Primary mediastinal large B-cell lymphoma pathophysiology

Template:Primary mediastinal large B-cell lymphoma pathophysiology

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]

Overview

Primary mediastinal large B-cell lymphoma arises from thymus. 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 pathophysiology primarily involves constitutional activation of JAK2 pathway through different genetic mechanisms involved, which are described.

Pathophysiology

• Primary mediastinal large B-cell lymphoma arises within the thymus.
• Patients present with a localized anterosuperior mediastinal mass.
• The mass is often bulky and frequently invades adjacent structures such as lungs, pleura, or pericardium.
• Spreads to supraclavicular and cervical lymph nodes.
• Pathophysiologically, tumor grows through constitutive STAT6 phosphorylation and DNA-binding activity.
• STAT6 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 which causes phosphorylation of IL-4 and IL-13 subsequently.
• The Janus kinase 2 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
  • Amplification of the REL oncogene
  • 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
  • The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.
  • Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.
  • Immunoglobulin genes clonally rearranged.

Immunophenotype:

• The immunophenotype of primary mediastinal large B-cell lymphoma is determined by histochemistry or flow cytometry.
• The tumor cells express B cell-associated antigens:
  • CD19
  • CD20
  • CD22
  • CD79a
  • CD45
• 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.
• Other markers that are relatively specific for primary mediastinal large B-cell lymphoma are CD200 and MAL.

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:
  • 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.

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  Primary mediastinal large B-cell lymphoma pathology .jpg

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  Primary medistinal large b-cell lymphoma pathology 1 .jpg

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  Primary mediastinal large B-cell lymphoma pathology 2.jpg Primary mediastinal large B-cell lymphoma immunoreactivity for CD30