or 4 disease [3] c) not necessary if PET scan & blood work are negative [3,23] 3) may be indicated (not routine [3]) a) liver biopsy b) exploratory or staging laparotomy no longer performed [3] c) splenectomy no longer performed [3] 4) pulmomary function testing prior to treatment [23] 5) cardiac stress testing prior to treatment [23] Radiology: 1) essential a) chest radiograph: may show mediastinal mass b) CT of neck, CT of thorax, CT of abdomen & pelvis with contrast c) whole body PET scan [3] if available [23] - interim PET scan predictive of outcome in patients treated with ABVD [14,16] d) CT/PET used to stage Hodgkin's disease [3] e) negative PET scan may obviate need for bone marrow biopsy 2) may be indicated a) lymphangiogram b) gallium scan c) bone scan d) bone radiographs e) ultrasonography f) magnetic resonance imaging Staging: - PET scan - see staging of lymphoma Differential diagnosis: 1) non-Hodgkin's lymphoma 2) sarcoidosis 3) infections (CMV, EBV, HIV, toxoplasmosis) 4) drug reaction 5) see lymphadenopathy Complications: 1) radiation therapy can result in acute & late complications a) mantle irradiation: - acute complications: - dry mouth - pharyngitis - fatigue - weight loss - Lhermitte's syndrome - paresthesias in the lower extremities with neck flexion - generally spontaneously resolves - pneumonitis (< 5%) - pulmonary fibrosis (< 1%). - late complications: - pericardial effusions - myocardial injury, coronary artery disease (RR=3) heart failure (RR=7) [15] - risk persists after 35 years [15] - valvular heart disease - hypothyroidism (30%) - emergence of 2nd-cancers - estimated increased risk is 4.6 fold [19] - breast cancer is the most common solid tumor* - lung cancer - skin cancer - leukemia, myelodysplastic syndrome -> AML - thyroid cancer 10-fold risk [19] - non-Hodgkin's lymphoma - mesothelioma - esophageal cancer - pancreatic cancer - gastrointestinal cancer [19] - increased second cancer risk persists for 35 years mostly due to radiation therapy [19] - no evidence that modern techniques of volume- & dose-limiting radiation reduce 2nd-cancer risk [19] b) para-aortic irradiation: - rarely associated with side effects c) pelvic irradiation: - acute complications: - diarrhea - bladder irritation - chronic complications: - bone marrow suppression - sterility 2) abnormal T-cell function with infection due to: - intracellular pathogens - Mycobacterium tuberculosis - Listeria - Salmonella - Cryptococcus - Mycobacterium avium 3) treatment confers increased risk for non-Hodgkin's lymphoma [3] * chemotherapy does not increase risk of breast cancer [3] Management: 1) general a) all patients with Hodgkin's disease should be treated with the intent to cure b) chemotherapy all patients, regardless of stage [3] - chemotherapy may cure 50% of patients with disseminated disease - complete response by PET scan after 2-3 cycles of chemotherapy may allow some patients with early stage Hodgkin's disease to forego radiation therapy [3] c) radiation may cure 80% of patients with localized disease - early-stage nodular Hodgkins' disease may be treated with radiation alone - outdated recommendation - chemotherapy all patients, regardless of stage [3] - more advanced stages should be treated with rituximab with chemotherapy [3] d) combination of chemotherapy + radiation therapy for early disease [3] e) risk-adapted regimens to avoid radiation & alkylating agents, whenever possible [19] 2) management of early disease [14] a) favorable prognosis - 2 cycles of ABVD plus 2000 cGy of radiation - if PET scan is negative after 2 cycles of chemotherapy for early-stage disease, > 90% likelihood of long-term response - these patients may forgo radiation [3] - 4-6 cycles of ABVD without radiation is an option [3] b) unfavorable prognosis (advanced disease or B-symptoms) - 4 cycles of ABVD plus 3000 cGy of radiation - 2 cycles of escalate BEACOPP + 2 cycles of ABVD + 3000 cGy of radiation (alternate) c) omission of radiation for non-bulky stage 1A/2A should be done only after consultation with radiation oncologist - these patients should receive at least 2-3 cycles of ABVD & interim CT/PET [3] d) assess for pulmonary toxicity prior to administration of bleomycin (component of ABVD & BEACOPP) e) patients age 16-60 years with advanced Hodgkin's disease should receive either - 6-8 cycles of ABVD - 6 cycles of escalated BEACOPP f) patients treated with ABVD should be considered for radiation therapy to sites of residual bulk > 1.5 cm on CT - unclear in PET scan negative patients benefit - PET scan positive patients should be biopsied or followed closely clinical/radiologic g) patients who progress on therapy should be considered for treatment intensification with transplantation 3) treatment based on stage (older recommendations) - see historical management of Hodgkin's disease 4) radiation therapy: a) up to 4000 cGy administered 1000 cGy per week b) since Hodgkin's disease spreads largely via lymphatics, 3 types of radiation fields were developed: - mantle: includes submandibular, cervical, supraclavicular, infraclavicular, axillary, mediastinal, & hilar lymph nodes - paraaortic: includes transverse processes of abdominal vertebral bodies & spleen - pelvic: includes common iliac, hypogastric, external iliac, & inguinal nodes c) when there is gross pelvic involvement, femoral nodes are also irradiated d) when pelvic & paraaortic fields are treated as a unit, the field is called an inverted Y field e) palliative radiation for - airway obstruction - spinal cord compression f) patients with stage IA or IIA Hodgkin's lymphoma (localized node involvement) treated with mantle or paraaortic radiation have up to 80% long term disease-free survival g) patients with stage IB & IIB have 70% survival h) patients with extensive mediastinal involvement tend to do worse i) patients who relapse with radiation therapy frequently respond to chemotherapy 5) chemotherapy a) ABVD (adriamycin, bleomycin, vinblastine, & dacarbazine) is preferred 1st line treatment [3] - 4 cycles of ABVD - 2-3 cycles may be sufficient for early stage (stage I & II) Hodgkin's disease [3,7,9] - toxicities of ABVD are similar to MOPP, but may beassociated with fewer secondary malignancies, but increased incidence of myocardial & pulmonary damage (see historical management of Hodgkin's disease for MOPP) - brentuximab vedotin (Adcetris) FDA-approved for relapse or refractory Hodgkin's lymphoma - bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine & prednisone (BEACOPP) for patients with disease activity demonstrated on PET scanafter 3 cycles of ABVD [3,8] - do not use (BEACOPP) in patients > 60 years of age [23] b) chemotherapy alone (without radiation) for stage 3 or 4 c) brentuximab vedotin, doxorubicin, vinblastine, & dacarbazine (A+AVD) superior to ABVD (5% disease progression, death) inpatients with advanced Hodgkin's disease [20] 6) chemotherapy + radiation a) ABVD chemotherapy + involved field radiation for stage 1 & 2 b) ABVD chemotherapy + mediastinal radiation for bulky mediastinal disease c) superior to radiation therapy alone [23] 7) stem cell transplantation a) refer all patients < 70 years of age to a transplantation center b) indicated after the 1st relapse from any 1st line treatment for Hodgkin's disease c) autologous hematopoietic stem-cell transplantation for recurrent chemotherapy-sensitive Hodgkin's disease [3] d) allogeneic hematopoietic stem-cell transplantation for recurrent Hodgkin's disease resistant to salvage chemotherapy e) high-dose chemotherapy followed by autologous stem cell transplantation for relapse [17] f) brentuximab vedotin for stem cell transplantation failure - nivolumab & pembrolizumab are approved for the treatment of patients with disease recurrence on brentuximab vedotin 8) reproductive counseling & consideration - sperm cryopreservation prior to therapy if man wishes to preserve fertility - oocyte collection, or ovarian tissue cryopreservation should be offered to women of reproductive age before treatment [23] 9) follow-up a) look for second cancer (see complications) b) mammography, MRI or both begun at age 40 or 8 years following radiation therapy* [3] c) women who received chest wall radiation* between age 10-30 are at high risk for breast cancer* - annual mammograms & breast MRI recommended [3,18] d) all post-radiation patients with chest pain should be evaluated for coronary artery disease regardless of age [3] * chemotherapy does not increase risk of breast cancer [3]

Interactions

disease interactions

Related

historical management of Hodgkin's disease Reed-Sternberg cell staging of lymphoma vaccination in patients with Hodgkin's disease

Specific

Hodgkin's disease, lymphocyte depleted type Hodgkin's disease, lymphocyte predominant type Hodgkin's disease, mixed cellularity type Hodgkin's disease, nodular sclerosing type nodular sclerosis

General

lymphoma (lymphosarcoma)

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1782, 1786
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 423-26
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 539
  5. Ferri's Clinical Advisor, Instant Diagnosis and Treatment, Ferri FF (ed), Mosby, Philadelphia, 2003
  6. Steidl C, Lee T, Shah SP et al Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med 2010 Mar 11; 362:875. PMID: 20220182 Free PMC Article http://content.nejm.org/cgi/content/full/362/10/875
  7. Engert A et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med 2010 Aug 12; 363:640. PMID: 20818855
  8. Kostakoglu L, Coleman M, Leonard JP et al PET predicts prognosis after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin's disease. J Nucl Med. 2002 Aug;43(8):1018-27. PMID: 12163626
  9. Ferme C, Eghbali H, Meerwaldt JH et al Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. PMID: 17989384
  10. Gallamini A, Hutchings M, Rigacci L et al Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 2007 Aug 20;25(24):3746-52. Epub 2007 Jul 23. PMID: 17646666
  11. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med. 1998 Nov 19;339(21):1506-14. PMID: 9819449
  12. Adams MJ, Lipsitz SR, Colan SD et al Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol. 2004 Aug 1;22(15):3139-48. PMID: 15284266
  13. Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol. 2011 Jul;154(1):23-31 PMID: 21539537
  14. Anello J, Feinberg B, Heinegg J, Lindsey R, Wojdylo C, Wong O. Medcsape Oncology. August 2014 Guidelines for Hodgkin lymphoma from British Committee for Standards in Haematology http://reference.medscape.com/features/slideshow/guidelines-review/august2014
  15. van Nimwegen FA et al Cardiovascular Disease After Hodgkin Lymphoma Treatment. 40-Year Disease Risk. JAMA Intern Med. Published online April 27, 2015 PMID: 25915855 http://archinte.jamanetwork.com/article.aspx?articleid=2278950 - Tonorezos E, Overholser L Caring for the Adult Survivor of Hodgkin Lymphoma. Highlighting the Need for Care Coordination. JAMA Intern Med. Published online April 27, 2015 PMID: 25915209 http://archinte.jamanetwork.com/article.aspx?articleid=2278946
  16. Kostakoglu L, Goldsmith SJ, Leonard JP et al FDG-PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease. Cancer. 2006 Dec 1;107(11):2678-87 PMID: 17063502
  17. Rancea M, Monsef I, von Tresckow B, Engert A, Skoetz N. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev. 2013 Jun 20;6:CD009411 PMID: 23784872
  18. Swerdlow AJ, Cooke R, Bates A et al Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. J Clin Oncol. 2012 Aug 1;30(22):2745-52 PMID: 22734026
  19. Schaapveld M, Aleman BM, van Eggermond AM et al Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma. N Engl J Med. 2015 Dec 24;373(26):2499-511 PMID: 26699166 - Radford J, Longo DL. Second Cancers after Treatment for Hodgkin's Lymphoma - Continuing Cause for Concern. N Engl J Med. 2015 Dec 24;373(26):2572-3 PMID: 26699173
  20. Connors JM, Jurczak W, Straus DJ et al Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med. Dec 10, 2017 PMID: 29224502 http://www.nejm.org/doi/full/10.1056/NEJMoa1708984 - Longo DL, DeVita DT Jr. Progress in the Treatment of Hodgkin's Lymphoma. N Engl J Med. Dec 10, 2017 PMID: 29224505 http://www.nejm.org/doi/full/10.1056/NEJMe1715141
  21. Hoppe RT, Advani RH, AI WZ, et al. NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018. J Natl Compr Canc Netw. 2018 Mar;16(3):245-254. PMID: 29523663 http://www.jnccn.org/content/16/3/245.long
  22. Minerd J. Expert critique by Taylor J Hodgkin Lymphoma Risk: 'Intriguing' Early Links Suggestive of Season Patterns, Role for Vitamin D Relates to biological evidence that vitamin D enhances antibody-dependent cellular cytotoxicity by rituximab. MedPage Today. ASCO Reading Room 06.06.2018 https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/73311 - Borchmann S, Muller H, Engert A. Hodgkin lymphoma has a seasonal pattern of incidence and mortality that depends on latitude. Sci Rep. 2017 Nov 2;7(1):14903. PMID: 29097683 Free PMC Article
  23. Eichenauer Da, Aleman BMP, Andre M, et al. Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. May 23, 2018. PMID: 29796651 https://academic.oup.com/annonc/advance-article/doi/10.1093/annonc/mdy080/4999396
  24. Ansell SM. Hodgkin Lymphoma: Diagnosis and Treatment. Mayo Clin Proc. 2015 Nov;90(11):1574-83. Review. PMID: 26541251
  25. Deng J et al. Risk of hematologic cancer in patient with undifferentiated pruritis. JAMA Dermatol 2022 Jul; 158:791. PMID: 35612839 PMCID: PMC9134041 (available on 2023-05-25) https://jamanetwork.com/journals/jamadermatology/fullarticle/2792454

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