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Hodgkin Lymphoma
Jennifer J. Gao, MD
Fred J. Schiffman, MD
image BASICS
Historical background:
  • Described in 1832 by Thomas Hodgkin in “On some morbid appearance of the absorbent glands and spleen”
  • First neoplasm to be (i) defined by cytologic grounds based on presence of Reed-Sternberg (RS) cells, (ii) clinically staged neoplastic disease, and (iii) treated with chemotherapy and/or radiotherapy
  • Neoplastic RS cells of monoclonal lymphoid B-cell origin within inflammatory background of lymphocytes (T-helper type 2 and regulatory T cells), eosinophils, histiocytes, and plasma cells (1,2)
  • Two subtypes: classic Hodgkin lymphoma (CHL, 95% of cases) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL, 3-8% of cases) (1)
    • NLPHL: B cells, neoplastic luteinizing hormone (LH) cells with multilobulated nuclei, small nucleoli, and popcorn-like appearance
    • CHL histologic subdivisions: nodular sclerosing (60%), mixed cellularity (30%), lymphocyte depleted (<10%), lymphocyte rich (<10%)
    • Frequency of lymph node involvement: cervical > mediastinal > axillary > paraaortic
  • Incidence: 2.8/100,000/year
  • Predominance: 8% of lymphoid malignancies (1)
Geriatric Considerations
Poorer prognosis if present at ≥ 60 years:
  • Less likely to tolerate intensive chemotherapy
  • Less likely to be included in clinical trial
Pediatric Considerations
Young females (<30 years of age) treated with thoracic radiation are at high risk for breast cancer, and early breast cancer screening is recommended.
Pregnancy Considerations
  • Abdominal ultrasonography to detect subdiaphragmatic disease
  • Treatment:
    • Delay until after delivery if asymptomatic and early-stage
    • ABVD safely used in 2nd and 3rd trimesters
    • Vinblastine monotherapy to control symptoms
    • 1st trimester: ABVD may or may not cause fetal malformations.
  • ~9,000 new cases in the United States annually
  • Mean age at diagnosis: 38 years
  • Hodgkin is most common in early adulthood (15 to 40) and then again after age 55 years.
˜190,000 living with Hodgkin lymphoma in the United States in 2012
  • RS cells likely derived from germinal center B cells with mutations in immunoglobulin variable chain
  • Seasonal features and higher frequencies with Epstein-Barr virus (EBV) suggest environmental factors.
  • T-lymphocyte defects persist even after successful treatment.
  • Human leukocyte antigen (HLA) is strongly associated with increased risk (2).
  • EBV positivity associated with increased risk (2)
  • Genome-wide association studies identified 19p13.3 at intron 2 of TCF3.
  • First-degree relative: 3 to 9 times risk
  • Siblings of younger patients: 7 times risk
  • Weak correlation between familial HL and HLA class I regions containing HLA A1, B5, B8, B18 alleles
  • Immunodeficiency (inherited or acquired)
  • Autoimmune disorders
  • EBV (2)
  • Seasonal factors
  • AIDS-defining illness
  • Predominantly mixed-cellularity or lymphocytedepleted histologic subtypes
  • At diagnosis: widespread disease, extranodal involvement, systemic symptoms
Focus on lymph nodes, spleen, and liver.
Non-Hodgkin lymphoma, infectious lymphadenopathy, solid tumor metastases, sarcoidosis, autoimmune disease, AIDS/HIV, drug reaction
Initial Tests (lab, imaging)
  • CBC and electrolytes
  • LFT, including hepatitis serologies
  • HIV
  • Pregnancy test
  • Pulmonary function tests (diffusion capacity of the lung for carbon monoxide for ABVD or BEACOPP)
  • Chest x-ray
  • CT of chest, abdomen, and pelvis
  • PET: for initial staging, midtreatment decision making, and end-of-treatment evaluation
  • Bone scan, gallium scan, abdominal ultrasound
  • EBV (2)
Follow-Up Tests & Special Considerations
  • Fertility considerations:
    • Semen cryopreservation if chemotherapy or pelvic radiation therapy
    • In vitro fertilization or ovarian tissue/oocyte cryopreservation
  • Radiation therapy (RT) considerations:
    • Splenic RT: pneumococcal, Haemophilus influenzae, meningococcal vaccine
Diagnostic Procedures/Other
  • Excisional lymph node biopsy
  • Immunohistochemistry
  • Bone marrow biopsy
  • Liver biopsy (in selected cases)
Test Interpretation
RS cell characteristics include the following:
  • Diameter: 20 to 50 &mgr;m
  • Abundant acidophilic cytoplasm
  • Bi- or polylobulated nucleus
  • Acidophilic nucleoli
  • CD30+, CD15+, CD45-, CD3-, CD20+ in 40% of cases
  • RS cells necessary but not sufficient for diagnosis (needs inflammatory background)
  • Ann Arbor staging with Cotswold modification
    • Stage I: single lymph node or of a single extralymphatic organ or site
    • Stage II: ≥2 lymph node regions on the same side of diaphragm alone or with involvement of extralymphatic organ or tissue
    • Stage III: node groups on both sides of the diaphragm
    • Stage IV: dissemination involving extranodal organs (except the spleen, which is considered lymphoid tissue)
    • Subclasses: A = no systemic symptoms; B = systemic symptoms (fever, night sweats, weight loss >10% body weight); X = bulky disease (widened mediastinum, > intrathoracic diameter, or >10-cm nodal mass)
    • Pathologic stage at given site denoted by: M = bone marrow, H = liver, L = lung, O = bone, P = pleura, D = skin:
      • Splenectomy, liver biopsy, lymph node biopsy, bone marrow biopsy mandatory for pathologic staging
  • Goal: Aim for cure.
  • All subsequent treatment and follow-up care recommendations based on National Comprehensive Cancer Network (NCCN) consensus. Please refer to NCCN Practice Guidelines in Oncology for Hodgkin lymphoma.
First Line
  • ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine:
    • Highly emetic, severe phlebitis
    • Monitor cardiac function on doxorubicin.
    • Dacarbazine cannot be omitted without loss of efficacy (3).
  • BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone:
    • Bleomycin: risk of pulmonary toxicity, death; test dose may be administered prior to first cycle
  • Stage I/II with no risk factors: two cycles ABVD followed by 20 Gy involved field radiotherapy (IFRT)
  • Stage I/II with risk factors (large mediastinal mass, unfavorable histology, age, extranodal disease, erythrocyte sedimentation rate (ESR), B symptoms, number of nodal areas): four cycles chemotherapy (BEACOPP and/or ABVD) followed by 30 Gy IFRT
  • Stage III/IV: four to six cycles chemotherapy (BEACOPP and/or ABVD) and consider autologous stem cell transplant (SCT) or radiotherapy
  • P.491

  • Relapsed and refractory: high-dose conditioning therapy (HDCT) followed by autologous SCT:
    • Maintenance therapy: trials with brentuximab vedotin (anti-CD30) and lenalidomide under way
    • Brentuximab vedotin: anti-CD30, use in relapsed HL after two prior lines of treatment have been tried, side effects include peripheral neuropathy, nausea, fatigue, neutropenia, diarrhea (4)
    • Allogeneic SCT to be considered if failed autologous SCT (used in trials only)
    • Consolidation with brentuximab vedotin after autologous SCT improves progression free survival in those at risk for relapse or progression after transplantation (5).
Second Line
  • Median survival <3 years if fail second-line therapy, including SCT
  • SCT in progressive disease or relapse:
    • High-dose chemotherapy and autologous stem cell transplant (HDCT/autoSCT): improved eventfree and progression-free survival compared with conventional chemotherapy but not overall survival; can achieve disease-free survival in 30-40% of patients after alloSCT (6,7)
    • Reduced intensity conditioning (RIC) with bischloroethylnitrosourea (BCNU), etoposide, cytarabine, melphalan (BEAM) followed by allogeneic transplant (alloSCT) to induce graft-versus-tumor (GVT) effect in patients who have relapsed after autoSCT, complete response seen in 81%, nonrelapse mortality of 13% at 1 year, 1-year relapse rate of 36% (6,8)
  • Rituximab: excellent activity against lymphocytepredominant variant due to CD20+ lymphocytes
  • Brentuximab vedotin: anti-CD30 chimeric antibody conjugated to synthetic antimicrotubule agent monomethyl auristatin E:
    • Approved by the U.S. Food and Drug Administration (FDA) in 2011 for patients who failed/not candidate for SCT or failure of two prior multiagent chemotherapy regimens
  • Nivolumab: anti-PD1 therapy with response in 20 out of 23 patients (9)
  • Novel agents undergoing studies: NF-&kgr;B inhibitors (bortezomib), mammalian target of rapamycin (mTOR) inhibitors (everolimus), immunomodulators (lenalidomide), cell signaling targets histone deacetylase (HDAC) inhibitors (vorinostat, panobinostat, mocetinostat)
Patient Monitoring
  • During therapy: CBC, nutrition, and hydration
  • Restage with PET after two to four cycles of chemotherapy: sensitive prognostic indicator
  • Posttreatment monitoring:
    • History and physical (H&P): q2-4mo for first 2 years, then q3-6mo for next 3 to 5 years
    • Laboratory studies
      • CBC, platelets, ESR, chemistry profile q2-4mo for 1 to 2 years, then q3-6mo for next 3 to 5 years
      • Thyroid-stimulating hormone (TSH) annually if radiation to neck
    • Imaging:
      • Chest: chest x-ray or CT q6-12mo during first 2 to 5 years
      • Abdominal/pelvic: CT q6-12mo during first 2 to 3 years
      • Annual breast mammogram or MRI beginning 8 to 10 years after therapy or at age 40 years if chest or axillary irradiation
      • Surveillance PET should not be done routinely due to risk of false-positive findings.
  • Splenic irradiation or splenectomy as part of Hodgkin treatment increases risk of secondary cancers (leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, solid cancers) (10).
  • Reproductive impact
  • Risks of secondary malignancy
  • Oral and dental care during therapy
  • Leukemia & Lymphoma Society (http://www.lls.org/)
  • Cure rate for classic Hodgkin lymphoma: 80%
  • Relapse or progression of disease rate: 5-20%
  • Overall survival rates:
    • 1-year survival: 92%
    • 5-year survival: 85%
    • 10-year survival: 81%
  • International prognostic score for advanced disease:
    • Age ≥45 years
    • Male gender
    • Albumin <4 g/dL
    • Hemoglobin <10.5 g/dL
    • Lymphocytopenia: <600 lymphocyte cells/dL or lymphocytes <8% of WBC
    • WBC ≥15,000 cells/dL
    • Stage IV disease
  • Main cause of death
    • Initial 5 years: Hodgkin lymphoma
    • After 5 to 10 years: leukemia, myelodysplastic syndrome
    • After 20 years: second primary malignancy, cardiovascular disease
1. Goel A, Fan W, Patel AA, et al. Nodular lymphocyte predominant Hodgkin lymphoma: biology, diagnosis and treatment. Clin Lymphoma Myeloma Leuk. 2014;14(4):261-270.
2. Cozen W, Timofeeva MN, Li D, et al. A metaanalysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun. 2014;5:3856.
3. Behringer K, Goergen H, Hitz F, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385(9976):1418-1427.
4. Siddiqi T, Thomas SH, Chen R. Role of brentuximab vedotin in the treatment of relapsed or refractory Hodgkin lymphoma. Pharmgenomics Pers Med. 2014;7:79-85.
5. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
6. Lim AB, Ritchie DS. Hodgkin lymphoma, allogeneic transplant and the graft-versus-tumor effect: size does matter. Leuk Lymphoma. 2014;55(6):1223-1224.
7. Rancea M, von Tresckow B, Monsef I, et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed or refractory Hodgkin lymphoma: a systematic review with meta-analysis. Crit Rev Oncol Hematol. 2014;92(1):1-10.
8. Sobol U, Rodriguez T, Smith S, et al. Sevenyear follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. Leuk Lymphoma. 2014;55(6):1281-1287.
9. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319.
10. Mosalpuria K, Loberiza F Jr. Splenectomy and second malignancies in patients with Hodgkin lymphoma: is there a causal relationship? Leuk Lymphoma. 2015;56(1):10-11.
Additional Reading
  • Armitage JO. Early-stage Hodgkin's lymphoma. N Engl J Med. 2010;363(7):653-662.
  • Borchmann P, Eichenauer DA, Engert A. State of the art in the treatment of Hodgkin lymphoma. Nat Rev Clin Oncol. 2012;9(8):450-459.
  • Czuczman M, Straus D, Gribben J, et al. Management options, survivorship, and emerging treatment strategies for follicular and Hodgkin lymphomas. Leuk Lymphoma. 2010;51(Suppl 1):41-49.
  • Dinner S, Advani R. Targeted therapy in relapsed classical Hodgkin lymphoma. J Natl Compr Canc Netw. 2013;11(8):968-976.
  • National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER stat fact sheet: Hodgkin lymphoma. http://seer.cancer.gov/statfacts/html/hodg.html.
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Hodgkin lymphoma. Version 2. 2013. http://www.nccn.org/.
  • von Tresckow B, Engert A. Refractory Hodgkin lymphoma. Curr Opin Oncol. 2013;25(5):463-469.
  • C81.90 Hodgkin lymphoma, unspecified, unspecified site
  • C81.91 Hodgkin lymphoma, unsp, lymph nodes of head, face, and neck
  • C81.92 Hodgkin lymphoma, unspecified, intrathoracic lymph nodes
Clinical Pearls
  • Neoplastic disease of lymphatics
  • RS cells of monoclonal lymphoid B-cell origin within inflammatory background of lymphocytes
  • Two subtypes: CHL, 95% of cases and NLPHL, 5% of cases
  • Cure rate for CHL: 80%
  • 5-year survival: ˜86%
  • Relapse or progression of disease rate: 5-20%
  • Immunotherapy with PD1 blockade currently underway and promising