HODGKIN LYMPHOMA

Rory M. Shallis, MD • John L. Reagan, MD

 BASICS

DESCRIPTION

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

•  Two subtypes: classic Hodgkin lymphoma (CHL, 95% of cases) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, 3–8% of cases)

–  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

EPIDEMIOLOGY

•  Incidence: 2.8/100,000/year

•  Predominance: 8% of lymphoid malignancies

•  Typically diagnosed at age 20 to 34 years with mean age 39 years at diagnosis given decreasing bimodal age distribution

•  1.3:1 male-to-female ratio

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.

Incidence

Approximately 8,500 new cases in the United States annually

Prevalence

Approximately 220,000 living with Hodgkin lymphoma in the United States in 2015

ETIOLOGY AND PATHOPHYSIOLOGY

•  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 (1).

•  EBV positivity associated with increased risk

•  Genome-wide association studies identified 19p13.3 at intron 2 of TCF3.

Genetics

•  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

RISK FACTORS

•  Immunodeficiency (inherited or acquired)

•  Autoimmune disorders

•  EBV

•  Seasonal factors

COMMONLY ASSOCIATED CONDITIONS

In HIV:

•  AIDS-defining illness

•  Predominantly mixed-cellularity or lymphocyte-depleted histologic subtypes

•  At diagnosis: widespread disease, extranodal involvement, systemic symptoms

 DIAGNOSIS

HISTORY

•  Asymptomatic lymphadenopathy (cervical/supraclavicular)

•  Pel-Ebstein (cyclic) fever

•  Constitutional symptoms: night sweats, weight loss, fatigue, anorexia

•  Alcohol-induced pain

•  Pruritus

PHYSICAL EXAM

•  Lymphadenopathy 70% (cervical > supraclavicular > axillary)

•  Splenomegaly

•  Hepatomegaly

DIFFERENTIAL DIAGNOSIS

Non-Hodgkin lymphoma, infectious lymphadenopathy, solid tumor metastases, sarcoidosis, autoimmune disease, AIDS/HIV, drug reaction

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

•  CBC with differential

•  Comprehensive metabolic panel

•  LFT, LDH

•  ESR

•  HIV, EBV

•  Pregnancy test for women of childbearing age

•  Echocardiogram (in anticipation of treatment with anthracycline)

•  Pulmonary function tests (diffusion capacity of the lung for CO in anticipation of treatment with bleomycin)

•  Chest x-ray

•  CT with contrast of chest, abdomen, and pelvis

•  PET: for initial staging, midtreatment decision making, and end-of-treatment evaluation

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 if cytopenia with negative PET (2)

•  Liver biopsy (in selected cases)

Test Interpretation

RS cell characteristics include the following:

•  Diameter: 20 to 50 μm

•  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)

 TREATMENT

•  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 (>1/3 intrathoracic, diameter, or >10-cm nodal mass)

–  Classified into three groups: early stage (I or II) favorable, early stage unfavorable (presence of either B symptoms, large mediastinal adenopathy, 3 or more nodal sites of disease, extranodal involvements, or an ESR >50), or advanced stage (III or IV)

•  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.

MEDICATION

First Line

•  Stage IA/favorable: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) × 2 then 20 Gy involved site radiation therapy (ISRT) (1):

–  Highly emetic, severe phlebitis

–  Doxorubicin: risk of cardiotoxicity; monitor LVEF.

–  Bleomycin: risk of pulmonary toxicity, death; test dose may be administered prior to first cycle.

–  Dacarbazine cannot be omitted without loss of efficacy.

•  Stage IIA/favorable (same as for I) or ABVD × 3 + additional ABVD × 1 pending PET response +/− 30 Gy ISRT, or ABVD x 2 or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) × 2 + 30 Gy ISRT, or Stanford V × 8 weeks + 30 Gy ISRT

•  Stage I/II unfavorable/nonbulky: ABVD × 4 then ABVD × 2 +/− ISRT or Stanford V × 12 weeks + ISRT or BEACOPP + ISRT

•  Stage I/II unfavorable/bulky: same as for nonbulky but ABVD × 2 with ISRT or Stanford V × 12 with ISRT

•  Stage III/IV: ABVD × 2 then ABVD or BEACOPP × 4 +/− ISRT or Stanford V × 12 + ISRT unless refractory or BEACOPP × 6 +/− ISRT pending PET response

Second Line

•  Reserved for patients with relapse or disease refractory to first-line treatment

•  Standard is for chemotherapy agents not used for initial treatment and then high-dose therapy with autologous stem cell transplant (HDT/ASCT) +/− ISRT.

–  HDT/ASCT shows improved EFS/PFS compared with conventional chemotherapy but not overall survival; can achieve disease-free survival in 30–40% of patients after auto SCT

–  Allogeneic SCT to be considered if failed autologous SCT (used in trials only)

•  Brentuximab vedotin (anti-CD30 chimeric antibody conjugated to synthetic antimicrotubule agent monomethyl auristatin E) FDA approved for use as maintenance therapy × 1 year in relapsed HL after HDT/ASCT or failed two prior lines of multiagent chemotherapy. Improves PFS in those at risk for relapse or progression after transplantation (3). Recent phase II study data show 3-year OS and PFS rates were 73% and 58%, respectively (4,5).

–  Side effects include peripheral neuropathy, nausea, fatigue, neutropenia, diarrhea (4).

–  May also be used prior to HDT/ASCT to avoid toxicity with HDT (6)

•  Nivolumab (anti-PD1) may be used for patients who have failed HCT/ASCT and brentuximab vedotin therapy (6).

•  Rituximab may be considered as monotherapy or in combination with chemotherapy for refractory or relapsed lymphocyte-predominant/NLPHL (7).

•  Third-line novel agents undergoing studies: NF-κB inhibitors (bortezomib), mammalian target of rapamycin (mTOR) inhibitors (everolimus), immunomodulators (lenalidomide), cell signaling targets histone deacetylase (HDAC) inhibitors (vorinostat, panobinostat, mocetinostat)

•  Median survival <3 years if fail second-line therapy, including SCT

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

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): q3–6mo for first 2 years, then q6–12mo for next 3 to 5 years, then annually

–  Laboratory studies

  CBC, platelets, BMP, ESR (if elevated at time of diagnosis), as indicated clinically

  Thyroid-stimulating hormone (TSH) annually if radiation to neck

–  Imaging:

  CT is appropriate 6, 12, and 24 months posttreatment as well as when clinically indicated.

  Annual breast mammogram beginning 8 to 10 years after therapy or at age 40 years (whichever first) if chest or axillary irradiation (annual breast MRI as well if initially radiated between ages 10 and 30 years) according to American Cancer Society

  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) as well as encapsulated organism infection warranting pneumococcal, meningococcal, and H. influenzae vaccination 5 to 7 years posttreatment according to CDC guidelines.

•  Annual influenza vaccine

PATIENT EDUCATION

•  Reproductive impact

•  Risks of secondary malignancy

•  Oral and dental care during therapy

•  Leukemia & Lymphoma Society (http://www.lls.org/)

PROGNOSIS

•  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: 86% (91% if localized)

–  10-year survival: 80%

•  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

REFERENCES

1.  Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640–652.

2.  El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy had little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naïve patients with Hodgkin lymphoma. J Clin Oncol. 2012;30(36):4508–4514.

3.  Moskowitz CH, Nadamanee A, Masszi T, et al. The Aethera trial: results of a randomized, double-blind, placebo-controlled phase 3 study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma. Blood. 2014;124(21):673.

4.  Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(8):1236–1243.

5.  Chen RW, Palmer J, Martin P, et al. Results of a phase II trial of brentuximab vedotin as first line salvage therapy in relapsed/refractory HL prior to AHCT. Blood. 2014;124(21):501.

6.  Ansell S, Armand P, Timmerman JM. et al. Nivolumab in patients (Pts) with relapsed or refractory classical Hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow-up of a phase 1 study (CA209-039). Blood. 2015;126(23):583.

7.  Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2014;32(9):912–918.

ADDITIONAL READING

•  American Cancer Society. American Cancer Society Recommendations for Early Breast Cancer Detection in Women without Breast Symptoms. Atlanta, GA: American Cancer Society.

•  Centers for Disease Control and Prevention. Vaccines that Might Be Indicated for Adults Aged 19 Years or Older Based on Medical and Other Indications. Atlanta, GA: Centers for Disease Control and Prevention.

•  National Cancer Institute, Surveillance, Epidemiology, and End Results Program. SEER stat fact sheet: Hodgkin lymphoma. http://seer.cancer.gov/statfacts/html/hodg.html. Accessed November 2, 2016.

•  National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Hodgkin lymphoma. http://www.nccn.org/. Accessed November 25, 2016.

•  Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

 CODES

ICD10

•  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 CD30 and PD1 blockade currently underway and promising