(See also Overview of Lymphoma.)
In the US, about 8,000 new cases of Hodgkin lymphoma are diagnosed annually. The male:female ratio is 1.4:1. Hodgkin lymphoma is rare before age 10 and is most common between ages 15 and 40; a 2nd peak occurs in people > 60.
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 (eg, family history) and environmental associations (eg, occupation, such as woodworking); history of treatment with phenytoin, radiation therapy, or chemotherapy; infection with Epstein-Barr virus [EBV], Mycobacterium tuberculosis, herpesvirus type 6, HIV) play a role. Risk is slightly increased in people with
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 can result from infection or progressive disease.
Most patients with Hodgkin lymphoma present with painless cervical or axillary adenopathy. Although the mechanism is unclear, pain rarely may occur in diseased areas immediately after drinking alcoholic beverages, sometimes providing an early indication of the diagnosis.
Other manifestations develop as the disease spreads through the reticuloendothelial system, generally to contiguous sites. Intense pruritus refractory to usual therapies may occur early. Constitutional symptoms include fever, night sweats, and loss of appetite resulting in unintentional weight loss (> 10% of body weight in previous 6 months), which may signify involvement of internal lymph nodes (mediastinal or retroperitoneal), viscera (liver), or bone marrow. Splenomegaly is often present; hepatomegaly is unusual. 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 fractures. Intracranial, gastric, and cutaneous lesions are rare and when present can suggest uncontrolled HIV-associated Hodgkin lymphoma.
Local compression by tumor masses often causes symptoms, including
Jaundice secondary to intrahepatic or extrahepatic bile duct obstruction
Leg edema (lymphedema) secondary to lymphatic obstruction in the pelvis or groin
Severe dyspnea and wheezing secondary to tracheobronchial compression due to mediastinal disease
Lung cavitation or mass secondary to infiltration of lung parenchyma, which may simulate lobar consolidation or bronchopneumonia
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 physical examination or routine chest x-ray (1). Similar lymphadenopathy can result from viral infections such as infectious mononucleosis (EBV) or cytomegalovirus (CMV) infection, toxoplasmosis, non-Hodgkin lymphoma, or leukemia. Similar chest x-ray findings can result from lung cancer, sarcoidosis, or tuberculosis. Evaluation of a mediastinal mass is discussed elsewhere.
Chest x-ray or physical examination abnormalities should be confirmed with CT or positron emission tomography (PET) scan of the chest in order to choose the most efficient biopsy procedure. If only mediastinal nodes are enlarged, mediastinoscopy, video-assisted thoroscopy (VATS), or a Chamberlain procedure (a limited left anterior thoracostomy allowing biopsy of mediastinal lymph nodes inaccessible by cervical mediastinoscopy) may be indicated. CT-guided core needle biopsy may also be considered; fine-needle aspiration is often inadequate for the diagnosis of Hodgkin lymphoma.
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 table Histopathologic Subtypes of Hodgkin Lymphoma); there is also a nodular lymphocyte-predominant type that represents only about 5% of all Hodgkin lymphoma cases. Certain antigens on Reed-Sternberg cells may help differentiate Hodgkin lymphoma from non-Hodgkin lymphoma, and classic Hodgkin lymphoma from the nodular lymphocyte-predominant type.
Complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and kidney function and liver tests are generally done. Test results may be abnormal but are nondiagnostic.
CBC may show slight polymorphonuclear leukocytosis. Lymphocytopenia may occur early and is an adverse prognostic factor. 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, an elevated serum ferritin, and increased bone marrow iron. Pancytopenia is occasionally caused by bone marrow invasion, more commonly in the lymphocyte-depleted subtype.
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 the presence of inflammatory cytokines from active Hodgkin lymphoma. These tests are sometimes done to evaluate non-specific symptoms and can suggest Hodgkin lymphoma; they are not done on all lymphoma patients. Erythrocyte sedimentation rate (ESR), an indirect marker of inflammation, is more commonly ordered and predicts a less favorable outcome.
Hypersplenism may occur in patients with marked splenomegaly.
A combined fluorodeoxyglucose (FDG)-PET/CT scan of the chest, abdomen, and pelvis is the imaging study of choice for staging Hodgkin lymphoma (see below). Bone lesions are detected more commonly with the use of FDG-PET imaging. If combined FDG-PET/CT is not available, a contrast-enhanced CT scan of the chest, abdomen, and pelvis is done.
Other tests are done depending on findings (eg, MRI for symptoms of cord compression). A bone marrow biopsy is usually only done if a PET/CT scan is not obtained and if the findings might alter management. Other recommended tests include cardiac ejection fraction if the use of anthracyclines is anticipated and pulmonary function tests if bleomycin is being considered.
Histopathologic Subtypes of Hodgkin Lymphoma (WHO Classification)
After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table Lugano Staging of Hodgkin and Non-Hodgkin Lymphomas) incorporates
Physical examination findings
Results of imaging tests, including CT of the chest, abdomen, and pelvis, and functional imaging with FDG-PET
Sometimes bone marrow biopsy
Laparotomy is not required for staging.
Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma
1. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32(27):3059-3068, 2014.
About 85 to 90% of patients with limited-stage classic Hodgkin lymphoma are cured compared with 75 to 80% of patients with advanced-stage disease. Limited-stage disease is frequently subdivided into favorable and unfavorable prognostic groups. Unfavorable disease is based on risk factors, for example, the presence of bulky disease, ≥ 4 nodal sites involved, age > 50, and erythrocyte sedimentation rate (ESR) > 50 mm/hour with no B symptoms or > 30 mm/hour with B symptoms (weight loss, fever, or night sweats). Risk factors in advanced-stage Hodgkin lymphoma include male sex, age > 45 years, and signs of tumor-induced inflammation (low albumin, anemia, leukocytosis, and lymphopenia). However, which risk factors are recommended is still subject to revision. Patients who do not achieve complete remission with treatment or who relapse within 12 months have a poor prognosis.
The choice of treatment modality is complex and depends on the precise stage of disease. Before treatment and when applicable, men should be offered sperm banking, and women should discuss options to preserve fertility with their oncologists and a fertility specialist.
Limited-stage disease is generally treated with an abbreviated chemotherapy regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation therapy. In patients with bulky mediastinal disease, chemotherapy may be of longer duration or of a different type, and radiation therapy is often included.
Advanced-stage disease may be treated based on the findings of one of two large randomized trials. In the RATHL (Response-Adapted Therapy in Advanced Hodgkin Lymphoma) trial, patients were treated with ABVD, and those who had a negative PET scan after 2 cycles received 4 additional cycles with AVD (no bleomycin), while those who had a positive PET scan were escalated to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone—1). In the ECHELON-1 trial, patients treated with AVD plus the anti-CD30 antibody-drug conjugate brentuximab vedotin had superior outcomes to patients treated with ABVD, with higher-risk younger patients appearing to benefit more (2).
Multiple second-line chemotherapy regimens are considered acceptable for patients who are not cured with first-line therapy. For patients who achieve a good response to second-line therapy, high-dose chemotherapy and autologous stem cell transplantation should be considered.
Brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab are used for treatment of patients with Hodgkin lymphoma who have received at least 2 prior forms of therapy.
Chemotherapy, particularly with drugs such as the alkylating agents (mechlorethamine, cyclophosphamide, procarbazine), doxorubicin, and etoposide, increase the risk of leukemia between years 3 and 10 post-therapy. Radiation therapy carries increased risk of malignant solid tumors (eg, breast, gastrointestinal, lung, thyroid, soft tissue). Doxorubicin as well as mediastinal radiation increases the risk of cardiomyopathy, coronary atherosclerosis and valvular heart disease. Bleomycin can induce lung injury, which can be severe and rarely fatal.
All patients who are not PET-negative at the end of induction therapy should have a biopsy or be followed closely with serial imaging; if residual disease is present, additional treatment is necessary. Once in remission, patients should be followed for signs and symptoms of relapse for 5 years. Those with manifestations of relapse should have imaging with PET/CT or CT alone. Routine, scheduled imaging in asymptomatic patients is no longer considered mandatory. For a schedule of posttreatment surveillance, see table Hodgkin Lymphoma Posttreatment Surveillance.
Hodgkin Lymphoma Posttreatment Surveillance
1. Johnson P, Federico M, Kirkwood A, et al: Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med 374(25):2419– 2429, 2016.
2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 378(4):331–344, 2018. Epub 2017 Dec 10.
Hodgkin lymphoma is of B cell origin.
Patients usually present with painless lymphadenopathy or with incidental cervical or mediastinal adenopathy discovered on chest x-ray or physical exam.
Biopsy shows pathognomonic, binucleated Reed-Sternberg cells.
Most patients are cured using combination chemotherapy and sometimes additional systemic therapies or radiation therapy.
Brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab are newer therapies that are rapidly changing the landscape of therapy for Hodgkin lymphoma.
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