Clinicopathological and molecular features of sporadic colorectal cancers with DNA mismatch repair deficiency: A single center experience

DNA mismatch repair (MMR) proteins may play an important role in colorectal carcinogenesis. In our study, the clinicopathological features of defective MMR in sporadic colorectal adenocarcinomas (CRCs) cases were examined. This is a retrospective study, 457 consecutive cases of colorectal carcinoma with immunohistochemical (IHC) studies for DNA MMR were included.The immunohistochemically (IHC) MMR results of 457 cases were; nuclear expression was intact (proficient, pMMR) in 401 (87.7%) cases and loss of nuclear expression (deficient, dMMR) was found in 56 cases (12.3%). High probability of Lynch syndrome ratio was 2.4% (11/457) in all cases. The loss of PMS2 was predominantly detected in dMMRcases (78.6%). Seventy eight percent of dMMR tumors were located in the proximal colon. In dMMR tumors, prominent peritumoral lymphoid aggregates (LAs) (85.7%) and tumor-infiltrating lymphocytes (TILs) (78.6%) were observed. Among 56 colorectal cancers, we observed expanding /pushing growth pattern in 41 tumors (73.2%), and infiltrative growth pattern in 15 cancers (16.8%). Medullary, mucinous and signet ring cell carcinomas were observed in approximately half of the cases, but there was no statistically significant relationship. Eighty nine percent of dMMR cases had advanced pathologic tumor stage (pT3 or pT4), and this rate was 82.5% in pMMR cases. The average number of positive lymph nodes in cases with dMMR was higher than in pMMR. KRAS mutations were detected in 7.2% (4/13) patients and 14.3% (8/13) patients with MLH1 promoter methylation was observed. Seventy percent of patients with dMMR were alive (n=44) and the mean age of the patients who died was higher. A statistically significant relationship was found between the patients who died and the mean age of surviving patients (p = 0.036). We conclude that the dMMR patients constitutes have a number of distinctive clinicopathological features subtype of sporadic CRC. The overall frequency of defective MMR in colorectal carcinoma cases was found to be Turkish population similar to western studies. dMMR in CRCs were more likely to be of advanced pathologic tumor stage to have a mucinous tumor component and positive LN to show PMS2 loss and to harbour higher numbers of both peritumoral LAs and TILs. They were also more likely to be proximal colon and to occur in male.

PDF

___

1. Pai RK, Gonzalo DH, Schaeffer DF. Epithelial neoplasms of the colon. in: noffsinger ae, editors . fenoglio-preiser’s gastrointestinal pathology. philadelphia. Wolters Kluwer; 2017, p 2123-329.

2. Redston M, Driman DK. Epithelial Neoplasms of the Large Intestine. In: Odze RD, Goldblum JR, editors. Odze And Goldblum Surgıcal Pathology of The GI Tract, Lıver, Biliary Tract, And Pancreas. Philadelphia: Saunders, Elsevier; 2015, p 737-78.

3. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108.

4. Lin CC, Lai YL, Lin TC, et al. Clinicopathologic features and prognostic analysis of MSI-high colon cancer. Int J Colorectal Dis. 2012;27:277-86.

5. Kang S, Na Y, Joung SY, et al. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Medicine (Baltimore). 2018;97:e0019.

6. Gologan A, Krasinskas A, Hunt J, et al. Performance of the revised Bethesda guidelines for identification of colorectal carcinomas with a high level of microsatellite instability. Arch Pathol Lab Med. 2005;129:1390-7.

7. Umar A. Lynch syndrome (HNPCC) and microsatellite instability. Dis Markers. 2004;20:179-80.

8. Alexander J, Watanabe T, Wu TT, et al. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527-35.

9. Natsume S, Yamaguchi T, Takao M, et al. Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients. Jpn J Clin Oncol. 2018;48:609-18.

10. Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917-23.

11. Young J, Simms LA, Biden KG, et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol. 2001;159:2107- 16.

12. Lin CC, Lai YL, Lin TC, et al. Clinicopathologic features and prognostic analysis of MSI-high colon cancer. Int J Colorectal Dis. 2012;27:277-86.

13. Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821-9.

14. Benatti P, Gafà R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332-40.

15. Kim CG, Ahn JB, Jung M, et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. Br J Cancer. 2016;115:25-33.

16. Michael-Robinson JM, Biemer-Hüttmann A, et al. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut. 2001;48:360-6.

17. Graham DM, Appelman HD. Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990;3:332-5.

18. Ueno H, Hashiguchi Y, Shimazaki H, et al. Objective criteria for crohn-like lymphoid reaction in colorectal cancer. Am J Clin Pathol. 2013;139:434-41.

19. Ueno H, Kajiwara Y, Shimazaki H, et al. New criteria for histologic grading of colorectal cancer. Am J Surg Pathol. 2012;36:193-201.

20. Konishi T, Shimada Y, Lee LH, et al. Poorly differentiated clusters predict colon cancer recurrence: an in-depth comparative analysis of invasive-front prognostic markers. Am J Surg Pathol. 2018;42:705-14.

21. Johncilla M, Chen Z, Sweeney J, et al. Tumor grade is prognostically relevant among mismatch repair deficient colorectal carcinomas. Am J Surg Pathol. 2018;42:1686-92.

22. Lee VWK, Chan KF. Tumor budding and poorly-differentiated cluster in prognostication in Stage II colon cancer. Pathol Res Pract. 2018;214:402-7.

23. Ueno H, Shirouzu K, Eishi Y, et al. Study Group for Perineural Invasion projected by the Japanese Society for Cancer of the Colon and Rectum (JSCCR). Characterization of perineural invasion as a component of colorectal cancer staging. Am J Surg Pathol. 2013;37:1542-9.

24. Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371-5.

25. Lim SB, Yu CS, Jang SJ, et al. Prognostic significance of lymphovascular invasion in sporadic colorectal cancer. Dis Colon Rectum. 2010;53:377-84.

26. Sato T, Ueno H, Mochizuki H, et al. Objective criteria for the grading of venous invasion in colorectal cancer. Am J Surg Pathol. 2010;34:454-62.

27. Ueno H, Kanemitsu Y, Sekine S, et al. Desmoplastic Pattern at the Tumor Front Defines Poor-prognosis Subtypes of Colorectal Cancer. Am J Surg Pathol. 2017;41:1506-12.

28. Pollheimer MJ, Kornprat P, Lindtner RA, et al. Tumor necrosis is a new promising prognostic factor in colorectal cancer. Hum Pathol. 2010;41:1749-57.

29. Morikawa T, Kuchiba A, Qian ZR, et al. Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer. Ann Surg Oncol. 2012;19:1944-53.

30. Puppa G, Maisonneuve P, Sonzogni A, et al. Pathological assessment of pericolonic tumor deposits in advanced colonic carcinoma: relevance to prognosis and tumor staging. Mod Pathol. 2007;20:843-55.

31. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum version: Colon Rectum 4.0.0.0 Protocol Posting Date: June 2017 Includes pTNM requirements from the 8th Edition, AJCC Staging Manual.(Date of access :23.09.2019) https://www.cap.org/ protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates

32. Jin M, Roth R, Rock JB, et al. The impact of tumor deposits on colonic adenocarcinoma AJCC TNM staging and outcome. Am J Surg Pathol. 2015;39:109-15.

33. Cohen R, Pellat A, Boussion H, et al. Immunotherapy and Metastatic Colorectal Cancers With Microsatellite Instability or Mismatch Repair Deficiency Bull Cancer. 2019;106:137-42.

34. Vogelaar FJ, Erning FNV, Reimers MS, et al. The prognostic value of microsatellite instability, KRAS, BRAF and PIK3CA mutations in stage ii colon cancer patients. Mol Med. 2016;21:1038-46.

35. Lim SB, Jeong SY, Lee MR, et al. Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis. 2004;19:533- 7. 36. Shin US, Cho SS, Moon SM, et al. Is Microsatellite instability really a good prognostic factor of colorectal cancer? Ann Coloproctol. 2014;30:28-34.

37. Klingbiel D, Saridaki Z, Roth AD, et al. Prognosis of stage ii and iii colon cancer treated with adjuvant 5-fluorouracil or folfiri in relation to microsatellite status: Results of the PETACC-3 Trial Ann Oncol. 2015;26:126-32.

38. Angela Hyde, Daniel Fontaine, Susan Stuckless, et al. A histology-based model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol. 2010;34:1820-9.

39. Yamaura T, Miyoshi H, Maekawa H, et al. Accurate diagnosis of mismatch repair deficiency in colorectal cancer using high-quality DNA samples from cultured stem cells. Oncotarget. 2018;9:37534-48.

40. Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831-9.

41. Greenson JK, Bonner JD, Ben-Yzhak O, 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.

42. Alpert L, Pai RK, Srivastava A, et al. Colorectal Carcinomas With Isolated Loss of PMS2 Staining by Immunohistochemistry.Arch Pathol Lab Med. 2018;142:523-8.