Molecular characterization of appendiceal goblet cell carcinoid.

Abstract

231 Background: Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. There are a few reports focusing on the molecular differences between GCC and other appendiceal tumors such as adenocarcinoma and neuroendocrine tumor (NET). Methods: A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas and 14 NETs) were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) / mismatch repair (MMR) status was tested with a combination of NGS, IHC and fragment analysis. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 were tested by IHC (SP142). Molecular characteristics of GCCs are compared with those of adenocarcinomas and NETs, using Chi-square test. Results: The top five genes with most frequent mutation rate in GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), KRAS (7.5%) and CHEK2 (4.0%). Compared to adenocarcinomas, GCCs showed significantly lower mutation rates in KRAS (7.5% vs 60.4%), GNAS (3.8% vs 34.4%), APC (1.9% vs 11.7%), while significantly higher mutation rates in CDH1 (3.8% vs 0.7%), CHEK2 (4.0% vs 0.3%), CDC73 (2.0% vs 0.0%), ERCC2 (2.0% vs 0.0%) and FGFR2 (1.9% vs 0.0%). Compared to NETs, GCCs showed significantly lower mutation rate in KRAS (7.5% vs 28.6%), APC (1.9% vs 28.6%), BRCA2 (0.0% vs 7.1%) and FANCA (0.0% vs 7.1%), with all p < 0.05. In GCCs, MSI-H/dMMR, TML-high (> 17mut/Mb) and PD-L1 expression were seen in 0.0%, 0.0% and 2.0%, respectively. No significant difference was observed in these immune-related markers’ frequency, compared to adenocarcinomas and NETs. Conclusions: GCCs had considerably distinct mutational profile compared to appendiceal adenocarcinomas and NETs. Understanding these molecular characteristics may be critical for a development of effective treatment strategy in GCC.

Current Management of Appendiceal Neoplasms

“…Approximately 10% and 6% of GCAs have KRAS and GNAS hotspot mutations, respectively, which is less frequent than mutation rates for either gene in appendiceal MANs or nonmucinous adenocarcinoma. 11,51 The frequency of high tumor mutation burden or high microsatellite instability in GCA has been reported to range from 0% to 3%. 11,51 As with most appendiceal tumors, GCAs are typically diagnosed on pathology after surgery for presumed appendicitis.…”

“…11,51 The frequency of high tumor mutation burden or high microsatellite instability in GCA has been reported to range from 0% to 3%. 11,51 As with most appendiceal tumors, GCAs are typically diagnosed on pathology after surgery for presumed appendicitis. Workup at that time should include contrast-enhanced CT of the chest/abdomen/pelvis, although hematogenous spread is rare.…”

“…63 Approximately 2% to 3% of AAs have high tumor mutation burden status, almost all attributable to high microsatellite instability status. 11,51 Patients diagnosed with AA should undergo a metastatic workup similar to colon cancer. 65 This includes contrastenhanced CT of the chest/abdomen/pelvis as well as biochemical testing, including CEA.…”

Appendiceal Goblet Cell Adenocarcinoma: A Historically Informed Reading of 6 Cases

“…On the other hand, goblet cell tumors relatively frequently show molecular alterations in WNT signaling and in chromatin remodeling genes, 54,55,59 neither of which are commonly found in conventional appendiceal neuroendocrine tumors or adenocarcinoma. Recently, Arai et al 58 ) account for a small subset of GCC patients. In addition, microsatellite instability high/deficient mismatch repair, tumor mutational burdenhigh (17 mutations/Mb), and programmed death-ligand 1 expression in GCA were seen in 0 of 52 (0%), 0 of 53 (0), and 1 of 51 (2.0%) of GCA, respectively, with no significant difference among these 3 types of tumors.…”