At the time of diagnosis of hodgkin’s lymphoma, which of the following areas is often involved?

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 typically include painless lymphadenopathy, sometimes with fever, night sweats, unintentional weight loss, pruritus, splenomegaly, and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is curative in most cases and consists of chemotherapy with or without other treatment modalities, including antibody-drug conjugates, immunotherapy, and radiation therapy.

In the US, about 8,000 new cases of Hodgkin lymphoma are diagnosed annually, and about 900 people die of the disease. 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 play a role. eg, Environmental associations connected with Hodgkin lymphoma include history of treatment with phenytoin, radiation therapy, or chemotherapy and 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

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

• 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.

• Lymph node biopsy

• FDG-PET/CT of chest, abdomen, and pelvis for staging

• MRI if neurologic symptoms are present

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

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

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 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

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 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

Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more

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 thoracoscopy (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)

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

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.

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.

• Symptoms

• Physical examination findings

• Results of imaging tests, including CT of the chest, abdomen, and pelvis, and functional imaging with FDG-PET

Laparotomy is not required for staging.

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

• Presence of bulky disease

• ≥ 4 nodal sites involved

• Age > 50 years

• 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

• Signs of tumor-induced inflammation (low albumin, anemia, leukocytosis, and lymphopenia)

However, selection of which risk factors to use in estimating prognosis is still subject to revision. Patients who do not achieve complete remission with treatment or who relapse within 12 months have a poor prognosis.

• Chemotherapy

• Antibody-drug conjugate (eg, brentuximab vedotin)

• Immunotherapy (eg, immune checkpoint inhibitors)

• Radiation therapy

• Sometimes autologous stem cell transplantation

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.

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, 3 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

). Bleomycin is generally avoided in patients >60 years due to increased risk of pulmonary toxicity, and optimal management of older or frail patients is not standardized.

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, defined as reappearance of disease at sites of prior disease or at new sites, should have imaging with PET/CT or CT alone. Routine, scheduled imaging in asymptomatic patients is not mandatory. For a schedule of posttreatment surveillance, see table Hodgkin Lymphoma Posttreatment Surveillance Hodgkin Lymphoma Posttreatment Surveillance

.

• 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 examination.

• Biopsy shows pathognomonic, binucleated Reed-Sternberg cells.

• Most patients are cured using combination chemotherapy and sometimes additional systemic therapies or radiation therapy.

• Subsequent therapeutic options include high-dose chemotherapy, autologous stem cell transplantation, or brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab.

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