Search

Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations.We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E.We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04).SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.

Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, β2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with =10% mucin may differ from pMMR MADs and tumors with10% mucin, a finding that may impact immune-oncology based therapeutics.