Polydorides, Alexandros D.

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC ( P <0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P =0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8) , APC (n=3) , FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

Objectives: To report the results of a rigorous quality control (QC) process in the grading of total mesorectal excision (TME) specimens during a multicenter prospective phase 2 trial of transanal TME. Background: Grading of TME specimens is based on the macroscopic assessment of the mesorectum and standardized through synoptic pathology reporting. TME grade is a strong predictor of outcomes with incomplete (IC) TME associated with increased rates of local recurrence relative to complete or near complete (NC) TME. Although TME grade serves as an endpoint in most rectal cancer trials, in protocols incorporating centralized review of TME specimens for quality assurance, discordance in grading and the management thereof has not been previously described. Methods: A phase 2 prospective transanal TME trial was conducted from 2017 to 2022 across 11 North American centers with TME quality as the primary study endpoint. QC measures included (1) training of site pathologists in TME protocols, (2) blinded grading of de-identified TME specimen photographs by central pathologists, and (3) reconciliation of major discordance before trial reporting. Cohen Kappa statistic was used to assess agreement in grading. Results: Overall agreement in grading of 100 TME specimens between site and central reviewer was rated as fair, (κ = 0.35; 95% CI: 0.10–0.61; P < 0.0001). Concordance was noted in 54%, with minor and major discordance in 32% and 14% of cases, respectively. Upon reconciliation, 13/14 (93%) major discordances were resolved. Pre versus postreconciliation rates of complete or NC and IC TME are 77%/16% and 7% versus 69%/21% and 10%. Reconciliation resulted in a major upgrade (IC–NC; N = 1) or major downgrade (NC/C–IC, N = 4) in 5 cases overall (5%). Conclusions: A 14% rate of major discordance was observed in TME grading between the site and central reviewers. The resolution resulted in a major change in final TME grade in 5% of cases, which suggests that reported rates or TME completeness are likely overestimated in trials. QC through a central review of TME photographs and reconciliation of major discordances is strongly recommended.