Primary mediastinal large B-cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

Synonyms and keywords:: Mediastinal B-cell lymphoma; Mediastinal large B-cell lymphoma, PMBCL, Primary mediastinal B-cell lymphoma.

Overview

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). It is also considered a distinct type of non-Hodgkin lymphoma (NHL) in the World Health Organization (WHO) classification system. It occurs in the thymus gland. The small gland in the center of the chest behind the sternum where lymphocytes mature, multiply and become T cells. or lymph nodes in the center of the chest. On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma. The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years. The symptoms of the primary mediastinal large B-cell lymphoma include fever, weight loss, night sweats, skin rash, facial swelling, cough, shortness of breath, and painless swelling in the neck, axilla, groin, thorax, or abdomen. Lymph node or mediastinal mass biopsy is diagnostic of primary mediastinal large B-cell lymphoma. The predominant therapy for primary mediastinal large B-cell lymphoma is chemotherapy. Adjunctive radiotherapy, stem cell transplant, and biological therapy may be required. The optimal therapy for primary mediastinal large B-cell lymphoma depends on the clinical presentation.

Classification

  • Primary mediastinal B-cell lymphoma was recognized as a sub type of diffuse large B-cell lymphoma since the 1994 in Revised European American Lymphoma Classification.[1]
  • It has been regarded as a unique clinical and biological entity since the 2001 according to World Health Organization classification.[2]

Pathophysiology

Genetics:

  • Genes involved in the pathogenesis of primary mediastinal large B-cell lymphoma include:
    • Comparative genomic hybridzation demonstrated gains in chromosome 9p24 and 2p15
    • Genomic hybridization in chromosome X-p11.4-21
    • Translocations involving the CIITA gene[6]
    • Amplification of the REL oncogene[7]
    • Hyperdiploid karyotypes, often with gains in the region on chromosome 9p containing the JAK2 gene and the genes encoding PD-L1 and PD-L2, ligands for the receptor PD-1[8]
    • The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.[9]
    • Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.[10]
    • Immunoglobulin genes clonally rearranged.

Immunophenotype:

Microscopic Pathology:

  • On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma.
  • The tumor is composed of large cells with variable nuclear features, cells may resemble:[14][15]
    • Centroblasts
    • Large centrocytes
    • Multilobated cells, often with pale or "clear" cytoplasm
    • Less frequently, the tumor cells resemble immunoblasts
    • Reed-Sternberg-like cells
    • Some cases have also presented with fine, compartmentalizing sclerosis.

Causes

  • There are no established causes of primary mediastinal B-cell lymphoma.

Differentiating ((Page name)) from Other Diseases

Epidemiology and Demographics

Age:

  • The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years.[18]

Gender:

  • Females are more commonly affected with primary mediastinal large B-cell lymphoma than males.[18]

Risk Factors

  • There are no established risk factors for primary mediastinal large B-cell lymphoma.

Screening

  • According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for primary mediastinal large B-cell lymphoma.[19]

Natural History, Complications, and Prognosis

Common complications :

Less common complication :

  • The bone marrow is rarely affected by this type of lymphoma.
  • Recurrence or relapse often occurs in organs or tissues outside the lymph nodes (extranodal sites), such as the kidneys or central nervous system.

Prognosis:

  • Prognosis is generally good after aggressive therapy, which usually combines chemotherapy with mediastinal irradiation. However if relapse occurs , it depends on paucity of molecular level of tumor cells, and their ability to evade immune system.
  • Initial studies suggest that a more favorable course may be predicted by one of the following :
    • Low tumor metabolic activity which is determined by decreased total lesion glycolysis (a measure of FDG uptake) on FDG-PET imaging at baseline or after initial therapy. [20]
    • Further study is needed to confirm the prognostic value of PET before it can be used to modify initial treatment plans.

Diagnosis

Diagnostic Study of Choice

Biopsy:

  • The diagnosis of primary mediastinal large B cell lymphoma relies on the exclusion of adequate tissue, which offers most difficulty due to the location of the tumor, therefore an excisional biopsy is usually not possible.
  • Therefore, surgical biopsy is highly preferred.[21]
  • Due to fibrosis, needle aspirates are often paucicellular and fail to provide information about the tissue.
  • Small biopsies may be non-diagnostic because the lesion is not sampled adequately or because crush artifact or extensive necrosis, fibrosis, or cystic change obscures the diagnostic lesion.
  • Similarly, core biopsies mostly contain fibrotic tissue or tumor cells that are disrupted and not useful.
  • To obtain sufficient tissue for biopsy , patients usually undergo either one of the following techniques:[21]

Staging

  • Staging for primary mediastinal large B-cell lymphoma is provided in the following table:[22]
Revised staging system for primary nodal lymphomas (Lugano classification)
Stage Involvement Extranodal (E) status
Limited
Stage I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement
Stage II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
Stage II bulky II as above with "bulky" disease Not applicable
Advanced
Stage III Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement Not applicable
Stage IV Additional noncontiguous extralymphatic involvement Not applicable

History and Symptoms

Symptoms of the primary mediastinal large B-cell lymphoma include:

Physical Examination

Vitals

Skin

HEENT

Thorax

Abdomen

Extremities

Laboratory Findings

Laboratory tests for primary mediastinal large B-cell lymphoma include:

Electrocardiogram

  • There are no ECG findings associated with primary mediastinal large B-cell lymphoma.

Chest X-Ray

  • Chest X-ray may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma. Finding on chest X-ray suggestive of primary mediastinal large B-cell lymphoma includes large anterior mediastinal mass.[16]
An Xray showing mediastinal large B-cell lymphoma.Source: Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 8655

Biopsy

  • Lymph node or mediastinal mass biopsy is diagnostic of primary mediastinal large B-cell lymphoma.

Echocardiography

  • Echocardiography may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

CT

CT scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

CT scan of Femur showing giant cell tumor. courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 8655

MRI

MRI scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

Cardiac MRI short axis T1 at the level of mitral valve reveals a large mediastinal mass infiltrating and obliterating the SVC causing SVC obstruction. The tumor extends into the right atrium (red arrow) and invades the tricuspid valve.Accessed on March 07, 2016

Other Imaging Findings

  • PET scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.
  • In contrast to CT imaging, FDG-PET is a functional imaging tool that can distinguish between viable tumor and necrosis or fibrosis in a residual mass.[23]

Other diagnostic studies

  • Monoclonal anti-MAL antibody is now commercially used in order to identify primary mediastinal large B-cell lymphoma. It provides good sensitivity and high specificity for diagnosis of primary mediastinal large B-cell lymphoma. [24]

Treatment

Medical Therapy

Treatment of primary mediastinal large B-cell lymphoma[15]
Therapy Description
Chemotherapy
Biological therapy
Radiation therapy
Stem cell transplant
  • A stem cell transplant may be offered to some people if their lymphoma returns or relapses after treatment.
  • The choice of initial treatment depends on stage of disease at the time of presentation. Following are different treatment regimens that are recommended for various stages:

Induction Chemotherapy:

Radiotherapy:

  • Radiotherapy is usually indicated to prevent relapse and recurrence of disease after chemotherapy induction especially after following R-CHOP regimen.[20]
  • In aggressive disease, radiation therapy has been proven to be beneficial in patients with good-prognosis stage I and nonbulky stage II disease.[25]

High-Dose Chemotherapy and Autologous Stem Cell Transplantation:

Relapsed disease:

Salvage therapy:

Surgery

  • Surgical intervention is not recommended for the management of primary mediastinal large B-cell lymphoma.

Primary Prevention

  • There are no established measures for the primary prevention of primary mediastinal large B-cell lymphoma.

Secondary Prevention

  • There are no established measures for the secondary prevention of primary mediastinal large B-cell lymphoma.

References

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  3. Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016
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