Gastrointestinal Goblet Cell Adenocarcinomas Harbor Distinctive Clinicopathological, Immune, and Genomic Landscape

Goblet cell adenocarcinoma (GCA) is a rare amphicrine tumor and difficult to diagnose. GCA is traditionally found in the appendix, but extra-appendiceal GCA may be underestimated. Intestinal adenocarcinoma with signet ring cell component is also very rare, and some signet ring cell carcinomas are well cohesive, having some similar morphological features to GCAs. It is necessary to differentiate GCA from intestinal adenocarcinomas with cohesive signet ring cell component (IACSRCC). The goal of this study is to find occurrence of extra-appendiceal GCA and characterize the histological, immunohistochemical, transcriptional, and immune landscape of GCA. We collected 12 cases of GCAs and 10 IACSRCCs and reviewed the clinicopathologic characters of these cases. Immunohistochemical stains were performed with synaptophysin, chromogranin A, CD56, somatostatin receptor (SSTR) 2, and Ki-67. Whole transcriptome RNA-sequencing was performed, and data were used to analyze differential gene expression and predict immune cell infiltration levels in GCA and IACSRCC. RNA-sequencing data for colorectal adenocarcinoma were gathered from TCGA data portal. Of the 12 patients with GCA, there were 4 women and 8 men. There were three appendiceal cases and nine extra-appendiceal cases. GCAs were immunohistochemically different from IACSRCC. GCA also had different levels of B-cell and CD8+ T-cell infiltration compared to both colorectal adenocarcinoma and cohesive IACSRCCs. Differential gene expression analysis showed distinct gene expression patterns in GCA compared to colorectal adenocarcinoma, with a number of cancer-related differentially expressed genes, including upregulation of TMEM14A, GOLT1A, DSCC1, and HSD17B8, and downregulation of KCNQ1OT1 and MXRA5. GCA also had several differentially expressed genes compared to IACSRCCs, including upregulation of PRSS21, EPPIN, RPRM, TNFRSF12A, and BZRAP1, and downregulation of HIST1H2BE, TCN1, AC069363.1, RP11-538I12.2, and REG4. In summary, the number of extra-appendiceal GCA was underestimated in Chinese patients. GCA can be seen as a distinct morphological, immunohistochemical, transcriptomic, and immunological entity. The classic low-grade component of GCA and the immunoreactivity for neuroendocrine markers are the key points to diagnosing GCA.