Molecular Landscape and Association With Crohn Disease of Poorly Cohesive Carcinomas of the Nonampullary Small Bowel

Abstract

Objectives Poorly cohesive carcinomas (PCCs) are neoplasms defined by a predominantly dyshesive growth pattern with single cell or cord-like stromal infiltration. The ­distinctive clinicopathologic and prognostic features of small bowel PCCs (SB-PCCs) in comparison with conventional-type small intestinal adenocarcinomas have only recently been characterized. However, as SB-PCCs’ genetic profile is still unknown, we aimed to analyze the molecular landscape of SB-PCCs. Methods A next-generation sequencing analysis through Trusight Oncology 500 on a series of 15 nonampullary SB-PCCs was performed. Results The most frequently found gene alterations were TP53 (53%) and RHOA (13%) mutations and KRAS amplification (13%), whereas KRAS, BRAF, and PIK3CA mutations were not identified. Most SB-PCCs (80%) were associated with Crohn disease, including both RHOA-mutated SB-PCCs, which featured a non-SRC-type histology, and showed a peculiar appendiceal-type, low-grade goblet cell adenocarcinoma (GCA)–like component. Rarely, SB-PCCs showed high microsatellite instability, mutations in IDH1 and ERBB2 genes, or FGFR2 amplification (one case each), which are established or promising therapeutic targets in such aggressive cancers. Conclusions SB-PCCs may harbor RHOA mutations, which are reminiscent of the diffuse subtype of gastric cancers or appendiceal GCAs, while KRAS and PIK3CA mutations, commonly involved in colorectal and small bowel adenocarcinomas, are not typical of such cancers.

IDH1‐mutated Crohn's disease‐associated small bowel adenocarcinomas: Distinctive pathological features and association with MGMT methylation and serrated‐type dysplasia

“…[1][2][3][4] Crohn's disease-associated SBAs (CrD-SBAs), which arise predominantly from inflamed areas of the ileum, show distinctive clinicopathological and immunophenotypical features in comparison with sporadic or coeliac disease-associated SBAs. 1,[5][6][7][8][9][10][11][12][13][14] In addition, although the pathogenetic mechanisms of CrD-SBA development and progression remain poorly known, accumulating evidence suggests that CrD-SBAs may emerge through a distinct molecular pathway of tumorigenesis. [7][8][9]15 On one hand, CrD-SBAs have been reported to show a lower frequency of somatic APC and KRAS mutations in comparison with sporadic SBAs and less frequent mismatch repair (MMR) deficiency and nuclear b-catenin accumulation compared to coeliac disease-associated SBAs.…”

“…However, very few IDH1mutated (IDH1-MUT) CrD-SBAs have been reported to date (11 cases from the literature). 9,14,15,25,26 Starting from these premises, in the present study, we aimed to test an international multicentre series of surgically resected CrD-SBAs for IDH1 mutations and to compare the clinicopathological features, as well as MGMT and LINE-1 methylation profiles, between IDH1-MUT and IDH1 wild-type (IDH1-WT) CrD-SBAs.…”

“…Although small bowel adenocarcinoma (SBA) is a rare malignancy, patients with Crohn's disease (CrD) have an increased risk for the development of SBAs related to long‐standing intestinal inflammation 1–4 . Crohn's disease‐associated SBAs (CrD‐SBAs), which arise predominantly from inflamed areas of the ileum, show distinctive clinicopathological and immunophenotypical features in comparison with sporadic or coeliac disease‐associated SBAs 1,5–14 . In addition, although the pathogenetic mechanisms of CrD‐SBA development and progression remain poorly known, accumulating evidence suggests that CrD‐SBAs may emerge through a distinct molecular pathway of tumorigenesis 7–9,15 .…”

“…suggested that IDH1 status should be screened in all CrD‐SBAs. However, very few IDH1 ‐mutated ( IDH1 ‐MUT) CrD‐SBAs have been reported to date (11 cases from the literature) 9,14,15,25,26 …”

Poorly cohesive duodenal carcinoma mixed with signet ring cell carcinoma with systemic metastasis: a case report and literature review

“…According to the fifth edition of the WHO Classification of Tumors of the Digestive System ( 3 ), among tumors of the small intestine and ampullary region, poorly cohesive carcinoma (PCC) is classified as adenocarcinoma of the small intestine not otherwise specified (SBAs-NOS). Among the subtypes of poorly cohesive small intestinal carcinomas, PCC not otherwise specified (PCC-NOS) consisting of less than 10% signet ring cells accounts for the majority, while PCC-NOS and signet ring cell carcinomas with 10%–90% signet ring cell components are relatively rare ( 4 , 5 ). More than 96% of signet ring cell cancers occur in the stomach, with the remainder occurring primarily in the breast, gallbladder, pancreas, bladder, and intestine ( 6 , 7 ).…”