Mediastinal Lymphoma 

Primary mediastinal B-cell lymphoma (PMBL) is a diffuse, large B-cell lymphoma (see image below), that arises in the thymus and mainly affects young adults. PMBL was recognized as a specific entity in the Revised European-American Classification of Lymphoid Neoplasms (REAL) and accounts for approximately 5% of all patients with aggressive lymphomas, a frequency roughly similar to that of Burkitt lymphoma and lymphoblastic lymphoma.

New evidence with gene expression profiling suggests that this disease may resemble Hodgkin lymphoma more than other types of diffuse large B-cell lymphoma.^{[1, 2, 3]} Because of its skewed age distribution, PMBL accounts for a much higher proportion of both younger patients and those undergoing autologous transplantation. Fifty to eighty percent of patients are cured with a modern intensive combination chemotherapy that is often followed by involved field radiation or autologous transplantation.

For more information, see B-Cell Lymphoma.

A rapidly proliferating tumor that arises in the anterior mediastinum, Primary mediastinal B-cell lymphoma (PMBL) often causes symptoms via the compression of intrathoracic structures (ie, superior vena cava syndrome) or via the invasion of lungs, pleura, and pericardium. Spread of disease to parenchymal organs, such as the liver, the kidneys, or the central nervous system, is common at the time of recurrence.^{[4, 5]}

Primary mediastinal B-cell lymphoma (PMBL) accounts for approximately 5% of the lymphomas in the Western world. It accounts for a higher percentage of lymphomas in younger people.

The incidence of PMBL outside of the Western world is not clearly defined. In a Japanese series of over 800 patients seen in a single university setting, roughly 7% had non-Hodgkin lymphoma of the mediastinum, but the specific histology is not reported.^[6]

PMBL has an aggressive course and, if untreated, causes death in those affected. With appropriate management, however, 50-80% of patients can be cured. PMBL is slightly more common in females than in males. This sex distribution is the opposite of that for other types of lymphoma. The median age at diagnosis is 30 years. Very few patients diagnosed with PMBL are older than 50 years.

The cause of primary mediastinal B-cell lymphoma (PMBL) is unknown. Although a clear familial or genetic predisposition has not been identified, a Scandinavian registry study showed an increased risk of non-Hodgkin lymphoma for family members of patients with a prior diagnosis of lymphoma.^[7] Whether or not this is true for other populations is unknown. No relationship to toxic or noxious agents exists.A constitutive activation of NF-κB pathways, which induces cell proliferation (based on recent evidence). Amplification of the REL and JAK2 genes may also contribute to pathogenesis.^[8]

History

Primary mediastinal B-cell lymphoma (PMBL) is a mediastinal tumor that grows rapidly and is sometimes palpable in the supraclavicular area. Superior vena cava syndrome is common. Phrenic nerve palsy, dysphagia, hoarseness, and breast swelling (in women) can occur. Shortness of breath can be due to pleural effusion or massive mediastinal mass. Systemic symptoms (fever, weight loss, night sweats) occur in 30% of patients.

If recurrence develops, a hematogenous pattern of spread to parenchymal organs, such as the liver, kidneys, or brain, is common.

Physical Examination

Physical examination may reveal the following:

• Superior vena cava syndrome, with congestion of face and upper extremities
• Palpable mass in the supraclavicular area
• Dullness at the lung bases
• Respiratory distress
• Peripheral adenopathy (unusual except in the supraclavicular area)

Performance status should be noted because this is an important prognostic indicator.^[9]

The differential diagnosis of primary mediastinal B-cell lymphoma (PMBL) includes the following:

• Acute Lymphoblastic Leukemia
• Germ Cell Tumors
• Hodgkin Disease
• Lymphoblastic Lymphoma
• Malignant Anaplastic (Ki 1+) Lymphoma
• Thymoma

Diagnostic considerations

Differentiating PMBL from other malignancies that involve the mediastinum is extremely important because the diagnosis affects management and outcome. The differential diagnosis of PMBL includes carcinoma and grey zone lymphoma, which is a very rare subtype of lymphoma that has pathobiologic features of both Hodgkin and non-Hodgkin lymphoma.^[10]

Laboratory studies

Perform a CBC count with differential and platelets. Perform electrolyte panel and liver function tests.

Elevation in the serum lactic dehydrogenase (LDH) or β-2 microglobulin level value is an adverse prognostic feature.

The markers alpha-fetoprotein and β-human chorionic gonadotropin (βHCG) are often highly elevated in patients with mediastinal germ cell tumors, constituting an important differential diagnosis in males.

Imaging Studies

Obtain a chest radiograph (posteroanterior, lateral). A mass larger than one third of the diameter of the thorax is considered large and indicates a poor prognosis.

Obtain CT scans (chest, abdomen, pelvis). Extension to the pleura, pericardium, and even the chest wall is common. Invasion of the liver, kidneys, and peripheral lymph nodes is more common at the time of recurrence.

Findings on a gallium scan are almost always strongly positive. Findings are negative following successful treatment.

Positron emission tomography (PET) scans are becoming more widely used. PET represents a convenient, and probably more sensitive, alternative to a gallium scan.

Several investigators have demonstrated that an early metabolic response (ie, complete resolution of all PET-avid disease) following 1-4 cycles of chemotherapy is predictive of an excellent outcome. Similarly, negative PET scan findings at the end of treatment carry a good prognosis. However, false-positive results of PET activity can occur as a result of inflammation, thymic rebound, infection, or granulomatous disease. The specific positive and negative predictive values of PET for patients with PMBL are not known.

Consider other imaging studies if they are clinically indicated (eg, head CT scan or MRI, if the patient has neurologic problems; see image below). Consider performing a multiple gated acquisition (MUGA) scan to assess cardiac function before anthracycline-based chemotherapy.

Diagnostic procedures

Adequate diagnostic biopsy is needed and may require surgery. Ancillary studies, which include immunohistochemistry, immunophenotyping (flow cytometry), and gene rearrangement studies, are often necessary to establish the diagnosis.

Bone marrow aspirate and biopsy are necessary for staging. A unilateral sample is sufficient if the biopsy specimen is larger than 2 cm.

Biopsy of a lymph node or of the mediastinal mass with the use of mediastinoscopy or parasternotomy is necessary. Fine-needle aspiration is usually not diagnostic in this disorder due to lack of morphologic architecture and the difficulty in distinguishing PMBL from other lymphomas.^[11]

Other tests should be performed if clinically indicated (eg, thoracentesis for pleural effusion, lumbar puncture for neurologic symptoms).

Histologic findings

Diffuse infiltrate consists of large cells. Clear cells are common. Fibrosis occurs variably in some areas of the tumor. Immunophenotype is as follows: CD19⁺ and CD20⁺, but CD21^- and HLA-DR^- (in contrast to other diffuse large B-cell lymphomas). The B-cell receptor gene is rearranged.

Emergency care for patients with superior vena cava syndrome consists of the initiation of chemotherapy. Emergency radiation is usually not necessary.

Chemotherapy

Combination chemotherapy is the mainstay of treatment for primary mediastinal B-cell lymphoma (PMBL). Regimens are complex, and doses vary depending on a patient's weight and body surface area. They usually contain corticosteroids, an anthracycline, an alkylating agent, and a vinca alkaloid. The introduction of the monoclonal anti-CD20 agent rituximab (Rituxan) has improved the outcome for patients with large B-cell lymphoma.^[12]

The standard front-line regimen in the United States is cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone combined with rituximab (CHOP-R). Others, mainly in Europe, use the methotrexate, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, and bleomycin (MACOP-B) regimen, which is also routinely combined with rituximab.^{[13, 14, 15]}

Other regimens that have been successfully utilized in small series of patients include etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) and LNH 87.^[16]

Rituximab is a monoclonal anti-CD20 agent that destroys B lymphocytes. When combined with chemotherapy agents (eg, in CHOP-R), it greatly improves cure rates in large cell lymphoma, with minimal additive side effects.

Patients are initially treated with 6 cycles of chemotherapy. Traditionally, CHOP-R is administered every 3 weeks. A European study suggested that in patients with high serum lactic acid dehydrogenase (LDH) levels, biweekly administration with growth factor (filgrastim) support may be advantageous.

Consolidation therapy

In many centers, involved-field radiation is administered to the mediastinum after completion of the chemotherapy. In other centers, patients undergo high-dose chemotherapy and autologous stem cell transplantation after the completion of combination chemotherapy.

High-dose chemotherapy and autologous transplantation are complex procedures that involve the collection of stem cells, the administration of high doses of chemotherapy, and the reinfusion of the stem cells. The procedure usually requires admission to the hospital and support with transfusions, cytokines, and antibiotics. This procedure causes considerable, but transient, morbidity. However, because of advances in supportive care, the mortality associated with this procedure is minimal.

Management is guided by an evaluation of the response based on CT and gallium or positron emission tomography (PET) scans. The authors recommend autologous stem cell transplantation only if the PET scan findings remain positive after chemotherapy is completed.

For patients with recurrent lymphoma, high-dose chemotherapy and autologous or allogeneic stem cell transplantation are the treatments of choice.^[17]

Treatment in pregnancy

Some patients are young women who may be pregnant at the time of diagnosis. The management of malignancy during pregnancy raises specific and complex issues. Concern for the patient's health needs to be balanced with the potential teratogenicity of the chemotherapy and the radiation administered for diagnostic examinations or as part of treatment.

Termination of pregnancy is often recommended if the diagnosis is made in the first trimester. However, this is not acceptable to all patients. In cases in which pregnancy is continued, the administration of chemotherapy drugs without undue teratogenicity is often possible. Staging and restaging examinations are minimized. Radiography is avoided, and MRI or ultrasonography procedures are used instead.

The administration of corticosteroids may exacerbate problems such as preeclampsia or glucose intolerance. Close collaboration with an obstetrician is required.

Consultations

Patients should be referred to a medical hematologist or oncologist for treatment.

Follow-up

The vast majority of patients can be successfully treated on an outpatient basis for front-line care.

Patients with relapsed or refractory disease, as demonstrated in the image below, are typically considered for stem cell transplantation. In this case, the reinduction of remission with chemotherapy as well as the high-dose chemotherapy used for transplant are usually administered in the inpatient setting.

After completion of treatment, patients are usually seen in the outpatient clinic, at regular intervals of 2-3 months, for the first year.

Complications

The chemotherapeutic drugs used for the management of lymphoma have numerous adverse effects. Nausea and vomiting are common but can be avoided with the use of appropriate antiemetics. Hair loss occurs in most patients but is completely reversible after the completion of treatment.

Mild peripheral neuropathy due to chemotherapy is common. Patients experience numbness in fingertips and toes. Motor neuropathy is unusual.

Myelosuppression (bone marrow suppression) and moderate pancytopenia occur after every treatment cycle. Blood counts typically reach their nadir approximately 10 days after the completion of a treatment cycle. Fatigue is common.

Neutropenic fever and infection are common complications of chemotherapy and require immediate treatment. Approximately 10-20% of patients develop excessive neutropenia or an infectious complication. Quinolone antibiotics such as levofloxacin or ofloxacin are often administered to prevent such infections, although their use remains somewhat controversial. If an autologous transplant is considered, prophylactic antibacterials (quinolone), antifungals (fluconazole), and antivirals (acyclovir or valacyclovir) are generally used. Treatment with recombinant cytokines such as filgrastim (Neupogen), pegfilgrastim (Neulasta), or sargramostim (Leukine) is recommended. These cytokines hasten the recovery of blood counts and may allow the timely administration of treatment cycles. Routine administration of cytokines may permit more rapid and intense administration of chemotherapy (eg, CHOP-R every 2 weeks or EPOCH-R) and may improve cure rates.

Cardiac toxicity due to chemotherapy is unusual but can occur. Cardiac toxicity from anthracyclines is dose dependent and rare in the typical young patient with PMBL. Serial monitoring with echocardiograms or multiple gated acquisition (MUGA) scans may be necessary in individual cases. Typically, patients undergo a MUGA scan to evaluate the left ventricular ejection fraction prior to the initiation of chemotherapy. A MUGA scan is performed in most centers only if clinical concerns arise in regard to cardiomyopathy.

The use of cardioprotectant agents may allow the administration of higher doses of anthracyclines, but these cardioprotectant agents might affect the efficacy of chemotherapy. Therefore, cardioprotectant agents are not routinely recommended.

Quinolone antibiotics such as levofloxacin or moxifloxacin are sometimes administered to prevent infections. Their usefulness remains somewhat controversial.

Rituximab is generally safe. It can cause fever and chills, particularly during the first administration. Rare cases of anaphylactic reaction have been reported. Recently, cases of hepatitis B virus (HBV) reactivation that have resulted in fulminant hepatitis and death have been reported. Persons at high risk of HBV infection should be screened before the initiation of rituximab. Carriers of HBV should be closely monitored for clinical and laboratory signs of active HBV infection and hepatitis during and up to several months after rituximab therapy.

Acute adverse effects of radiation are usually limited and include erythema of the skin and, sometimes, radiation pneumonitis.

Late adverse effects related to treatment include decreased fertility, a slightly increased incidence of secondary cancers in radiation fields (especially breast cancer among women treated during adolescence), and a slightly increased risk for secondary leukemia, especially among patients treated with combined modality therapy (ie, chemotherapy and radiation).

In addition, coronary artery disease may be more common and may have an earlier onset if substantial areas of the heart are exposed to radiation. Smoking and alcohol abuse should be avoided because of their association with cancer and heart disease.

Initial treatment cures 50-80% of all patients with primary mediastinal B-cell lymphoma (PMBL). If the gallium (or PET) scan findings are negative after treatment and a complete radiologic remission is obtained, the prognosis is excellent.

Practically all recurrences occur in the first year after diagnosis. A patient in continuous remission for 2 years after the initial diagnosis is highly likely to be cured.

Patients who do not respond to the initial treatment or who develop disease recurrence should undergo high-dose chemotherapy and autologous transplantation. Approximately one third of these patients achieve long-term remissions.

Neither the International Prognostic Index (IPI) nor the age-adjusted IPI (aaIPI) are necessarily predictive of outcome, and new prognostic models are needed.

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma.