(See also Overview of Lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma and non-Hodgkin lymphoma (see table Comparison of... read more .)
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] Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more , Mycobacterium tuberculosis Tuberculosis (TB) Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more , herpesvirus type 6 Overview of Herpesvirus Infections Eight types of herpesviruses infect humans (see Table: Herpesviruses That Infect Humans). After initial infection, all herpesviruses remain latent within specific host cells and may subsequently... read more , HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ) play a role. Risk is slightly increased in people with
Certain types of immunosuppression (eg, posttransplant patients taking immunosuppressants)
Congenital immunodeficiency disorders (eg, ataxia-telangiectasia Ataxia-Telangiectasia Ataxia-telangiectasia results from a DNA repair defect that frequently results in humoral and cellular deficiency; it causes progressive cerebellar ataxia, oculocutaneous telangiectasias, and... read more , Klinefelter syndrome Klinefelter Syndrome (47,XXY) Klinefelter syndrome is the presence of two or more X chromosomes plus one Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis... read more , Chédiak-Higashi syndrome Chédiak-Higashi Syndrome Chédiak-Higashi syndrome is a rare, autosomal recessive syndrome characterized by impaired lysis of phagocytized bacteria, resulting in recurrent bacterial respiratory and other infections and... read more , Wiskott-Aldrich syndrome Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome results from a combined B- and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. (See also Overview of Immunodeficiency Disorders... read more )
Certain autoimmune disorders (rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily involves the joints. RA causes damage mediated by cytokines, chemokines, and metalloproteases. Characteristically... read more , celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more , Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes due... read more , systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more )
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 Lymphedema Lymphedema is edema of a limb due to lymphatic hypoplasia (primary) or to obstruction or disruption (secondary) of lymphatic vessels. Symptoms and signs are brawny, fibrous, nonpitting edema... read more ) 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 Diagnosis reference Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more ). Similar lymphadenopathy can result from viral infections such as infectious mononucleosis Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more (EBV) or cytomegalovirus (CMV) infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , toxoplasmosis Toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more , non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more , or leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more . Similar chest x-ray findings can result from lung cancer Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more , or tuberculosis Tuberculosis (TB) Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more . Evaluation of a mediastinal mass Diagnosis Mediastinal masses are caused by a variety of cysts and tumors; likely causes differ by patient age and by location of the mass (anterior, middle, or posterior mediastinum). The masses may be... read more 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 thorocoscopy (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 Histopathologic Subtypes of Hodgkin Lymphoma (WHO Classification) Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more ); 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 Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more , 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 Hypersplenism Hypersplenism is cytopenia caused by splenomegaly. (See also Overview of the Spleen.) Hypersplenism is a secondary process that can arise from splenomegaly of almost any cause (see table Common... read more 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.
After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table Lugano Staging of Hodgkin and Non-Hodgkin Lymphomas Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more ) incorporates
Laparotomy is not required for staging.
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 Radiation Therapy for Cancer Radiation therapy can cure many cancers (see also Overview of Cancer Therapy), particularly those that are localized or that can be completely encompassed within a radiation field. Radiation... read more . 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 Treatment references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more ). 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 Treatment references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more ).
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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more 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 Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more , coronary atherosclerosis Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle... read more and valvular heart disease Overview of Cardiac Valvular Disorders Any heart valve can become stenotic or insufficient (also termed regurgitant or incompetent), causing hemodynamic changes long before symptoms. Most often, valvular stenosis or insufficiency... read more . 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 Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more .
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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