Hodgkin lymphoma

Hodgkin lymphoma (HL) is a malignant lymphoma that is typically of B-cell origin. The incidence of HL has a bimodal age distribution, with peaks in the 3^rd and 6^th–8^th decades of life. The WHO classifies HL into two types: classical HL (CHL) and nodular lymphocyte-predominant HL (NLPHL). CHL is further divided into four subtypes, which are nodular sclerosis (most common), mixed cellularity, lymphocyte-depleted, and lymphocyte-rich CHL. Risk factors for developing HL include a history of infectious mononucleosis caused by the Epstein-Barr virus (EBV) and immunodeficiency (e.g., HIV infection). HL typically presents with painless cervical lymphadenopathy, fever, night sweats, and involuntary weight loss. Pel-Ebstein fevers (cyclical fever with periods of both high and normal temperature) and alcohol-induced pain at affected lymph nodes are less common but specific for HL. Suspicious lymph nodes are excised and definitive diagnosis is made via histological analysis, which characteristically reveals pathognomonic Reed‑Sternberg cells (malignant B-cells). The modified Ann Arbor classification (Cotswold staging system) is used to stage HL based on both the localization of the lymphoma with respect to the diaphragm and on the presence of systemic symptoms. Treatment is typically initiated with curative intent. In early stages, treatment is generally limited to involved-field radiation and chemotherapy. In later stages, when local radiation is often unsuccessful or not feasible due to tumor spread, polychemotherapy is the mainstay of treatment.

• 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
  • Cervical lymph nodes (in ∼ 60–70% of patients) > axillary lymph nodes (in ∼ 25–35% of patients) > inguinal lymph nodes (in ∼ 8–15% of patients) ^[5]
  • Involvement of a single group of lymph nodes
  • Contiguous pattern of lymph node spread
  • Mediastinal mass → chest pain, dry cough, and shortness of breath
  • Splenomegaly or hepatomegaly may occur if the spleen or liver are involved.
• B symptoms ^[5]
  • Night sweats, weight loss > 10% in the past 6 months, fever > 38°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)

Hodgkin vs. non-Hodgkin lymphoma

Differential diagnoses of lymphadenopathy

Examining lymph nodes can yield important diagnostic clues. Generalized lymphadenopathy is usually a sign of systemic illness, such as HIV, mycobacterial infection (e.g., tuberculosis), infectious mononucleosis, systemic lupus erythematosus, or serum sickness. Signs of malignancy include rapid growth, painlessness, hardness/coarseness, and being fixed to underlying or surrounding tissue. Most often, though, there is no discernible cause or pathology.

Differential diagnosis of B symptoms

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

Differential diagnosis of granulomatous disease

• See “Differential diagnosis of granulomatous disease.”

The differential diagnoses listed here are not exhaustive.

Diagnosis of HL is primarily based on medical history and clinical features (B symptoms, localization of lymph node involvement) and is confirmed with lymph node biopsy.

Blood tests

• Complete blood count
  • Elevated or decreased WBC count
  • Anemia
  • Eosinophilia
• Serum chemistry
  • ↑ LDH
  • Hypercalcemia; : most commonly due to paraneoplastic production of 1,25-dihydroxyvitamin D

Histology

• Obligatory diagnostic step
• Lymph node excision
  • 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 results 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.

Imaging

• Chest x-ray or CT-scan: detection and measurement of masses and enlarged lymph nodes in chest, abdomen, and pelvis
• Bone scintigraphy or PET-CT: performed before treatment to assess disease spread

• Early stage (I and II): combination of chemotherapy and radiation therapy
  • The most widely used chemotherapy approach is ABVD: adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
• Advanced stage (III and IV and often II with bulky disease): combination chemotherapy with radiation therapy in select cases
  • Three possible treatment approaches are commonly considered:
    • ABVD
    • Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone
    • BEACOPP: bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (vincristine), procarbazine, prednisone
• Primary refractory or relapsed disease: trial of alternative chemotherapy or consideration of high-dose chemotherapy and autologous stem cell transplantation

Independent of stage, treatment is typically initiated with curative intent.

• Good prognosis
  • 5-year survival rate ∼ 80–90% (in children > 90%)
  • Best prognosis: lymphocyte-rich classical HL and (LRHL) and nodular lymphocyte predominant HL (NLPHL)
• Prognosis is largely determined by disease stage (i.e., lower stage has a better prognosis)
• ∼ 10–20% of patients will develop secondary malignancies (especially lung cancer; related to radiation therapy and chemotherapy) ^[8]
• Unfavorable factors for Hodgkin lymphoma (relevant when selecting a treatment regimen)
  • High ESR
  • High LDH
  • Involvement of three or more lymph node areas
  • Large mediastinal tumor
  • Bulky disease (tumors measuring ≥ 10 cm across) ^[9][10]
• International Prognostic Score (IPS): evaluation of prognosis in patients with advanced disease (for each factor present, the patient receives one point)
  • IPS factors
    • Albumin < 4 g/dL
    • Hemoglobin < 10.5 g/dL
    • Gender ♂
    • Age ≥ 45 years
    • Stage IV disease
    • Leukocytosis: white cell count (WBC) > 15,000/μL
    • Lymphopenia: lymphocyte count < 8% of WBC count and/or absolute lymphocyte count < 600 cells/μL
  • IPS categories: Based on the calculated IPS, patients can be categorized as follows:
    • Good prognosis (IPS 0–1)
    • Fair prognosis (IPS 2–3)
    • Poor prognosis (IPS 4–7)

Staging 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.