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 centre 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. 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.[1][2]

Classification

  • Primary mediastinal B-cell lymphoma was recognized as a sub type of diffuse large B-cell lymphoma since the 1994 Revised European American Lymphoma Classification.[3]
  • It has been regarded as a unique clinical and biological entity since the 2001 World Health Organization classification.[4]

Pathophysiology

  • Primary mediastinal large B-cell lymphoma most likely arises within the thymus.[1][5]
  • Patients present with a localized anterosuperior mediastinal mass.
  • The mass is often bulky and frequently invades adjacent structures such as lungs, pleura, or pericardium.
  • Spread to supraclavicular and cervical lymph nodes can occur.
  • Pathophysiologically, tumor grows through constitutive STAT 6 phosphorylation and DNA-binding activity.[6]
  • STAT 6 phosphorylation activates Interleukin 4/ interleukin-13 signalling pathway.
  • Constitutive STAT6 phosphorylation and DNA-binding activity is detected is proved through immunohistochemical analysis.
  • Another proposed mechanism of autocrine pathway is amplification of JAK 2 pathway involves phosphorylation of IL-4 and IL-13.
  • The Janus kinase 2 (JAK2) is also constitutively phosphorylated in the primary mediastinal large B-cell lymphoma.
  • Primary mediastinal large B-cell lymphoma is treated with JAK2 inhibitor AG490, resulted in partially decreased STAT6 phosphorylation, which suggests that JAK2 is partially involved in STAT6 activation in these cells.

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[7]
  • Amplification of the REL oncogene[8]
  • 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[9]
  • The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.[10]
  • Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.[11]
  • Immunoglobulin genes clonally rearranged.

Immunophenotype:

  • The immunophenotype of PMBL is determined by histochemistry or flow cytometry.
  • The tumor cells express B cell-associated antigens (CD19, CD20, CD22, CD79a) and CD45.[10]
  • Weak expression of CD30 is often present
  • The tumor cells also stain for TRAF-1 and nuclear c-Rel. These two markers are also expressed by the Reed-Sternberg cells, but are not present in other forms of diffuse large B cell lymphoma. [12]
  • Other markers that are relatively specific for PMBL are CD200 and MAL.[13][14]

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:[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

Primary mediastinal large B-cell lymphoma must be differentiated from other diseases such as:

Epidemiology and Demographics

Primary mediastinal large B-cell lymphoma comprises of 7% of overall diffuse large B cell lymphoma's and 2.4 % of all Non hodgkin lymphomas. [17]

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

  • Primary mediastinal large B-cell lymphoma is usually a fast-growing lymphoma.
  • Patients often have localized disease in the chest at first.
  • If left untreated, primary mediastinal large B-cell lymphoma can cause:
    • shortness of breath
    • cough
    • chest pain
  • Primary mediastinal large B-cell lymphoma can also partially block the main vein (superior vena cava) that carries blood from the upper body to the heart and cause superior vena cava syndrome.

Common complications :

  • Compression of vessels in the neck often causes following symptoms :
    • Dyspnea
    • Facial swelling
    • Fullness of head on bending forwards
    • Arm swelling
    • Dysphagia
    • Cerebral edema
    • Headache
    • Confusion
    • Coma
  • Potential Oncologic emergencies are:
    • Acute airway obstruction
    • Pericardial tamponade
    • Hyperuricemia and tumor lysis syndrome
    • Thrombosis of major neck or superior thoracic veins
  • Patients with large mediastinal masses are at increased risk of respiratory or cardiac arrest during general anesthesia or heavy sedation.
  • Patients who present with cardiorespiratory symptoms or radiographic evidence of tracheal obstruction are at greatest risk of perioperative respiratory morbidity.

Less common complication :

  • Less common complication includes:
    • Tumor lysis syndrome is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation.
    • Deposition of uric acid and/or calcium phosphate crystals in the renal tubules results in acute renal failure.
  • 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 tissue biopsy is usually not possible.
  • In context of these situations, surgical biopsy is highly preferred.[21]
  • Due to fibrosis (which is often extensive), 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 often contain only fibrotic tissue or tumor cells that are disrupted and not diagnostically useful.
  • To obtain sufficient tissue for biopsy , patients usually undergo either one of the following techniques[21]
    • Cervical mediastinoscopy
    • Anterior mediastinotomy
    • Thoracoscopy

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:

  • Fever
  • Weight loss
  • Night sweats
  • Skin rash
  • Shortness of breath
  • Facial swelling
  • Cough
  • Painless swelling in the neck, axilla, groin, thorax, and abdomen

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]

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.

MRI

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

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 PMBL. It provides good sensitivity and high specificity fot diagnosis of primary mediastinal large B-cell lymphoma. [24]

Treatment

Medical Therapy

Treatment of primary mediastinal large B-cell lymphoma[2]
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

  • R-CHOP chemotherapy which includes rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone is preferred regimen for limited disease but it is not suggested alone, follow up with Radiotherapy is highly recommended to prevent relapse of disease.
  • Dose adjusted da-EPOCH-Retoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab
    • This is best for those patients who which to avoid radiotherapy, such as young patients (<30 yrs) or women who have concerns with irradiation of breast tissue.

However investigators from Europe have suggested that MACOP-B(methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) may be superior to CHOP in the management of PMBL.

Radiotherapy

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

High-Dose Chemotherapy and Autologous Stem Cell Transplantation

  • The use of high-dose chemotherapy and autologous stem cell transplantation in patients with aggressive disease proves to be beneficial in some cases. However studies are being performed to determine its efficacy and role in prevention of relapse of disease.[26]

Relapsed disease

  • Patients with relapsed disease often have systemic involvement and many also have extranodal diseas, in the parenchymal organs, including kidneys, liver, and CNS.[27]
  • These patients are recommended to undergo salvage systemic chemotherapy followed by stem cell collection and subsequent transplantation.[28]
  • The authors favor rituximab, ifosfamide, carboplatin, and etoposide (RICE) as a salvage approach, although other regimens are acceptable.
  • Patients who demonstrate improvement on PET scan are recoomended for transplantation.
  • Patients who have refractory disease should be offered clinical trials, although some can be considered for allogeneic bone marrow transplantation.

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 [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and


References

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