Primary mediastinal large B-cell lymphoma pathophysiology: Difference between revisions

Jump to navigation Jump to search
 
(3 intermediate revisions by 2 users not shown)
Line 1: Line 1:
__NOTOC__
__NOTOC__
{{Primary mediastinal large B-cell lymphoma pathophysiology}}
 
{{Primary mediastinal large B-cell lymphoma}}


{{CMG}}; {{AE}} {{Badria}}, {{AS}}
{{CMG}}; {{AE}} {{Badria}}, {{AS}}
Line 7: Line 8:


==Pathophysiology==
==Pathophysiology==
* Primary mediastinal large B-cell lymphoma most likely arises within the [[thymus]].<ref name="seer.cancer.gov">Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016 </ref><ref name="pmid2423430">{{cite journal |vauthors=Addis BJ, Isaacson PG |title=Large cell lymphoma of the mediastinum: a B-cell tumour of probable thymic origin |journal=Histopathology |volume=10 |issue=4 |pages=379–90 |date=April 1986 |pmid=2423430 |doi= |url=}}</ref>  
* Primary mediastinal large B-cell lymphoma arises within the [[thymus]].<ref name="seer.cancer.gov">Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016 </ref><ref name="pmid2423430">{{cite journal |vauthors=Addis BJ, Isaacson PG |title=Large cell lymphoma of the mediastinum: a B-cell tumour of probable thymic origin |journal=Histopathology |volume=10 |issue=4 |pages=379–90 |date=April 1986 |pmid=2423430 |doi= |url=}}</ref>  
* Patients present with a [[Localized disease|localized]] anterosuperior [[mediastinal mass]].  
* Patients present with a [[Localized disease|localized]] anterosuperior [[mediastinal mass]].  
* The mass is often bulky and frequently invades adjacent structures such as [[lungs]], [[pleura]], or [[pericardium]].  
* The mass is often bulky and frequently invades adjacent structures such as [[lungs]], [[pleura]], or [[pericardium]].  
* Spreads to [[supraclavicular]] and [[cervical]] [[lymph nodes]].
* Spreads to [[supraclavicular]] and [[cervical]] [[lymph nodes]].
* Pathophysiologically,  tumor grows through constitutive [[STAT]] 6 [[phosphorylation]] and DNA-binding activity.<ref name="pmid15044251">{{cite journal |vauthors=Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland ML, Le Gouvello S, Gaulard P, Leroy K, Castellano F |title=Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma |journal=Blood |volume=104 |issue=2 |pages=543–9 |date=July 2004 |pmid=15044251 |doi=10.1182/blood-2003-10-3545 |url=}}</ref>
* Pathophysiologically,  [[tumor]] grows through constitutive [[STAT6]] [[phosphorylation]] and DNA-binding activity.<ref name="pmid15044251">{{cite journal |vauthors=Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland ML, Le Gouvello S, Gaulard P, Leroy K, Castellano F |title=Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma |journal=Blood |volume=104 |issue=2 |pages=543–9 |date=July 2004 |pmid=15044251 |doi=10.1182/blood-2003-10-3545 |url=}}</ref>
* [[STAT6]] [[phosphorylation]] activates [[Interleukin 4]]/ [[Interleukin 13|interleukin-13]] signalling pathway.  
* [[STAT6]] [[phosphorylation]] activates [[Interleukin 4]]/ [[Interleukin 13|interleukin-13]] signalling pathway.  
* Constitutive [[STAT6]] [[phosphorylation]] and DNA-binding activity is detected is proved through [[immunohistochemical]] analysis.  
* Constitutive [[STAT6]] [[phosphorylation]] and DNA-binding activity is detected is proved through [[immunohistochemical]] analysis.  
* Another proposed mechanism of [[Autocrine signalling|autocrine]] pathway is [[amplification]] of [[JAK2|JAK 2]] pathway which causes [[phosphorylation]] of [[IL-4]] and [[IL-13]] subsequently.   
* Another proposed mechanism of [[Autocrine signalling|autocrine]] pathway is [[amplification]] of [[JAK2|JAK 2]] pathway which causes [[phosphorylation]] of [[IL-4]] and [[IL-13]] subsequently.   
* The [[Janus kinase]] 2 (JAK2) is also constitutively [[Phosphorylation|phosphorylated]] in the primary mediastinal large B-cell lymphoma.
* The [[Janus kinase]] 2 is also constitutively [[Phosphorylation|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.
* 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.


Line 31: Line 32:
===Immunophenotype:===
===Immunophenotype:===
* The [[immunophenotype]] of primary mediastinal large B-cell lymphoma is determined by [[histochemistry]] or [[flow cytometry]].
* 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]]) and [[CD45]].<ref name="pmid2788371">{{cite journal |vauthors=Lamarre L, Jacobson JO, Aisenberg AC, Harris NL |title=Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases |journal=Am. J. Surg. Pathol. |volume=13 |issue=9 |pages=730–9 |date=September 1989 |pmid=2788371 |doi= |url=}}</ref>
* The tumor cells express B cell-associated antigens:<ref name="pmid2788371">{{cite journal |vauthors=Lamarre L, Jacobson JO, Aisenberg AC, Harris NL |title=Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases |journal=Am. J. Surg. Pathol. |volume=13 |issue=9 |pages=730–9 |date=September 1989 |pmid=2788371 |doi= |url=}}</ref>  
** [[CD19]]
** [[CD20]]
** [[CD22]]
** [[CD79a]]
** [[CD45]]
* Weak expression of [[CD30]] is often present.
* Weak expression of [[CD30]] is often present.
* The [[tumor]] cells also stain for [[TRAF1|TRAF-1]] and [[REL|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]]. <ref name="pmid15644776">{{cite journal |vauthors=Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL |title=TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas |journal=Am. J. Surg. Pathol. |volume=29 |issue=2 |pages=196–203 |date=February 2005 |pmid=15644776 |doi= |url=}}</ref>
* The [[tumor]] cells also stain for [[TRAF1|TRAF-1]] and [[REL|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]]. <ref name="pmid15644776">{{cite journal |vauthors=Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL |title=TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas |journal=Am. J. Surg. Pathol. |volume=29 |issue=2 |pages=196–203 |date=February 2005 |pmid=15644776 |doi= |url=}}</ref>
* Other markers that are relatively specific for primary mediastinal large B-cell lymphoma are [[CD200]] and [[MAL2 (gene)|MAL]].<ref name="pmid22899296">{{cite journal |vauthors=Dorfman DM, Shahsafaei A, Alonso MA |title=Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1637–43 |date=December 2012 |pmid=22899296 |doi=10.1038/modpathol.2012.129 |url=}}</ref><ref name="pmid12429796">{{cite journal |vauthors=Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Möller P, Leroy K, Gaulard P |title=MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas |journal=Mod. Pathol. |volume=15 |issue=11 |pages=1172–80 |date=November 2002 |pmid=12429796 |doi=10.1097/01.MP.0000032534.81894.B3 |url=}}</ref>
* Other markers that are relatively specific for primary mediastinal large B-cell lymphoma are [[CD200]] and [[MAL2 (gene)|MAL]].<ref name="pmid22899296">{{cite journal |vauthors=Dorfman DM, Shahsafaei A, Alonso MA |title=Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1637–43 |date=December 2012 |pmid=22899296 |doi=10.1038/modpathol.2012.129 |url=}}</ref><ref name="pmid12429796">{{cite journal |vauthors=Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Möller P, Leroy K, Gaulard P |title=MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas |journal=Mod. Pathol. |volume=15 |issue=11 |pages=1172–80 |date=November 2002 |pmid=12429796 |doi=10.1097/01.MP.0000032534.81894.B3 |url=}}</ref>
===Microscopic Pathology:===
===Microscopic Pathology:===
Line 42: Line 49:
** Multilobated cells, often with pale or "clear" [[cytoplasm]]  
** Multilobated cells, often with pale or "clear" [[cytoplasm]]  
** Less frequently, the tumor cells resemble [[Immunoblast|immunoblasts]]
** Less frequently, the tumor cells resemble [[Immunoblast|immunoblasts]]
** Reed-Sternberg-like cells  
** [[Reed-Sternberg cell|Reed-Sternberg]]-like cells  
** Some cases have also presented with fine, compartmentalizing sclerosis.
** Some cases have also presented with fine, compartmentalizing [[sclerosis]].
<gallery widths="150" mode="packed" heights="150" perrow="3" showfilename="yes">
File:Primary mediastinal large B-cell lymphoma pathology .jpg
File:Primary medistinal large b-cell lymphoma pathology 1 .jpg
File:Primary mediastinal large B-cell lymphoma pathology 2.jpg|Primary mediastinal large B-cell lymphoma immunoreactivity for CD30<ref name="hindawi">Primary mediastinal large B-cell lymphoma.Hindawi Publishing Corporation. http://www.hindawi.com/journals/crihem/2012/197347/. Accessed on March 07, 2016 </ref>
</gallery>
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 17:59, 28 April 2019


Primary mediastinal large B-cell lymphoma Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Primary Mediastinal Large B-cell Lymphoma from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound]]

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Primary mediastinal large B-cell lymphoma pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Primary mediastinal large B-cell lymphoma pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Primary mediastinal large B-cell lymphoma pathophysiology

CDC on Primary mediastinal large B-cell lymphoma pathophysiology

Primary mediastinal large B-cell lymphoma pathophysiology in the news

Blogs on Primary mediastinal large B-cell lymphoma pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for 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

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:

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]

References

  1. Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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

Template:WH Template:WS