Molecular Characterization of Appendiceal Goblet Cell Carcinoid

Abstract

Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. We aimed to reveal the molecular profiles of GCC compared with other appendiceal tumors, such as adenocarcinomas and neuroendocrine tumors. A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas, and 14 neuroendocrine tumors) were tested with next-generation sequencing (NGS) on a 592-gene panel and IHC. Microsatellite instability (MSI)/mismatch repair (MMR) status was tested with a combination of NGS, IHC, and fragment analyses. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 expression was tested by IHC (SP142). The most prevalent mutated genes within GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), and KRAS (7.5%). Pathway-specific alterations were dominantly observed in cell cycle, MAPK, epigenetic, and TGFβ signaling pathways. GCCs as compared with adenocarcinomas exhibited significantly lower mutation rates in KRAS, GNAS, and APC, and significantly higher mutation rates in CDH1, CHEK2, CDC73, ERCC2, and FGFR2. GCCs as compared with neuroendocrine tumors showed significantly lower mutation rates in KRAS, APC, BRCA2, and FANCA. In GCCs, MSI high/MMR deficient, TMB high (≥17 mutations/Mb), and PD-L1 expression were seen in 0.0%, 0.0%, and 2.0% of tumors, respectively. No significant differences were observed in any immunotherapy-related markers examined when compared with adenocarcinomas and neuroendocrine tumors. In conclusion, GCCs had considerably distinct mutational profiles compared with appendiceal adenocarcinomas and neuroendocrine tumors. Understanding these molecular characteristics may be critical for the development of novel and more effective treatment strategies for GCC.

Goblet Cell Adenocarcinoma of the Appendix: A Systematic Review and Incidence and Survival of 1,225 Cases From an English Cancer Registry

“…Genetic studies in GCA were inconclusive on histogenesis. A commonly reported aetiopathogenic factor was the occurrence of Tumour Protein 53 mutation ( 33 , 45 , 79 ), which in one study was only found in poorly differentiated tumours, possibly suggesting that it is the cause of high-grade transformation ( 45 ). However, the presence of TP53 mutation was inconsistent between studies ( 68 , 75 , 100 ).…”

“…Multiple authors reported no Epidermal growth factor receptor, BRAF (59), KRAS (41,42,59), or Adenomatous polyposis coli (APC) (41,42) mutations in GCA, suggesting that its molecular pathogenesis is significantly different from that of colorectal adenocarcinoma, although again this was not a unanimous finding (33,45). Low rates of microsatellite instability (59), programmed death ligand 1 (PD-L1), and tumour mutational burden (TMB) suggest that GCA is an immunologically "cold" tumour (33).…”

Ovarian Endometrioid Adenocarcinomas With Infiltrative “Adenofibroma-like” Morphology and Aberrant ß-catenin Expression: Tumors That Coexpress CDX2 and LEF1 With Frequent Neuroendocrine Marker Expression, Diminished/Lost PAX8 and Possible Association With Endometrioid Type II Stem Cell Outgrowths in the Fallopian Tube

“…1F). Certainly, the aberrant cytoplasmic and nuclear β-catenin expression in these ovarian endometrioid adenocarcinomas can be helpful in making this distinction, as aberrant β-catenin expression 14 and CTNNB1 mutations 15,16 are not characteristic of appendiceal goblet cell adenocarcinomas. In addition, none of our tumors were positive for CK20, whereas goblet cell adenocarcinomas are frequently positive 13 , and all our cases expressed ER at least focally (albeit often with weak intensity).…”

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

“…Because GCAs are predominantly tumors of mucin secreting cells, they were reclassified as goblet cell adenocarcinomas in the current World Health Organization (WHO) classification of the digestive system (1). GCA was almost exclusively found in the appendix (1); however, more and more extra-appendiceal GCAs are being reported in the literature (3)(4)(5)(6). We suspect that the number of extra-appendiceal GCA is underestimated, because GCA was considered as a special tumor that exclusively existed in the appendix.…”

“…We attempt to reveal the difference between GCAs and intestinal adenocarcinoma with cohesive signet ring cell component (IACSRCC). Early GCA mutational profiling showed it to be distinct from intestinal neuroendocrine tumors (NETs) and conventional intestinal adenocarcinoma (3,9), where common genetic mutations in KRAS, GNAS, and APC were uncommon in GCAs (3,9). However, no studies have to date investigated distinctions between GCA and colorectal adenocarcinoma and the morphologically similar IACSRCCs, in terms of both gene expression and the tumor immune microenvironment.…”