Research Article
BibTex RIS Cite

Effect of microsatellite instability on histopathological parameters and prognosis in colon cancers

Year 2023, Volume: 48 Issue: 1, 1 - 10, 31.03.2023
https://doi.org/10.17826/cumj.1217604

Abstract

Purpose: The aim of this study was to compare the clinicopathological features, while evaluating the frequency of MSI, and the survival rates in these patients in our patient group with MSI and microsatellite stabil (MSS) colorectal carcinomas (CRCs).
Materials and Methods: We retrospectively enrolled 146 patients who underwent colon resection between the years of 2014-2022. The expression of MSI status was evaluated by immunohistochemistry. The association of MSI status, presense of tumor-infiltrating lymphocytes (TILs), and tumor budding score with a patient’s survival was assessed by the Kaplan–Meier method and Cox regression analysis.
Results: There were 104 (71.2%) MSS cases and, 42 (28.8%) MSI cases. 15 (10.3%) MSI tumors were found to be MSI-low, and 27 (18.5%) to be MSI-high. MSI tumors were significantly associated with younger patients (<50), earlier stage (T1-T2), right localization, lower rate of lymph node metastasis, presence of mucinous component and TILs response. The Cox-regression model revealed TILs, tumor budding score, and MSI are variables that significantly affect survival. The presence of TILs exhibited a protective effect (Hazard ratio (HR)=0.446), which decreased the mortality risk by 2.24 times for the follow-up period, while the presence of high TBS increased the risk of mortality by HR=3.22.
Conclusion: This study revealed that patients with MSI CRCs may show unique clinicopathological features and should be evaluated using some guiding parameters that will improve survival.

References

  • 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2020;70:313.
  • 2. Zhang C, Cui M, Xing J, Yang H, Yao Z, Zhang N. et al. Clinicopathologic features and prognosis of synchronous and metachronous multiple primary colorectal cancer. Clin Transl Oncol. 2021;23:335-43.
  • 3. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394-401.
  • 4. Corti C, Sajjadi E, Fusco N. Determination of mismatch repair status in human cancer and its clinical significance: does one size fit all? Adv Anat Pathol. 2019; 26:270-79.
  • 5. Kawakami H, Zaanan A, and Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16:1-15.
  • 6. Poulogiannis G, Frayling IM, Arends MJ. DNA mismatch repair deficiency in sporadic colorectal cancer and lynch syndrome. Histopathology. 2010;56:167-79.
  • 7. Umar A, Boland CR, Terdiman JP, Syngal S, Chapelle ADL, Rüschoff J et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-68.
  • 8. Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam cancer. 2004;3:93-100.
  • 9. El Agy F, Otmani IE, Mazti A, Lahmidani N, Oussaden A, El Abkari M et al. Implication of microsatellite instability pathway in outcome of colon cancer in Moroccan population. Dis Markers. 2019.
  • 10. Hewish M, Lord CJ, Martin SA, Cunningham D, Ashworth A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol. 2010;7:197-208.
  • 11. Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30:1299-311.
  • 12. Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouche O, Tabernero J et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. JNCI: J Natl Cancer Inst. 2017;109.
  • 13. Whitehall V, Leggett B. Microsatellite instability: detection and management in sporadic colorectal cancer. J Gastroenterol Hepatol. 2011;26:1697-9.
  • 14. Chapusot C, Martin L, Mungra N, Rageot D, Bouvier AM, Kopp CB et al. Sporadic colorectal cancers with defective mismatch repair display a number of specific morphological characteristics: relationship between the expression of hMLH1 and hMSH2 proteins and clinicopathological features of 273 adenocarcinomas. Histopathology. 2003;43:40-7.
  • 15. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563-70.
  • 16. Elias E, Mukherji D, Faraj W, Khalife M, Dimassi H, Eloubeidi M et al. Lymph-node ratio is an independent prognostic factor in patients with stage III colorectal cancer: a retrospective study from the Middle East. World J Surg Oncol. 2012;10:1-7.
  • 17. Karahan B, Argon A, Yıldırım M, Vardar E. Relationship between MLH-1, MSH-2, PMS-2, MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol. 2015;8:4044
  • 18. Weiss JM, Pfau PR, O’Connor ES, King J, LoConte N, Kennedy G et al. Mortality by stage for right-versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results-Medicare data. J Clin Oncol. 2011;29:4401.
  • 19. Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg.2004;91:469-75.
  • 20. Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y, Shima K et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15:6412-20.
  • 21. Drescher KM, Sharma P, Watson P, Gatalica Z, Thibodeau SN, Lynch HT. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam cancer. 2009;8:231-9.
  • 22. Idos GE, Kwok J, Bonthala N, Kysh L, Gruber SB, Qu C. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci Rep. 2020;10:1-14.
  • 23. Rozek LS, Schmit SL, Greenson JK, Tomsho LP, Rennert HS, Rennert G et al. Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst. 2016;108.
  • 24. Sinicrope FA, Smyrk TC, Foster NR, Meyers JP, Thibodeau SN, Golber RM et al. Association of tumor infiltrating lymphocytes (TILs) with molecular subtype and prognosis in stage III colon cancers (CC) from a FOLFOX-based adjuvant chemotherapy trial. J Clin Oncol. 2016;3518.
  • 25. Compton, C. Prognostic factors in cancer. Arch Pathol Lab Med. 2002;126:384-5.
  • 26. Zlobec I, Minoo P, Terracciano L, Baker K, Lugli A. Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers. Histopathology. 2011;59:482-95.
  • 27. Graham RP, Vierkant RA, Tillmans LS, Wang AH, Laird PW, Weisenberger DJ et al. Tumor budding in colorectal carcinoma: confirmation of prognostic significance and histologic cut off in a population-based cohort. Am J Surg Pathol. 2015;39:1340.
  • 28. Lang-Schwarz B, Melcher F, Haumaier K, Lang-Schwarz K, Rupprecht T, Vieth M et al. Budding and tumor-infiltrating lymphocytes combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups. Hum Pathol. 2018;79:160-7.
  • 29. Kloor M & von Knebel Doeberitz M. The immune biology of microsatellite unstable cancer. Trends Cancer. 2018;367-84.
  • 30. Vilkin M, Halpern S, Morgenstern, Brazovski E, Gingold-Belfer R, Boltin D et al. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation?. Hum Pathol. 2014;45:2029-36.

Kolon kanserlerinde mikrosatellite instabilitenin histopatolojik parametreler ve prognoz üzerine etkisi

Year 2023, Volume: 48 Issue: 1, 1 - 10, 31.03.2023
https://doi.org/10.17826/cumj.1217604

Abstract

Amaç: Bu çalışmada, MSİ ile mikrosatellit stabil (MSS) kolorektal karsinomlu (KRK) hasta grubumuzda, klinikopatolojik özellikleri karşılaştırmayı, MSİ sıklığını ve bu hastalarda sağkalım oranlarını değerlendirmeyi amaçladık
Gereç ve Yöntem: Çalışmaya retrospektif olarak 2014-2022 yılları arasında kolon rezeksiyonu yapılan 146 hasta dahil edildi. MSI durumu, immünohistokimyal belirteçlerle değerlendirildi. MSI durumu, tümörü infiltre eden lenfositlerin (TIL'ler) varlığı ve tümör tomurcuklanma skorunun sağkalım ile olan ilişkisi, Kaplan-Meier yöntemi ve Cox regresyon analizi ile değerlendirildi.
Bulgular: Olgularımızın 104’ü (%71,2) MSS, 42’si (%28,8) MSİ’dir. MSI tümörlerin 15’i (%10,3) MSI-düşük, 27’si (%18,5) MSİ-yüksek olarak bulundu. MSİ tümörler, genç yaş (<50 yaş), erken evre (T1-T2), sağ kolon lokalizasyonu, düşük lenf nodu metastazı oranı, müsinöz komponent ve TİL varlığı ile istatistiksel olarak anlamlı şekilde ilişkiliydi. Cox-regresyon modeli, TIL'lerin, tümör tomurcuklanma skorunun ve MSİ'nin sağkalımı önemli ölçüde etkileyen değişkenler olduğunu ortaya çıkardı. TIL'lerin varlığı, takip süresince ölüm riskini 2,24 kat azaltan koruyucu bir etki (Tehlike oranı (HR)=0,446) sergilerken, yüksek tümör tomurcuklanma skorunun ölüm riskini (HR=3,22) artırdığı bulundu.
Sonuç: Çalışmamızda, MSİ KRK’li hastaların, kendilerine özgü klinikopatolojik özellikler gösterebileceği ve sağkalımda yol gösterici bazı parametrelerle birlikte değerlendirilmesi gerektiği vurgulanmaktadır.

References

  • 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2020;70:313.
  • 2. Zhang C, Cui M, Xing J, Yang H, Yao Z, Zhang N. et al. Clinicopathologic features and prognosis of synchronous and metachronous multiple primary colorectal cancer. Clin Transl Oncol. 2021;23:335-43.
  • 3. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394-401.
  • 4. Corti C, Sajjadi E, Fusco N. Determination of mismatch repair status in human cancer and its clinical significance: does one size fit all? Adv Anat Pathol. 2019; 26:270-79.
  • 5. Kawakami H, Zaanan A, and Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16:1-15.
  • 6. Poulogiannis G, Frayling IM, Arends MJ. DNA mismatch repair deficiency in sporadic colorectal cancer and lynch syndrome. Histopathology. 2010;56:167-79.
  • 7. Umar A, Boland CR, Terdiman JP, Syngal S, Chapelle ADL, Rüschoff J et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-68.
  • 8. Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam cancer. 2004;3:93-100.
  • 9. El Agy F, Otmani IE, Mazti A, Lahmidani N, Oussaden A, El Abkari M et al. Implication of microsatellite instability pathway in outcome of colon cancer in Moroccan population. Dis Markers. 2019.
  • 10. Hewish M, Lord CJ, Martin SA, Cunningham D, Ashworth A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol. 2010;7:197-208.
  • 11. Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30:1299-311.
  • 12. Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouche O, Tabernero J et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. JNCI: J Natl Cancer Inst. 2017;109.
  • 13. Whitehall V, Leggett B. Microsatellite instability: detection and management in sporadic colorectal cancer. J Gastroenterol Hepatol. 2011;26:1697-9.
  • 14. Chapusot C, Martin L, Mungra N, Rageot D, Bouvier AM, Kopp CB et al. Sporadic colorectal cancers with defective mismatch repair display a number of specific morphological characteristics: relationship between the expression of hMLH1 and hMSH2 proteins and clinicopathological features of 273 adenocarcinomas. Histopathology. 2003;43:40-7.
  • 15. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563-70.
  • 16. Elias E, Mukherji D, Faraj W, Khalife M, Dimassi H, Eloubeidi M et al. Lymph-node ratio is an independent prognostic factor in patients with stage III colorectal cancer: a retrospective study from the Middle East. World J Surg Oncol. 2012;10:1-7.
  • 17. Karahan B, Argon A, Yıldırım M, Vardar E. Relationship between MLH-1, MSH-2, PMS-2, MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol. 2015;8:4044
  • 18. Weiss JM, Pfau PR, O’Connor ES, King J, LoConte N, Kennedy G et al. Mortality by stage for right-versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results-Medicare data. J Clin Oncol. 2011;29:4401.
  • 19. Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg.2004;91:469-75.
  • 20. Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y, Shima K et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15:6412-20.
  • 21. Drescher KM, Sharma P, Watson P, Gatalica Z, Thibodeau SN, Lynch HT. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam cancer. 2009;8:231-9.
  • 22. Idos GE, Kwok J, Bonthala N, Kysh L, Gruber SB, Qu C. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci Rep. 2020;10:1-14.
  • 23. Rozek LS, Schmit SL, Greenson JK, Tomsho LP, Rennert HS, Rennert G et al. Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst. 2016;108.
  • 24. Sinicrope FA, Smyrk TC, Foster NR, Meyers JP, Thibodeau SN, Golber RM et al. Association of tumor infiltrating lymphocytes (TILs) with molecular subtype and prognosis in stage III colon cancers (CC) from a FOLFOX-based adjuvant chemotherapy trial. J Clin Oncol. 2016;3518.
  • 25. Compton, C. Prognostic factors in cancer. Arch Pathol Lab Med. 2002;126:384-5.
  • 26. Zlobec I, Minoo P, Terracciano L, Baker K, Lugli A. Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers. Histopathology. 2011;59:482-95.
  • 27. Graham RP, Vierkant RA, Tillmans LS, Wang AH, Laird PW, Weisenberger DJ et al. Tumor budding in colorectal carcinoma: confirmation of prognostic significance and histologic cut off in a population-based cohort. Am J Surg Pathol. 2015;39:1340.
  • 28. Lang-Schwarz B, Melcher F, Haumaier K, Lang-Schwarz K, Rupprecht T, Vieth M et al. Budding and tumor-infiltrating lymphocytes combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups. Hum Pathol. 2018;79:160-7.
  • 29. Kloor M & von Knebel Doeberitz M. The immune biology of microsatellite unstable cancer. Trends Cancer. 2018;367-84.
  • 30. Vilkin M, Halpern S, Morgenstern, Brazovski E, Gingold-Belfer R, Boltin D et al. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation?. Hum Pathol. 2014;45:2029-36.
There are 30 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research
Authors

Tuğba Toyran 0000-0001-9135-0265

Kivilcim Erdogan 0000-0002-4951-8703

Emine Kılıç Bağır 0000-0002-1447-1060

Arbil Açıkalın 0000-0001-6118-9853

Merve Aksın 0000-0002-9212-3256

Semra Paydaş 0000-0003-4642-3693

Burak Mete 0000-0002-0780-6176

Seyda Erdogan 0000-0002-4113-2080

Publication Date March 31, 2023
Acceptance Date December 28, 2022
Published in Issue Year 2023 Volume: 48 Issue: 1

Cite

MLA Toyran, Tuğba et al. “Effect of Microsatellite Instability on Histopathological Parameters and Prognosis in Colon Cancers”. Cukurova Medical Journal, vol. 48, no. 1, 2023, pp. 1-10, doi:10.17826/cumj.1217604.