Primary mediastinal large B-cell lymphoma pathophysiology
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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]
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.[1][2]
- 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.[3]
- 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[4]
- Amplification of the REL oncogene[5]
- 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[6]
- The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.[7]
- Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.[8]
- 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:[7]
- 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. [9]
- Other markers that are relatively specific for primary mediastinal large B-cell lymphoma are CD200 and MAL.[10][11]
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:[12][13]
- 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.
References
- ↑ Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016
- ↑ Addis BJ, Isaacson PG (April 1986). "Large cell lymphoma of the mediastinum: a B-cell tumour of probable thymic origin". Histopathology. 10 (4): 379–90. PMID 2423430.
- ↑ Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland ML, Le Gouvello S, Gaulard P, Leroy K, Castellano F (July 2004). "Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma". Blood. 104 (2): 543–9. doi:10.1182/blood-2003-10-3545. PMID 15044251.
- ↑ Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, Johnson NA, Zhao Y, Telenius A, Neriah SB, McPherson A, Meissner B, Okoye UC, Diepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Rimsza LM, Horsman DE, Staudt LM, Steidl U, Marra MA, Gascoyne RD (March 2011). "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers". Nature. 471 (7338): 377–81. doi:10.1038/nature09754. PMC 3902849. PMID 21368758.
- ↑ Joos S, Otaño-Joos MI, Ziegler S, Brüderlein S, du Manoir S, Bentz M, Möller P, Lichter P (February 1996). "Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene". Blood. 87 (4): 1571–8. PMID 8608249.
- ↑ Twa DD, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A, Tan KL, Slack GW, Gunawardana J, Lim RS, McPherson AW, Kridel R, Telenius A, Scott DW, Savage KJ, Shah SP, Gascoyne RD, Steidl C (March 2014). "Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma". Blood. 123 (13): 2062–5. doi:10.1182/blood-2013-10-535443. PMID 24497532.
- ↑ 7.0 7.1 Lamarre L, Jacobson JO, Aisenberg AC, Harris NL (September 1989). "Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases". Am. J. Surg. Pathol. 13 (9): 730–9. PMID 2788371.
- ↑ Weniger MA, Pulford K, Gesk S, Ehrlich S, Banham AH, Lyne L, Martin-Subero JI, Siebert R, Dyer MJ, Möller P, Barth TF (October 2006). "Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein are frequent in primary mediastinal B-cell lymphoma". Leukemia. 20 (10): 1880–2. doi:10.1038/sj.leu.2404324. PMID 16871282.
- ↑ Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL (February 2005). "TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas". Am. J. Surg. Pathol. 29 (2): 196–203. PMID 15644776.
- ↑ Dorfman DM, Shahsafaei A, Alonso MA (December 2012). "Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers". Mod. Pathol. 25 (12): 1637–43. doi:10.1038/modpathol.2012.129. PMID 22899296.
- ↑ Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Möller P, Leroy K, Gaulard P (November 2002). "MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas". Mod. Pathol. 15 (11): 1172–80. doi:10.1097/01.MP.0000032534.81894.B3. PMID 12429796.
- ↑ De Paepe P, Achten R, Verhoef G, Wlodarska I, Stul M, Vanhentenrijk V, Praet M, De Wolf-Peeters C (October 2005). "Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas". J. Clin. Oncol. 23 (28): 7060–8. doi:10.1200/JCO.2005.15.503. PMID 16129841.
- ↑ Primary mediastinal large B-cell lymphoma. Canadian Cancer Society. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-mediastinal-large-b-cell-lymphoma/?region=nb. Accessed on March 7, 2016