Splenic marginal zone lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Muhammad Affan M.D.[4], Sowminya Arikapudi, M.B,B.S. [5]

Overview

The exact pathogenesis of splenic marginal zone lymphoma (SMZL) is not clearly understood but according to some studies chronic immunologic stimulation and certain gene mutations are assumed to be involved. The common chromosomal aberrations and genetic mutations in splenic marginal zone lymphoma (SMZL) includes 7q32 deletion, gain of function mutation in 3q and NOTCH2, TP53, KLF2 gene mutations. These genes control certain cell regulation pathways that are involved in normal functioning of the cell. Hepatitis C viral antigen has also been assumed to be involved in its pathogenesis. Spleen, bone marrow, lymph nodes, liver and blood may be infiltrated with the tumor and have certain distintive features. On microscopic histopathological analysis, B-cells, villous lymphocytes, and sinus invasion are characteristic findings of splenic marginal zone lymphoma (SMZL).

Pathophysiology

Pathogenesis

Genetics

  • There are several pathways involved in the normal functioning of the cells. Genetic dysregulation may affect these pathways resulting in abnormal function.
  • Common genetic abnormalities and their affected pathways in splenic marginal zone lymphoma are summarized under:
Pathways Gene mutations

NFkB[24][25][19]

Apoptosis[26][27]

Cell communication[28][29][30]

Cell cycle control[15][27][30]

Lymphocyte development and regulation[28][25][30]

Chromosomal and transcriptional regulation[25][31]

Associated conditions

Microscopic Pathology

Spleen

  • Micronodular pattern of lymphocytic infiltration of the white pulp involving both mantle and marginal zone component.[39]
  • Biphasic distribution of neoplastic B-cell in the follicles i.e small cells having dense chromatin and scant cytoplasm surrounded by intermediate size cells of marginal zone having variable nuclear contour and relatively abundant cytoplasm with interspersed large B-cells.
  • Red pulp may also be involved either sparingly or diffusely penetrating the sinuses and cords.[40]

Bone Marrow:

Lymph nodes

Blood

References

  1. ↑ Fonte E, Agathangelidis A, Reverberi D, Ntoufa S, Scarfò L, Ranghetti P, Cutrona G, Tedeschi A, Xochelli A, Caligaris-Cappio F, Ponzoni M, Belessi C, Davis Z, Piris MA, Oscier D, Ghia P, Stamatopoulos K, Muzio M (November 2015). "Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation". Haematologica. 100 (11): 1460–8. doi:10.3324/haematol.2014.119933. PMC 4825289. PMID 26294727.
  2. ↑ Franco G, Guarnotta C, Frossi B, Piccaluga PP, Boveri E, Gulino A, Fuligni F, Rigoni A, Porcasi R, Buffa S, Betto E, Florena AM, Franco V, Iannitto E, Arcaini L, Pileri SA, Pucillo C, Colombo MP, Sangaletti S, Tripodo C (March 2014). "Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma". Blood. 123 (12): 1836–49. doi:10.1182/blood-2013-04-497271. PMID 24452203.
  3. ↑ Dunn-Walters DK, Boursier L, Spencer J, Isaacson PG (June 1998). "Analysis of immunoglobulin genes in splenic marginal zone lymphoma suggests ongoing mutation". Hum. Pathol. 29 (6): 585–93. PMID 9635678.
  4. ↑ Miranda RN, Cousar JB, Hammer RD, Collins RD, Vnencak-Jones CL (March 1999). "Somatic mutation analysis of IgH variable regions reveals that tumor cells of most parafollicular (monocytoid) B-cell lymphoma, splenic marginal zone B-cell lymphoma, and some hairy cell leukemia are composed of memory B lymphocytes". Hum. Pathol. 30 (3): 306–12. PMID 10088550.
  5. ↑ Tierens A, Delabie J, Pittaluga S, Driessen A, DeWolf-Peeters C (April 1998). "Mutation analysis of the rearranged immunoglobulin heavy chain genes of marginal zone cell lymphomas indicates an origin from different marginal zone B lymphocyte subsets". Blood. 91 (7): 2381–6. PMID 9516137.
  6. ↑ Camacho FI, Mollejo M, Mateo MS, Algara P, Navas C, Hernández JM, Santoja C, Solé F, Sánchez-Beato M, Piris MA (October 2001). "Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases". Am. J. Surg. Pathol. 25 (10): 1268–76. PMID 11688461.
  7. ↑ Stevenson F, Sahota S, Zhu D, Ottensmeier C, Chapman C, Oscier D, Hamblin T (April 1998). "Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes". Immunol. Rev. 162: 247–59. PMID 9602369.
  8. ↑ Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (May 2011). "The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications". Blood. 117 (19): 5019–32. doi:10.1182/blood-2011-01-293050. PMC 3109529. PMID 21300984.
  9. ↑ Spencer J, Perry ME, Dunn-Walters DK (September 1998). "Human marginal-zone B cells". Immunol. Today. 19 (9): 421–6. PMID 9745206.
  10. ↑ Timens W, Poppema S (September 1985). "Lymphocyte compartments in human spleen. An immunohistologic study in normal spleens and uninvolved spleens in Hodgkin's disease". Am. J. Pathol. 120 (3): 443–54. PMC 1887979. PMID 3898859.
  11. ↑ [1] Dunn-Walters DK, Boursier L, Spencer J, Isaacson PG. "Analysis of immunoglobulin genes in splenic marginal zone lymphoma suggests ongoing mutation." Hum Pathol. 1998 Jun;29(6):585-93. PMID: 9635678
  12. ↑ Boonstra R, Bosga-Bouwer A, van Imhoff GW, Krause V, Palmer M, Coupland RW, Dabbagh L, van den Berg E, van den Berg A, Poppema S (December 2003). "Splenic marginal zone lymphomas presenting with splenomegaly and typical immunophenotype are characterized by allelic loss in 7q31-32". Mod. Pathol. 16 (12): 1210–7. doi:10.1097/01.MP.0000095895.19756.77. PMID 14681321.
  13. ↑ Hernández JM, García JL, Gutiérrez NC, Mollejo M, Martínez-Climent JA, Flores T, González MB, Piris MA, San Miguel JF (May 2001). "Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics". Am. J. Pathol. 158 (5): 1843–50. doi:10.1016/S0002-9440(10)64140-5. PMC 1891967. PMID 11337382.
  14. ↑ Andersen CL, Gruszka-Westwood A, Atkinson S, Matutes E, Catovsky D, Pedersen RK, Pedersen BB, Pulczynski S, Hokland P, Jacobsen E, Koch J (January 2005). "Recurrent genomic imbalances in B-cell splenic marginal-zone lymphoma revealed by comparative genomic hybridization". Cancer Genet. Cytogenet. 156 (2): 122–8. doi:10.1016/j.cancergencyto.2004.04.026. PMID 15642391.
  15. ↑ 15.0 15.1 Salido M, Baró C, Oscier D, Stamatopoulos K, Dierlamm J, Matutes E, Traverse-Glehen A, Berger F, Felman P, Thieblemont C, Gesk S, Athanasiadou A, Davis Z, Gardiner A, Milla F, Ferrer A, Mollejo M, Calasanz MJ, Florensa L, Espinet B, Luño E, Wlodarska I, Verhoef G, García-Granero M, Salar A, Papadaki T, Serrano S, Piris MA, Solé F (September 2010). "Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group". Blood. 116 (9): 1479–88. doi:10.1182/blood-2010-02-267476. PMID 20479288.
  16. ↑ Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Famà R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbò F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R, Facchetti F, Arcaini L, Inghirami G, Bertoni F, Pileri SA, Deaglio S, Foà R, Dalla-Favera R, Pasqualucci L, Rabadan R, Gaidano G (August 2012). "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development". J. Exp. Med. 209 (9): 1537–51. doi:10.1084/jem.20120904. PMID 22891273.
  17. ↑ Trøen G, Wlodarska I, Warsame A, Hernández Llodrà S, De Wolf-Peeters C, Delabie J (July 2008). "NOTCH2 mutations in marginal zone lymphoma". Haematologica. 93 (7): 1107–9. doi:10.3324/haematol.11635. PMID 18508802.
  18. ↑ Piva R, Deaglio S, Famà R, Buonincontri R, Scarfò I, Bruscaggin A, Mereu E, Serra S, Spina V, Brusa D, Garaffo G, Monti S, Dal Bo M, Marasca R, Arcaini L, Neri A, Gattei V, Paulli M, Tiacci E, Bertoni F, Pileri SA, Foà R, Inghirami G, Gaidano G, Rossi D (February 2015). "The Krüppel-like factor 2 transcription factor gene is recurrently mutated in splenic marginal zone lymphoma". Leukemia. 29 (2): 503–7. doi:10.1038/leu.2014.294. PMID 25283840.
  19. ↑ 19.0 19.1 Rossi D, Deaglio S, Dominguez-Sola D, Rasi S, Vaisitti T, Agostinelli C, Spina V, Bruscaggin A, Monti S, Cerri M, Cresta S, Fangazio M, Arcaini L, Lucioni M, Marasca R, Thieblemont C, Capello D, Facchetti F, Kwee I, Pileri SA, Foà R, Bertoni F, Dalla-Favera R, Pasqualucci L, Gaidano G (November 2011). "Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma". Blood. 118 (18): 4930–4. doi:10.1182/blood-2011-06-359166. PMID 21881048.
  20. ↑ Spina V, Rossi D (August 2016). "NF-κB deregulation in splenic marginal zone lymphoma". Semin. Cancer Biol. 39: 61–7. doi:10.1016/j.semcancer.2016.08.002. PMID 27503810.
  21. ↑ Baldini L, Fracchiolla NS, Cro LM, Trecca D, Romitti L, Polli E, Maiolo AT, Neri A (July 1994). "Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin". Blood. 84 (1): 270–8. PMID 8018922.
  22. ↑ Gruszka-Westwood AM, Hamoudi RA, Matutes E, Tuset E, Catovsky D (June 2001). "p53 abnormalities in splenic lymphoma with villous lymphocytes". Blood. 97 (11): 3552–8. PMID 11369650.
  23. ↑ [2] Corcoran MM, Mould SJ, Orchard JA, Ibbotson RE, Chapman RM, Boright AP, Platt C, Tsui LC, Scherer SW, Oscier DG. "Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations." Oncogene. 1999 Nov 4;18(46):6271-7. PMID: 10597225
  24. ↑ Clipson A, Wang M, de Leval L, Ashton-Key M, Wotherspoon A, Vassiliou G, Bolli N, Grove C, Moody S, Escudero-Ibarz L, Gundem G, Brugger K, Xue X, Mi E, Bench A, Scott M, Liu H, Follows G, Robles EF, Martinez-Climent JA, Oscier D, Watkins AJ, Du MQ (May 2015). "KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype". Leukemia. 29 (5): 1177–85. doi:10.1038/leu.2014.330. PMID 25428260.
  25. ↑ 25.0 25.1 25.2 Parry M, Rose-Zerilli MJ, Ljungström V, Gibson J, Wang J, Walewska R, Parker H, Parker A, Davis Z, Gardiner A, McIver-Brown N, Kalpadakis C, Xochelli A, Anagnostopoulos A, Fazi C, de Castro DG, Dearden C, Pratt G, Rosenquist R, Ashton-Key M, Forconi F, Collins A, Ghia P, Matutes E, Pangalis G, Stamatopoulos K, Oscier D, Strefford JC (September 2015). "Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing". Clin. Cancer Res. 21 (18): 4174–4183. doi:10.1158/1078-0432.CCR-14-2759. PMC 4490180. PMID 25779943.
  26. ↑ Ruiz-Ballesteros E, Mollejo M, Rodriguez A, Camacho FI, Algara P, Martinez N, Pollán M, Sanchez-Aguilera A, Menarguez J, Campo E, Martinez P, Mateo M, Piris MA (September 2005). "Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis". Blood. 106 (5): 1831–8. doi:10.1182/blood-2004-10-3898. PMID 15914563.
  27. ↑ 27.0 27.1 Trøen G, Nygaard V, Jenssen TK, Ikonomou IM, Tierens A, Matutes E, Gruszka-Westwood A, Catovsky D, Myklebost O, Lauritzsen G, Hovig E, Delabie J (November 2004). "Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma". J Mol Diagn. 6 (4): 297–307. doi:10.1016/S1525-1578(10)60525-9. PMC 1867488. PMID 15507668.
  28. ↑ 28.0 28.1 Parry M, Rose-Zerilli MJ, Gibson J, Ennis S, Walewska R, Forster J, Parker H, Davis Z, Gardiner A, Collins A, Oscier DG, Strefford JC (2013). "Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma". PLoS ONE. 8 (12): e83244. doi:10.1371/journal.pone.0083244. PMC 3862727. PMID 24349473.
  29. ↑ Fresquet V, Robles EF, Parker A, Martinez-Useros J, Mena M, Malumbres R, Agirre X, Catarino S, Arteta D, Osaba L, Mollejo M, Hernandez-Rivas JM, Calasanz MJ, Daibata M, Dyer MJ, Prosper F, Vizcarra E, Piris MÁ, Oscier D, Martinez-Climent JA (September 2012). "High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma". Br. J. Haematol. 158 (6): 712–26. doi:10.1111/j.1365-2141.2012.09226.x. PMID 22816737.
  30. ↑ 30.0 30.1 30.2 Martínez N, Almaraz C, Vaqué JP, Varela I, Derdak S, Beltran S, Mollejo M, Campos-Martin Y, Agueda L, Rinaldi A, Kwee I, Gut M, Blanc J, Oscier D, Strefford JC, Martinez-Lopez J, Salar A, Sole F, Rodriguez-Peralto JL, Diez-Tascón C, García JF, Fraga M, Sebastián E, Alvés J, Menárguez J, González-Carreró J, Casado LF, Bayes M, Bertoni F, Gut I, Piris MA (June 2014). "Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation". Leukemia. 28 (6): 1334–40. doi:10.1038/leu.2013.365. PMID 24296945.
  31. ↑ Rinaldi A, Forconi F, Arcaini L, Mian M, Sozzi E, Zibellini S, Baldini L, Franceschetti S, Gaidano G, Marasca R, Mollejo M, Piris MA, Tucci A, Facchetti F, Bhagat G, Favera RD, Rancoita PM, Zucca E, Kwee I, Bertoni F (December 2010). "Immunogenetics features and genomic lesions in splenic marginal zone lymphoma". Br. J. Haematol. 151 (5): 435–9. PMID 21113978.
  32. ↑ Chuang SS, Liao YL, Chang ST, Hsieh YC, Kuo SY, Lu CL, Hwang WS, Lin IH, Tsao CJ, Huang WT (July 2010). "Hepatitis C virus infection is significantly associated with malignant lymphoma in Taiwan, particularly with nodal and splenic marginal zone lymphomas". J. Clin. Pathol. 63 (7): 595–8. doi:10.1136/jcp.2010.076810. PMID 20530156.
  33. ↑ Gurvits GE, Mahtani R, Halperin I (November 2007). "Hepatitis C virus and splenic marginal zone lymphoma with villous lymphocytes: away from conventional therapy". Scand. J. Gastroenterol. 42 (11): 1392–3. doi:10.1080/00365520701420800. PMID 17852855.
  34. ↑ Weng WK, Levy S (July 2003). "Hepatitis C virus (HCV) and lymphomagenesis". Leuk. Lymphoma. 44 (7): 1113–20. doi:10.1080/1042819031000076972. PMID 12916862.
  35. ↑ Quinn ER, Chan CH, Hadlock KG, Foung SK, Flint M, Levy S (December 2001). "The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis". Blood. 98 (13): 3745–9. PMID 11739181.
  36. ↑ Hermine O, Lefrère F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X (July 2002). "Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection". N. Engl. J. Med. 347 (2): 89–94. doi:10.1056/NEJMoa013376. PMID 12110736.
  37. ↑ Zinzani PL (2012). "The many faces of marginal zone lymphoma". Hematology Am Soc Hematol Educ Program. 2012: 426–32. doi:10.1182/asheducation-2012.1.426. PMID 23233614.
  38. ↑ Arcaini L, Rossi D, Paulli M (April 2016). "Splenic marginal zone lymphoma: from genetics to management". Blood. 127 (17): 2072–81. doi:10.1182/blood-2015-11-624312. PMID 26989207.
  39. ↑ Papadaki T, Stamatopoulos K, Belessi C, Pouliou E, Parasi A, Douka V, Laoutaris N, Fassas A, Anagnostopoulos A, Anagnostou D (March 2007). "Splenic marginal-zone lymphoma: one or more entities? A histologic, immunohistochemical, and molecular study of 42 cases". Am. J. Surg. Pathol. 31 (3): 438–46. doi:10.1097/01.pas.0000213419.08009.b0. PMID 17325486.
  40. ↑ Mollejo M, Algara P, Mateo MS, Sánchez-Beato M, Lloret E, Medina MT, Piris MA (January 2002). "Splenic small B-cell lymphoma with predominant red pulp involvement: a diffuse variant of splenic marginal zone lymphoma?". Histopathology. 40 (1): 22–30. PMID 11903595.
  41. ↑ Mohanpuria A, Kumar V, Suteri P, Marwah S, Nigam AS (July 2017). "Important Diagnostic Clues for Diagnosing Splenic Marginal Zone Lymphoma in Absence of Splenic Histology". J Clin Diagn Res. 11 (7): ED15–ED17. doi:10.7860/JCDR/2017/27149.10190. PMC 5583942. PMID 28892912.
  42. ↑ Iannitto E, Ambrosetti A, Ammatuna E, Colosio M, Florena AM, Tripodo C, Minardi V, Calvaruso G, Mitra ME, Pizzolo G, Menestrina F, Franco V (November 2004). "Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients". Cancer. 101 (9): 2050–7. doi:10.1002/cncr.20596. PMID 15389479.
  43. ↑ Kent SA, Variakojis D, Peterson LC (May 2002). "Comparative study of marginal zone lymphoma involving bone marrow". Am. J. Clin. Pathol. 117 (5): 698–708. doi:10.1309/MECJ-GLK1-WEBW-UEVE. PMID 12090417.
  44. ↑ Ponzoni M, Kanellis G, Pouliou E, Baliakas P, Scarfò L, Ferreri AJ, Doglioni C, Bikos V, Dagklis A, Anagnostopoulos A, Ghia P, Stamatopoulos K, Papadaki T (November 2012). "Bone marrow histopathology in the diagnostic evaluation of splenic marginal-zone and splenic diffuse red pulp small B-cell lymphoma: a reliable substitute for spleen histopathology?". Am. J. Surg. Pathol. 36 (11): 1609–18. doi:10.1097/PAS.0b013e318271243d. PMID 23073320.
  45. ↑ Mollejo M, Lloret E, Menárguez J, Piris MA, Isaacson PG (July 1997). "Lymph node involvement by splenic marginal zone lymphoma: morphological and immunohistochemical features". Am. J. Surg. Pathol. 21 (7): 772–80. PMID 9236833.
  46. ↑ Wolfe JM (1979). "The computer paper illusion". Perception. 8 (3): 347–8. doi:10.1068/p080347. PMID 534161.

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