Clinicopathologic Features of Synchronous Colorectal Carcinoma A Distinct Subset Arising From Multiple Sessile Serrated Adenomas and Associated With High Levels of Microsatellite Instability and Favorable Prognosis

Analysis of synchronous colorectal carcinomas can provide a unique model to examine the underlying molecular alterations in colorectal carcinoma, as synchronous tumors arise in a background of common genetic and environmental factors. We analyzed the clinicopathologic and molecular features of synchronous colorectal carcinomas compared with solitary carcinomas to correlate the histologic findings with molecular alterations and to identify the prognostic significance, if any, of synchronous colorectal carcinoma. Of the 4760 primary colorectal carcinomas resected for the years 2002 to 2012 at our institution, 58 patients (1.2%) harbored 2 invasive primary adenocarcinomas and comprise the synchronous colorectal carcinoma study group. A control group of consecutively resected solitary colorectal carcinomas from 109 patients was also analyzed. Compared with solitary colorectal carcinomas, synchronous colorectal carcinomas more frequently were identified in older patients (median age 70 vs. 60 y; P = 0.001), involved the right colon (42/58, 72% vs. 47/109, 43%; P = 0.0003), were more often microsatellite instability-high (MSI-H) (21/58, 36% vs. 13/109, 12%; P = 0.0005), and were more frequently associated with precursor sessile serrated adenomas (SSAs) (13/58, 22% vs. 2/109, 2%; P = 0.0001). A statistically significant difference in overall survival was identified between patients with synchronous and solitary colorectal carcinomas (5 y overall survival 92% vs. 56%, P = 0.02). A unique subgroup of 13 synchronous colorectal carcinomas demonstrated tumors arising from SSAs (SSA-associated). All SSA-associated synchronous colorectal carcinomas were seen in patients above 65 years of age, and 12/13 (92%) occurred in women. Most patients (12/13, 92%) with SSA-associated synchronous colorectal carcinomas demonstrated involvement of the right colon, and tumors were frequently stage I or II (9/13, 69%) and low grade (11/13, 85%). In 12/13 (92%) SSA-associated synchronous colorectal carcinomas, both tumors exhibited loss of MLH1 and PMS2 immunohistochemical expression with concurrent BRAF V600E mutation. Nine of 13 (69%) patients with SSA-associated colorectal carcinoma harbored additional SSAs. Three of 13 (15%) patients with SSA-associated synchronous colorectal carcinoma met the World Health Organization criteria for serrated polyposis. Notably, no patient with SSA-associated synchronous colorectal carcinoma developed disease recurrence or died of disease at last follow-up. In conclusion, synchronous colorectal carcinomas are enriched with MSI-H tumors, particularly those arising from SSAs, which contributes to the overall improved survival for patients with synchronous tumors compared with patients with solitary tumors. We demonstrate that SSA-associated synchronous colorectal carcinomas have a striking predilection for elderly women, are associated with a favorable prognosis, and are MSI-H and BRAF V600E positive.