Survival outcomes of poorly differentiated colorectal carcinoma variants: Insights from a single teaching institute☆

The morphologic diagnosis of colorectal carcinoma (CRC) is typically straight forward. However, there are certain subtypes of CRC that pose diagnostic challenges for daily practice due to sometimes overlapping morphologic and immunohistochemical features. These subtypes include poorly differentiated adenocarcinoma NOS, in the absence of conventional morphology (PDA-NOS), large cell neuroendocrine carcinoma (LCNEC), medullary carcinoma (MC), undifferentiated carcinoma (UC) and lymphoepithelioma-like carcinoma (LELC). This study aims to see if there is a survival difference between poorly differentiated variants of CRC, as well as other clinicopathological features that may affect prognosis. Additionally, we analyzed interobserver agreement among gastrointestinal pathologists (GP) at our institution in subclassifying poorly differentiated CRC. All consecutive patients with the diagnoses of PDA-NOS, MC, LCNEC, UC and LELC between July 2018 and July 2023 were included. Cox proportional regression test was used for multivariate analysis, while log-rank and Kaplan-Meier tests were used for univariate and survival analyses. Out of the same cohort of patients, 58 samples identified and reviewed by 3 GI-subspecialty-trained pathologists who were asked to assign the cases as PDANOS, LCNEC, MC, UC and LELC. Interobserver agreement was analyzed using Fleiss Kappa. Of the total 77 patients, 63 were PDA-NOS, 3 were LCNEC, 6 were MC, 4 were UC and 1 was LELC patients. Multivariate analysis using Cox proportional regression showed that tumor size (p = 0.001, HR = 1.22, 95% CI 1.08-1.38), patient age (p = 0.001, HR 1.73, 95% CI 1.24-2.40), and M stage (p = 0.02, HR 2.22, 95% CI 1.14-4.32) were significantly associated with worse OS. For the 58 cases analyzed, 3 GP agreed on 42 (72%) cases. The most common diagnosis was PDA-NOS and for 33 (57%) agreement was unanimous. There was moderate agreement (k 0.41-0.60) between all 3 GP. Our study evaluated the challenges associated with histological evaluation of colon cancers with poorly differentiated morphologies. Among the diagnoses considered in the study, MC and LCNEC had different prognostic implications compared to PDA-NOS and UC. Additionally, our GP showed moderate interobserver agreement, indicating that some level of variability in diagnosing poorly differentiated CRC subtypes may be inevitable.