A paired sequencing study of goblet cell adenocarcinomas with coincident sessile serrated lesions and low-grade appendiceal mucinous neoplasms

Appendiceal goblet cell carcinoma (GCA) is a rare tumor type that has no known precursor. In our diagnostic practice, we observed co-occurrence of GCA with sessile serrated lesions (SSLs) and low-grade appendiceal mucinous neoplasms (LAMNs). Reviewing clinical archives, we identified 35 in-house resections of GCA, in which six (17%) harbored coincident SSLs or LAMNs. Here, we performed paired next-generation sequencing of adenocarcinomas and the coincident lesions to investigate the possibility of shared clonal relationships. For comparison, we also performed paired sequencing on three conventional appendiceal adenocarcinomas with goblet cell differentiation and coincident SSLs or LAMNs. All nine sequenced SSLs or LAMNs harbored activating KRAS mutations, two with concurrent GNAS mutations. There were no apparent shared somatic alterations between the coincident lesions and the six GCAs, the latter of which harbored alterations in other genes including ARID1A, ERBB2, RHOA, and ARHGAP35. In the three conventional adenocarcinomas, there were shared somatic alterations between the adenocarcinomas and the coincident SSLs or LAMNs, including in KRAS, SMAD4, and TP53. In contrast to conventional adenocarcinoma, GCAs do not evidently arise from KRAS-mutated precursor lesions. Based on our paired sequencing study, GCAs were clonally unrelated to coincident KRAS-mutant SSLs and LAMNs, and the reason for the relatively high prevalence of co-occurring lesions among appendectomies containing GCA remains uncertain.