AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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Background

Primary mediastinal B-cell lymphoma (PMBL) is a diffuse large B-cell lymphoma 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 so than other types of diffuse large B-cell lymphoma. 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.

Pathophysiology

A rapidly proliferating tumor that arises in the anterior mediastinum (see Image 1), PMBL often causes symptoms via the compression of intrathoracic structures (ie, superior vena cava syndrome) or via the invasion of lungs, pleura, and pericardium. The disease's spread to parenchymal organs, such as the liver, the kidneys, or the central nervous system, is common at the time of recurrence.

Frequency

United States

PMBL accounts for approximately 5% of the lymphomas in the Western world. It accounts for a higher percentage of lymphomas in younger people.

International

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.

Mortality/Morbidity

• The disease has an aggressive course and, if untreated, causes death in those affected.
• With appropriate management, 50-80% of patients can be cured.

Sex

PMBL is slightly more common in females than in males. This sex distribution is the opposite of that for other types of lymphoma.

Age

• The median age at diagnosis is 30 years.
• Very few patients diagnosed with PMBL are older than 50 years.

CLINICAL

Section 3 of 11  

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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

• 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)

Causes

• The cause 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. Whether or not this is true for other populations is unknown.
• No relationship to toxic or noxious agents exists.
• A constitutive activation of NF-kB pathways, which induces cell proliferation (based on recent evidence). Amplification of the REL and JAK-2 genes may also contribute to pathogenesis.

DIFFERENTIALS

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Other Problems to be Considered

Carcinoma
Grey zone lymphoma (a very rare subtype of lymphoma that has pathobiologic features of both Hodgkin and non-Hodgkin lymphoma)

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Perform a CBC count with differential and platelets.
• Perform electrolyte panel and liver function tests.
• An elevated serum lactic dehydrogenase (LDH) value is an adverse prognostic feature.
• An elevated b-2 microglobulin level is also an adverse prognostic feature.
• The markers alpha-fetoprotein and b human chorionic gonadotropin (bHCG) 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 from a gallium scan are almost always strongly positive. Findings are negative following successful treatment. Recently, positron emission tomography (PET) scans are 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 due to inflammation, thymic rebound, infection, or granulomatous disease can occur. 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).

Other Tests

Consider performing a multiple gated acquisition (MUGA) scan to assess cardiac function before anthracycline-based chemotherapy.

Procedures

• 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 the 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.
• 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.

Staging

• Perform a physical examination with attention to lymphadenopathy, splenomegaly, and hepatomegaly. Performance status should be noted because this is an important prognostic indicator. Routine laboratory studies include serum lactic acid dehydrogenase (LDH) and serum b-2 microglobulin.
• Obtain a chest radiograph (posteroanterior and lateral). A mass larger than one third of the diameter of the thorax is considered large and indicates a poor prognosis.
• Obtain CT scans of the chest, abdomen, and pelvis. In addition, obtain a positron emission tomography (PET) or gallium scan.
• • Extension to the pleura, the pericardium, and even the chest wall is common.
  • Invasion of the liver, the kidneys, and the peripheral lymph nodes is more common at the time of recurrence.
• Gallium scan findings are almost always positive. Negative findings after treatment indicate a low risk of recurrence.
• Unilateral bone marrow aspirate and biopsy: Bone marrow involvement is very unusual in this type of lymphoma.
• Other tests, such as thoracentesis and lumbar puncture, should be considered when clinically indicated.

TREATMENT

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Medical Care

• Emergency care for patients with superior vena cava syndrome consists of the initiation of chemotherapy. Emergency radiation is usually not necessary.
• Patients are initially treated with 6 cycles of chemotherapy.
• • Cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone combined with rituximab (CHOP-R) is the most commonly used regimen in the United States. Rituximab is a monoclonal anti-CD20 agent that destroys B lymphocytes. When combined with CHOP-R, chemotherapy greatly improves cure rates in large cell lymphoma, with minimal additive side effects. Traditionally CHOP-R is administered every 3 weeks. A recent European study suggested that, in patients with high serum lactic acid dehydrogenase (LDH) levels, biweekly administration with growth factor (filgrastim) support may be advantageous.
  • Others, mainly in Europe, use the methotrexate, doxorubicin (Adriamycin), cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) regimen, which is also routinely combined with rituximab. Other regimens include etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) and LNH 87.
• 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.
• 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.

Surgical Care

Obtaining the diagnostic biopsy often requires surgery. Surgery has no other role.

Consultations

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

MEDICATION

Section 7 of 11  

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The mainstay of therapy consists of combination chemotherapy. 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 rituximab (a monoclonal anti-CD20 agent) has improved the outcome for patients with large B-cell lymphoma. The standard front-line regimen is R-CHOP, although other intensified regimens including DA-EPOCH-R and MACOP-B have been successfully utilized in small series of patients. Patients should be referred to a medical hematologist or oncologist for treatment.

Radiation to the mediastinum is often used as consolidation therapy. Others have recommended high-dose chemotherapy with stem cell support (autologous stem cell transplantation).

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.

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.

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. Approximately 10-20% of patients develop excessive neutropenia or an infectious complication. In such patients, 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.

Recent evidence suggests that routine administration of cytokines may permit more rapid and intense administration of chemotherapy (eg, cyclophosphamide, doxorubicin [Adriamycin], vincristine, and prednisone combined with rituximab [CHOP-R] q2wk or etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab [EPOCH-R]) and may improve cure rates. Cardiac toxicity from anthracyclines is dose dependent and rare in the typical young patient with primary mediastinal B-cell lymphoma (PMBL). Serial monitoring with echocardiograms or multiple gated acquisition (MUGA) scans may be necessary in individual cases. 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 (Rituxan). Carriers of HBV should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and up to several months after Rituxan therapy.

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

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.

FOLLOW-UP

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Further Inpatient Care

• The vast majority of patients can be successfully treated on an outpatient basis for front-line care.
• Patients with relapsed or refractory disease 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.

Further Outpatient Care

• Chemotherapy is usually administered on an outpatient basis every 2-3 weeks. CT and gallium (or positron emission tomography [PET]) scans are used to evaluate responses. The authors usually continue treatment for a minimum of 6 cycles of intensive chemotherapy. Patients who continue to harbor a positive mass based on PET scan findings after 6 cycles are offered autologous stem cell transplantation.
• After completion of treatment, patients are usually seen in the outpatient clinic, at regular intervals of 2-3 months, for the first year.
• 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.

Complications

• Neutropenic fever and infection are common complications of chemotherapy and require immediate treatment. 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.
• Nausea, vomiting, and hair loss are common. Effective nausea prevention typically includes H2 antagonists.
• Cardiac toxicity due to chemotherapy is unusual but can occur. Typically, patients undergo a multiple gated acquisition (MUGA) scan to evaluate the left ventricular ejection fraction prior to the initiation of chemotherapy. An MUGA scan is performed in most centers only if clinical concerns arise in regard to cardiomyopathy.
• Mild peripheral neuropathy due to chemotherapy is common. Patients experience numbness in fingertips and toes. Motor neuropathy is unusual.
• Rituximab can cause fever, chills, and, occasionally, hypotension. This is particularly common during the first cycle of treatment but is unusual with subsequent treatments. Rare anaphylactic reactions have been reported. Recent reports have shown that some patients with hematologic malignancies who were treated with rituximab have had hepatitis B virus (HBV) reactivation, with fulminant hepatitis, hepatic failure, and death. Persons at high risk of HBV infection should be screened before the initiation of Rituxan. Carriers of HBV should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and up to several months after rituximab (Rituxan) therapy.
• Late adverse effects related to treatment include decreased fertility, a slightly increased incidence for secondary cancers in radiation fields (especially breast cancer among women treated during adolescence), and a slightly increased risk for secondary leukemia, especially among those 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.

Prognosis

• Of all patients, 50-80% are cured with the initial treatment.
• If the gallium (or PET) scan findings are negative after treatment and a complete radiological 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.

Patient Education

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• The differential diagnoses with other malignancies that involve the mediastinum are extremely important because they affect management and outcome.
• 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.

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Example of mediastinal lymphoma at diagnosis: A large tumor mass is present in the anterior mediastinum, and an associated pleural effusion can also be seen.
	View Full Size Image
Media type:  CT

Media file 2:  Isolated CNS relapse of primary mediastinal B-cell lymphoma.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

• Altieri A, Bermejo JL, Hemminki K. Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database. Blood. Jul 15 2005;106(2):668-72. [Medline].
• Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. Jan 24 2002;346:235-42. [Medline]. [Full Text].
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• Hamlin PA, Portlock CS, Straus DJ, Noy A, Singer A, Horwitz SM, et al. Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan Kettering from 1980 to 1999. Br J Haematol. Sep 2005;130(5):691-9. [Medline].
• Lazzarino M, Orlandi E, Paulli M, Strater J, Klersy C, Gianelli U, et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients. J Clin Oncol. Apr 1997;15(4):1646-53. [Medline].
• Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rube C, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004;104:634-641. [Medline]. [Full Text].
• Popat U, Przepiork D, Champlin R, Pugh W, Amin K, Mehra R, et al. High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome. J Clin Oncol. Jan 1998;16(1):63-9. [Medline].
• Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. Sep 15 2003;198:851-62. [Medline]. [Full Text].
• Savage KJ, Al-Rajhi N, Voss N, Paltiel C, Klasa R, Gascoyne RD, et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. Jan 2006;17(1):123-30. [Medline].
• Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. Dec 1 2003;102(12):3871-9. [Medline].
• Takeda S, Miyoshi S, Akashi A, Ohta M, Minami M, Okumura M, et al. Clinical spectrum of primary mediastinal tumors: a comparison of adult and pediatric populations at a single Japanese institution. Journal Surgical Oncology. May 2003;83(1):24-30. [Medline].
• Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, et al. Mediastinal gray zone lymphoma: the missing link between classic Hodgkin''s lymphoma and mediastinal large B-cell lymphoma. Am J Surg Pathol. Nov 2005;29(11):1411-21. [Medline].
• van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review of pathology and management. Journal of Clinical Oncology. Mar 15 2001;19(6):1855-1864. [Medline]. [Full Text].
• Zinzani PL, Martelli M, Magagnoli M, Pescarmona E, Scaramucci L, Palombi F, et al. Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Blood. Nov 15 1999;94(10):3289-93. [Medline]. [Full Text].

Article Last Updated: Oct 12, 2007