Hodgkin lymphoma results from the clonal transformation of cells of B-cell origin, giving rise to pathognomic binucleated Reed-Sternberg cells. The cause is unknown, but genetic susceptibility and environmental associations (eg, occupation, such as woodworking; history of treatment with phenytoin, radiation therapy, or chemotherapy; infection with Epstein-Barr virus, Mycobacterium tuberculosis, herpesvirus type 6, HIV) play a role. Risk is slightly increased in people with certain types of immunosuppression (eg, posttransplant patients taking immunosuppressants); in people with congenital immunodeficiency disorders (eg, ataxia-telangiectasia, Klinefelter syndrome, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome); and in people with certain autoimmune disorders (RA, celiac sprue, Sjögren syndrome, SLE).

Most patients also develop a slowly progressive defect in cell-mediated immunity (T-cell function) that, in advanced disease, contributes to common bacterial and unusual fungal, viral, and protozoal infections. Humoral immunity (antibody production) is depressed in advanced disease. Death often results from sepsis.

Most patients present with painless cervical adenopathy. Although the mechanism is unclear, pain may occur in diseased areas immediately after drinking alcoholic beverages, thereby providing an early indication of the diagnosis.

Other manifestations develop as the disease spreads through the reticuloendothelial system, generally to contiguous sites. Intense pruritus may occur early. Constitutional symptoms include fever, night sweats, and unintentional weight loss (> 10% of body weight in previous 6 mo), which may signify involvement of internal lymph nodes (mediastinal or retroperitoneal), viscera (liver), or bone marrow. Splenomegaly is often present; hepatomegaly may be present. Pel-Ebstein fever (a few days of high fever regularly alternating with a few days to several weeks of normal or below-normal temperature) occasionally occurs. Cachexia is common as disease advances.

Bone involvement is often asymptomatic but may produce vertebral osteoblastic lesions (ivory vertebrae) and, rarely, pain with osteolytic lesions and compression fracture. Intracranial, gastric, and cutaneous lesions are rare and when present suggest HIV-associated Hodgkin lymphoma.

Local compression by tumor masses often causes symptoms, including

Epidural invasion that compresses the spinal cord may result in paraplegia. Horner syndrome and laryngeal paralysis may result when enlarged lymph nodes compress the cervical sympathetic and recurrent laryngeal nerves. Neuralgic pain follows nerve root compression.

Hodgkin lymphoma is usually suspected in patients with painless lymphadenopathy or mediastinal adenopathy detected on routine chest x-ray. Similar lymphadenopathy can result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, non-Hodgkin lymphoma, or leukemia. Similar chest x-ray findings can result from lung cancer, sarcoidosis, or TB (for evaluation of a mediastinal mass, see Mediastinal Masses : Diagnosis).

A chest x-ray is obtained if not already done. X-ray is usually followed by lymph node biopsy if findings are confirmed with CT or PET scan of the chest. If only mediastinal nodes are enlarged, mediastinoscopy or Chamberlain procedure (a limited left anterior thoracostomy allowing biopsy of mediastinal lymph nodes inaccessible by cervical mediastinoscopy) may be indicated. CT-guided biopsy may also be considered, but results of fine-needle aspiration are often inaccurate, so node core biopsy is needed. CBC, alkaline phosphatase, and kidney and liver function tests are generally done. Other tests are done depending on findings (eg, MRI for symptoms of cord compression).

Biopsy reveals Reed-Sternberg cells (large, binucleated cells) in a characteristically heterogeneous cellular infiltrate, consisting of histiocytes, lymphocytes, monocytes, plasma cells, and eosinophils. Classic Hodgkin lymphoma has 4 histopathologic subtypes (see Histopathologic Subtypes of Hodgkin Lymphoma (WHO Classification)); there is also a lymphocyte-predominant type. Certain antigens on Reed-Sternberg cells may help differentiate Hodgkin lymphoma from non-Hodgkin lymphoma, and classic Hodgkin lymphoma from the lymphocyte-predominant type.

Other test results may be abnormal but are nondiagnostic. CBC may show slight polymorphonuclear leukocytosis. Lymphocytopenia may occur early and become pronounced with advanced disease. Eosinophilia is present in about 20% of patients, and thrombocytosis may be present. Anemia, often microcytic, usually develops with advanced disease. In advanced anemia, defective iron reutilization is characterized by low serum iron, low iron-binding capacity, and increased bone marrow iron. Pancytopenia is occasionally caused by bone marrow invasion, usually by the lymphocyte-depleted type. Hypersplenism (see Hypersplenism) may occur in patients with marked splenomegaly. Elevated serum alkaline phosphatase levels may be present, but elevations do not always indicate bone marrow or liver involvement. Increases in leukocyte alkaline phosphatase, serum haptoglobin, and other acute-phase reactants usually reflect active disease.

In classic Hodgkin lymphoma, disease-free survival 5 yr after therapy is considered a cure. Relapse is very rare after 5 yr. Chemotherapy with or without radiation therapy achieves cure in 70 to 80% of patients. Increased potential for relapse depends on many factors, including male sex, age > 45 yr, involvement of multiple extranodal sites, and presence of constitutional symptoms at diagnosis. Patients who do not achieve complete remission or who relapse within 12 mo have a poor prognosis.

The choice of treatment modality is complex and depends on the precise stage of disease. Before treatment, men should be offered sperm banking, and women should discuss fertility options with their oncologists.

Stage IA, IIA, IB, or IIB disease is generally treated with an abbreviated chemotherapy regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) plus radiation therapy or with longer-course chemotherapy alone. Such treatment cures about 80% of patients. In patients with bulky mediastinal disease, chemotherapy may be of longer duration or of a different type, and radiation therapy is typically used.

Stage IIIA and IIIB disease is usually treated with ABVD combination chemotherapy alone. Cure rates of 75 to 80% have been achieved in patients with stage IIIA disease, and rates from 70 to 80% in patients with stage IIIB disease.

For stage IVA and IVB disease, ABVD combination chemotherapy is the standard regimen, producing complete remission in 70 to 80% of patients; > 50% remain disease-free at 5 yr. Other effective drugs include nitrosoureas, ifosfamide, procarbazine, cisplatin or carboplatin, and etoposide. Other drug combinations are bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (known as BEACOPP), and melchlorethamine, doxorubicin, vinblastine, vincristine, etoposide, bleomycin, and prednisone (known as Stanford V). Standford V incorporates involved field irradiation for consolidation.

Autologous transplantation using peripheral stem cell products should be considered for all physiologically eligible patients with relapsed or refractory Hodgkin lymphoma who respond to salvage chemotherapy.