Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

Abstract

There is some uncertainty about pathological grading of mucinous colorectal adenocarcinoma, defined as colorectal cancer demonstrating at least 50% mucinous differentiation. Under the WHO 2000 classification mucinous colorectal cancer was considered high grade. However under the current WHO 2010 classification microsatellite unstable/mismatch repair-deficient (MSI/MMRd) mucinous colorectal cancer is considered low grade, whereas microsatellite stable/mismatch repair proficient (MSS/MMRp) tumours are high grade. However there is little empirical evidence for this approach. We therefore compared the long term survival of patients with MSI/MMRd vs MSS/MMRp mucinous colorectal cancer in a large unselected cohort of patients undergoing surgery at our institution from 1998 to 2011. There were 2608 patients in the cohort, of which 264 (10.1%) were mucinous. 95 (36%) of the mucinous tumours were microsatellite unstable. The all-cause 5-year survival of mucinous MSI/MMRd colorectal cancer was similar to that of non-mucinous low-grade colorectal cancer (73 vs 67%, P = 0.368), and significantly better than that of both non-mucinous high-grade (73 vs 53%, Po 0.001) and mucinous MSS/MMRp colorectal cancer (73 vs 57%, P = 0.023). The 5-year survival of mucinous MSS/MMRp colorectal cancer was slightly better than that of non-mucinous high-grade patients (57 vs 53%, P = 0.027), but significantly worse than that of non-mucinous low-grade colorectal cancer (57 vs 67%, P = 0.018). In multivariate Cox regression analysis, conventional histological grade based on glandular differentiation maintained prognostic significance (P = 0.003) whereas MSI/MMRd status just failed to be statistically significant (P = 0.062). Our findings support the WHO 2010 approach that as a group mucinous MSS/MMRp colorectal cancers are biologically aggressive. However, grading based exclusively on MSI/MMR status may be overly simplistic as conventional grading based on the degree of glandular differentiation still holds greater prognostic significance in multivariate analysis.

Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component

“…Although properly identifying that the mucinous subtype of CRC may not have prognostic significance, it may connote potentially important biological and therapeutic information. Mucinous CRC have higher rates of MSI and lower rates of TP53 mutation than adenocarcinoma, and they also demonstrate higher expression of HATH1 and MUC2 . KRAS mutation may or may not be related to mucinous differentiation in CRC.…”

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis

“…Some studies have attempted to unravel the genetic etiology of mucinous adenocarcinoma of the colon and rectum by predominantly focusing on mutations in Kirsten rat sarcoma viral oncogene ( KRAS) , v‐Raf murine sarcoma viral oncogene homolog B ( BRAF ), inherited defects or epigenetic silencing of mismatch repair (MMR) proteins resulting in microsatellite instability (MSI) and the presence of the CpG island methylator phenotype (CIMP) . Mucinous tumors have been shown to be associated with an increased rate of BRAF mutations, MSI and CIMP and negatively associated with altered TP53 expression but little else has been described about the genetic mechanisms of these tumors beyond this .…”

Clinical features of colorectal mucinous and poorly differentiated adenocarcinomas; study concept of a propensity score analysis in a pooled data of 5530 patients

“…Clinical features of colorectal mucinous and poorly differentiated adenocarcinomas; study concept of a propensity score analysis in a pooled data of 5530 patients Mitsuro Kanda 1) , Koji Oba 2) , Hiromichi Maeda 3) , Toru Aoyama 4) , Michitaka Honda and Takaki Yoshikawa 10)…”

“…CRC comprise several histologic subtypes including signet ring cell carcinomas, mucinous, poorly differentiated and differentiated adenocarcinomas 1) . Mucinous CRC is defined as CRC in which extracellular mucin comprises >50% of the tumor volume and has been reported to account for 5-15% of CRC 2) . The clinical signature of mucinous CRC were that it more often affected young and female patients, frequently located on the proximal colon and had more later-stage presentations 2) .…”

“…Mucinous CRC is defined as CRC in which extracellular mucin comprises >50% of the tumor volume and has been reported to account for 5-15% of CRC 2) . The clinical signature of mucinous CRC were that it more often affected young and female patients, frequently located on the proximal colon and had more later-stage presentations 2) . Although some studies have reported worse survival outcomes and poorer response to chemotherapy in mucinous CRC, the prognostic relevance of the mucinous subtype is still controversially discussed, mainly because of the relatively rare incidence of this disease 3) .…”