Metachronous bile duct cancers originate from primary cancer clones

Metachronous tumors arising in the remnant bile duct after surgical resection for primary biliary tract cancers (BTCs) are rarely treated surgically and have not been well documented. This study aimed to clarify the clinicopathological and genomic features of metachronous tumors arising in the remnant bile duct. Consecutive 12 patients who underwent resection for metachronous BTCs arising in the remnant bile duct after primary surgical resection between 2008 and 2020 were enrolled. Clinicopathological analysis and genomic analysis using targeted amplicon sequencing for 31 biliary tract cancer-related genes, including TP53, APC, ARID1A, ARID2, BAP1, CDKN2A, CTNNB1, ELF3, ERBB2, GNAS, IDH1, KRAS, and SMAD4, and immunohistochemistry for p53, p16, SMAD4, ARID1A, and β-catenin, were performed on 12 matched pair of primary and metachronous BTCs. In the 12 patients, 7 metachronous tumors developed antegradely in the lower portion of the biliary tree, and the remaining 5 metachronous tumors developed retrogradely in the upper portion, with negative bile duct margin at the initial operations. Molecular analysis revealed mutations and copy number alterations in TP53 (87.5%), APC (20.8%), CTNNB1 (20.8%), KRAS (12.5%), GNAS (8.3%), and RNF43 (8.3%). In comparison analysis, the matched primary and metachronous tumors shared identical genomic features in 10 cases, except in 2 cases showing metachronous perihilar and distal bile duct carcinomas after gallbladder cancer resection. Seven patients survived without recurrence, 5 showed postoperative local recurrences, and 2 died. Nine patients achieved 5-year overall survival after primary surgery. In conclusion, among the 12 patients with subsequent metachronous BTCs, 10 originated from neoplastic clones of the primary carcinoma, indicating recurrence due to intramural metastases or intraductal disseminations. Repeated surgical approach for metachronous BTCs may provide definitive local control and potentially prolong survival in these patients.