Hodgkin lymphoma

Hodgkin lymphoma (HL) is a malignant lymphoma of B-cell origin. Incidence follows a bimodal age distribution, with peaks in the third, and sixth to eighth decades of life. The WHO classifies HL as either classical HL (CHL) or nodular lymphocyte predominant HL (NLPHL). Most patients (95%) with HL have CHL, which includes four histological subtypes: nodular sclerosing CHL (most common), mixed cellularity CHL, lymphocyte-rich CHL, and lymphocyte-depleted CHL. Risk factors for HL include Epstein-Barr virus (EBV) infection and immunodeficiency (e.g., due to HIV infection). Clinical features of HL include painless lymphadenopathy, hepatosplenomegaly, and B symptoms. Pel-Ebstein fevers and alcohol-induced pain in affected lymph nodes are rare but specific features of HL. Excisional biopsy of an affected lymph node or extranodal site is required to confirm the diagnosis; Hodgkin cells and Reed-Sternberg cells are present in CHL and popcorn cells are present in NLPHL. Staging is performed using the Lugano classification, which incorporates histopathology results, the presence of B symptoms, and PET-CT scan findings. Additional prognostic factors are used for risk stratification to guide treatment. Typically, limited-stage HL is treated with chemotherapy and radiation therapy, while advanced-stage HL is treated with chemotherapy alone. Overall, the prognosis is good with treatment. Patients require ongoing management for HL to monitor for disease recurrence and treatment-related complications (e.g., second cancers, cardiovascular disorders).

• Incidence
  • 2–3/100 000 per year [1]
  • Subtype variance with age (see “Pathology” below)
    • Young adults: nodular sclerosing HL
    • Elderly adults: mixed-cellularity HL
• Age: bimodal distribution [2]
  • 1^st peak: 25–30 years
  • 2^nd peak: 50–70 years
• Sex: ♂ > ♀ [2]
  • Male predominance, especially in pediatric cases
  • Exception: ♀ = ♂ in nodular sclerosing HL (most common type)

Epidemiological data refers to the US, unless otherwise specified.

The exact causes are unknown, but several risk factors have been associated with HL. [3][4]

• Strong association with Epstein-Barr virus (EBV)
• Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infection , chemotherapy
• Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis)

• Painless lymphadenopathy:
  • First develops in a single group of lymph nodes; : typically cervical; , supraclavicular, or mediastinal lymph nodes [5][6][7]
  • Spreads contiguously through the lymphatic system: cervical nodes → supraclavicular lymph nodes → axillary nodes → inguinal nodes [8]
• Splenomegaly or hepatomegaly [9]
• B symptoms [10]
  • Night sweats, weight loss > 10% in the past 6 months, fever > 38.0°C (> 100.4°F)
  • Can occur in a variety of diseases (see “Differential diagnosis of B symptoms” below)
  • In the case of confirmed HL, the presence of a single B symptom suffices for a positive diagnosis of B symptoms.
• Pel-Ebstein fever: intermittent fever with periods of high temperature for 1–2 weeks, followed by afebrile periods for 1–2 weeks; relatively rare but very specific for HL
• Alcohol-induced pain: pain in involved lymph nodes after ingestion of alcohol; relatively rare but highly specific for HL
• Pruritus: focal or generalized

• Biopsy is required to confirm the diagnosis of HL in patients with unexplained lymphadenopathy with or without B symptoms.
• Once the diagnosis is confirmed, further studies, including PET-CT, are required for staging of HL.

Initial studies

Laboratory studies and imaging are not required for diagnosis but are commonly performed for the evaluation of lymphadenopathy and B symptoms.

Laboratory studies

• CBC with differential [6]
  • Elevated or decreased WBC count [11]
  • Anemia
  • Eosinophilia
  • Thrombocytosis or thrombocytopenia
• CMP
  • Elevated transaminases and/or hyperbilirubinemia [12][13]
  • Elevated alkaline phosphatase [12]
  • Hypoalbuminemia [11]
  • Hypercalcemia (uncommon) due to paraneoplastic production of 1,25-dihydroxyvitamin D [12][14]
• ESR: elevated [6][12]
• LDH: elevated [12]

Imaging

• Ultrasound or CT scan: Consider in individuals with palpable lymphadenopathy and/or hepatosplenomegaly.
• CXR: Consider in individuals with generalized lymphadenopathy to evaluate for mediastinal lymphadenopathy.

Anemia, leukocytosis, leukopenia, elevated ESR, elevated LDH, and hypoalbuminemia are all poor prognostic factors.

Confirmatory biopsy [6][8][15]

• Modalities
  • Gold standard: excisional biopsy of an involved lymph node or extranodal site
  • Alternative: core needle biopsy
• Findings
  • Hodgkin cells and Reed-Sternberg cells: CHL
  • Popcorn cells: NLPHL

Excisional biopsy is the gold standard for diagnosing HL. [8]

Fine-needle aspiration is not recommended for suspected HL, as it cannot obtain sufficient tissue. [6][12]

Differential diagnoses of B symptoms

• Non-Hodgkin lymphomas, Hodgkin lymphomas
• Other hematopoietic malignancies (e.g., CML, ALL)
• Solid tumors
• Tuberculosis
• HIV

Hodgkin vs. non-Hodgkin lymphoma

Other differential diagnoses

• “Differential diagnoses of lymphadenopathy”
• “Differential diagnoses of granulomatous disease”

The differential diagnoses listed here are not exhaustive.

• Reed-Sternberg cells (RSCs)
  • Tumor cells that are pathognomonic of HL
  • Originate from B cells
  • Large cells with binuclear/bilobed nuclei with dark centers of chromatin and pale halos, which result in an owl-eye appearance on histopathologic examination.
  • CD15/CD30-positive
• Hodgkin cells: mononuclear, malignant B lymphocytes
• Inflammatory background containing the following cell types in varying numbers: lymphocytes, neutrophils, eosinophils, macrophages/histiocytes, plasma cells, and fibroblasts
• Granuloma formation

Reed-Sternberg cells are bi(2)nucleate with CD15/CD30 positivity. To recall the cell markers, remember that 2 x 15 = 30.

Lugano classification of lymphomas [9]

• The Lugano classification is used for staging of HL and staging of NHL.
• Imaging with PET-CT or CT scan is required. [9][18][19]

Staging of HL is based on the number of affected nodes, the presence or absence of B symptoms, and whether or not the disease is present on both sides of the diaphragm.

Individuals who have undergone PET-CT do not routinely require bone marrow biopsy. [6][15][20]

Bone marrow biopsy is only indicated for staging if PET-CT scan imaging is unavailable or if there is evidence of bone marrow infiltration, e.g., CBC with pancytopenia, and the PET-CT scan does not demonstrate bone marrow involvement. [8][9]

Following Lugano classification, patients are assessed for the presence or absence of prognostic factors to make risk-based treatment decisions. [8][15][21]

Unfavorable prognostic factors for limited-stage HL [6][20][21]

All patients with limited-stage HL are assessed for unfavorable prognostic factors. [8][15]

• Risk factors
  • High ESR [8][12]
  • High LDH [22]
  • B symptoms
  • Involvement of > 3 lymph node areas
  • ≥ 1 extranodal site
  • Bulky disease
  • Age ≥ 50 years
• Interpretation
  • Limited-stage favorable HL: Limited-stage HL without unfavorable prognostic factors
  • Limited-stage unfavorable HL: Limited-stage HL with unfavorable prognostic factors

International prognostic score (IPS) for advanced-stage HL

All patients with advanced-stage HL (i.e., Lugano classification III or IV) are assessed with the international prognostic score to guide treatment. [11][15][21]

• Risk factors: One point is given for each risk factor.
  • Hypoalbuminemia (< 4 g/dL)
  • Hemoglobin < 10.5 g/dL
  • Male sex
  • Age ≥ 45 years
  • Lugano classification stage IV
  • WBC ≥ 15,000/mm³
  • Lymphopenia: lymphocyte count < 8% or absolute lymphocyte count < 600/mm³
• Interpretation: Scores are used to estimate the freedom from progression (FFP) and overall survival (OS) at 5 years. [23][21]
  • IPS score 0–1: FFP ≥ 77%, OS ≥ 89%
  • IPS score 2–3: FFP ∼60–67%, OS ∼ 78-81%
  • IPS score 4–7: FFP < 51%, OS ≤ 61%

Newer prediction models, e.g., the Advanced-stage cHL International Prognostication Index (A-HIPI), may be more accurate than the IPS due to improvements in treatment options. [23][24]

Approach [15][18]

The following is performed by, or in coordination with, the patient's oncology team.

• Select a risk-based treatment option. Treatment for CHL includes: [25]
  • Limited-stage favorable HL: short courses of chemotherapy plus radiation therapy [15]
  • Limited-stage unfavorable HL: may be treated with longer courses of chemotherapy ± radiation therapy [15][26]
  • Advanced-stage HL: longer courses of chemotherapy without radiation therapy [15][21]
• Perform a pretreatment evaluation.
  • All patients: routine preparation for cancer treatment, including screening studies for pregnancy and underlying comorbidities
  • Doxorubicin candidates: ECHO [15]
  • Bleomycin candidates: pulmonary function testing with DLCO [27]
  • Splenic radiation candidates: additional vaccinations as part of infection prevention for asplenia [28][29]
• Provide ongoing supportive care.
  • After treatment, provide long-term management for HL.
  • See “Principles of cancer care” for information on multidisciplinary care, common cancer-related symptoms, and treatment-related complications.

HL treatment has high cure rates. For all stages of HL, the initial goal of treatment is remission. [8]

Chemotherapy [15][18][20]

• First-line treatment for all patients is typically ABVD: Adriamycin^® (doxorubicin), bleomycin, vinblastine, and dacarbazine. [6][12][15]
• Alternative treatments (e.g., in advanced-stage or refractory HL)
  • Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone
  • BEACOPP: bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin^® (vincristine), procarbazine, and prednisone

Radiation therapy [20][25]

• Indication: patients with limited-stage HL, after chemotherapy [6][25]
• Radiation should target involved lymph nodes and/or extranodal sites. [6]

Other treatments [15][20][25]

• Autologous stem cell transplantation: may be used after high-dose chemotherapy in patients with relapsed or refractory disease
• Immunotherapy (e.g., brentuximab, nivolumab, or pembrolizumab) may be used for:
  • Initial treatment of advanced HL
  • Prevention of relapse after autologous stem cell transplantation
  • Management of relapsed or refractory disease

Survivors of HL are at risk of disease recurrence (especially in the first 5 years after treatment) and long-term treatment-related complications. Counseling and screening are required to prevent and identify complications. [18]

Follow-up schedule [18]

• Oncology follow-up
  • Years 1–2: every 3–6 months
  • Year 3: every 6–12 months
  • Years ≥ 4: annually
• If cancer-free after 5 years, the primary care provider may take over annual follow-up care.

Screening [18][30]

Preventative health considerations

• Immunizations [18][35]
  • During treatment: Vaccinations are typically not recommended; inactivated seasonal vaccinations may be given if indicated.
  • After completion of treatment: Resume routine immunizations (3 months after chemotherapy, 6 months after immunotherapy).
  • Individuals with HSCT or functional asplenia: Evaluate the need for additional vaccines and boosters.
• Counsel on smoking cessation. [12]

• Overall, HL has a good prognosis with a 5-year survival rate of ∼ 80–90% (in children, > 95%). [18][20][36]
  • Lymphocyte-rich classical HL (LRHL) and nodular lymphocyte predominant HL (NLPHL) have the best prognoses among HL subtypes. [37][38]
  • Prognosis is largely determined by disease stage.
• There is an increased risk for treatment-related second malignancies (e.g., breast, lung, colorectal). [39]