Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival

Abstract

Colorectal cancer with microsatellite instability has a characteristic clinicopathologic profile, featuring rightsided, lymphocyte-rich tumors with a better prognosis than microsatellite stable (MSS) carcinoma. Mucinous and signet ring cell carcinomas are both over-represented among microsatellite instability-high cancers. The clinicopathologic features of mucinous microsatellite instability-high cancer parallel those of the overall microsatellite instability-high set, but it is not known whether the same is true for signet ring cell carcinoma, particularly given the fact that signet ring histology is a well-documented adverse prognostic factor. We recorded age, sex, tumor size, site, grade, stage, histologic pattern, growth pattern, Crohn-like reaction, vascular invasion and tumor-infiltrating lymphocytes in 72 resected signet ring cell carcinomas of the colorectum. Microsatellite instability was determined by a combination of polymerase chain reaction and immunohistochemical stains for hMLH1, hMSH2 and hMSH6. Tumors with instability at 430% of informative markers and/or loss of hMLH1 or hMSH2 expression were designated microsatellite instability-high; all others were classified as MSS. A total of 22 (31%) signet ring cell carcinomas were microsatellite instability-high. Compared to MSS signet ring cell carcinoma, they were more likely to be right-sided (81 vs 45%, P ¼ 0.005) and to affect older patients (68 vs 26%, P ¼ 0.0007) of female sex (59 vs 28%, P ¼ 0.03). Crohn-like reaction (45 vs 16%, P ¼ 0.02) and high tumor infiltrating lymphocyte counts (32 vs 8%, P ¼ 0.03) were more common in the microsatellite instability-high setting. There was no significant difference in 5-year survival in microsatellite instability-high vs MSS patients (41 vs 34%, P ¼ 0.3). In conclusion, approximately one-third of signet ring carcinomas of the colorectum are microsatellite instability-high. Microsatellite instability-high signet ring carcinomas share clinicopathologic features with other microsatellite instability-high cancers: older age group, female preponderance, right-sided location, Crohn-like reaction and numerous tumor-infiltrating lymphocytes. Microsatellite instability status does not appear to be a significant predictor of survival in signet ring cell carcinoma of the colorectum.

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

“…In this study, we analyzed the molecular features of 33 resected signet ring cell carcinomas and explored their correlation with outcome. High-level microsatellite instability has been reported in 25-31% of signet ring cell carcinomas, 15,35 which is similar to the 24% figure observed in this series. High-level microsatellite instability is a marker of favorable outcome in sporadic colorectal cancer, but does not favorably influence survival in signet ring cell carcinoma.…”

“…14 In a large study of 70 signet ring cell carcinomas, the 5-year survival in cancers with and without high-level microsatellite instability was 41% and 34% respectively; this marginal difference was not statistically significant. 15 The reason for aggressive behavior of signet ring cell carcinoma including tumors with high-level microsatellite instability is not clear. High-level microsatellite-unstable tumors tend to be diploid 38 and chromosomal instability is a relatively infrequent phenomenon; LOH is observed in 16-21% of cancers with high-level microsatellite instability, compared with 56-83% of microsatellite-stable tumors.…”

“…15 Although high-level microsatellite instability is considered a favorable prognostic factor in colorectal cancer, it does not favorably influence survival in signet ring cell carcinoma. 15 The reason for this discrepancy is not clear. It is well established that high level of chromosomal instability is associated with aggressive behavior in colorectal cancer.…”

“…31 Although genetic and epigenetic changes in colorectal cancer have been extensively studied, there are sparse data on the molecular features of signet ring cell carcinoma. 15,35 The relationship of molecular changes and survival in signet ring cell carcinoma remains unclear. It is likely that signet ring morphology is a marker for genetic abnormalities that confer the aggressive behavior associated with signet ring cell carcinoma irrespective of microsatellite-instability status.…”

Clinical significance of signet-ring cells in colorectal mucinous adenocarcinoma

“…2,4,5 Both colorectal mucinous adenocarcinoma and signet-ring cell carcinoma are associated with high-frequency microsatellite instability. [6][7][8] We also believe that there are clinicopathological differences between mucinous adenocarcinomas and signet-ring cell carcinomas, especially in the aggressiveness of biological behavior. Colorectal signet-ring cell carcinoma has an adverse prognostic significance independent of the stage at presentation.…”