Synchronous intracholecystic papillary-tubular neoplasm and pancreatic intraductal tubulopapillary neoplasm: A case report

Table 1 Clinicopathological comparison between intracholecystic papillary-tubular neoplasm and intraductal tubulopapillary neoplasm[4,6-12]

Feature	ICPN	ITPN
Age/sex tendency	Usually older adults; female predominance	Usually older adults; slight male predominance
Gross/imaging pattern	Polypoid or mass-forming intraluminal gallbladder lesion; may coexist with gallbladder wall thickening or suspected gallbladder cancer	Solid or mixed solid-cystic intraductal pancreatic mass; ductal dilatation may be present, and the lesions may mimic other pancreatic cystic neoplasms
Histological architecture	Papillary, tubular, or tubulopapillary architecture; heterogeneous epithelial lineages may include biliary, gastric, intestinal, and oncocytic phenotypes	Back-to-back tubules, cribriform or abortive papillary structures, high-grade cytology, and minimal or absent mucin
Dysplasia/invasion	Low- or high-grade dysplasia; invasive carcinoma may be present, but resected ICPN often has more a favorable prognosis than conventional gallbladder cancer	High-grade dysplasia is characteristic; invasive carcinoma is common in resected series, but prognosis after resection is generally better than that of conventional pancreatic ductal adenocarcinoma
Immunophenotype	Variable according to lineage; biliary-type lesions often express CK7 and MUC1, gastric-type lesions may express MUC5AC/MUC6, and intestinal-type lesions may express CDX2/CK20	Typically MUC1 and MUC6 positive, MUC2 negative, and MUC5AC absent or limited
Molecular features	Heterogeneous; reported alterations include KRAS, STK11, CTNNB1, APC, TP53, and lineage-associated changes	KRAS/GNAS alterations are uncommon, whereas PI3K pathway alterations, chromatin-remodeling alterations, FGFR2 fusions, and rare ALK fusions have been reported
Clinical implication	Surgical resection is recommended when feasible; if invasive carcinoma is present, management should follow gallbladder cancer principles and pathologic stage	Surgical resection is recommended when feasible; the invasive component, margin status, nodal status, and recurrence risk should guide surveillance

ICPN: Intracholecystic papillary-tubular neoplasm; ITPN: Intraductal tubulopapillary neoplasm; CK7: Cytokeratin 7; CK20: Cytokeratin 20; MUC1: Mucin 1; MUC5AC: Mucin 5AC; CDX2: Caudal type homeobox 2; PI3K: Phosphatidylinositol 3-kinase; FGFR2: Fibroblast growth factor receptor 2; ALK: Anaplastic lymphoma kinase.

Table 2 Reported synchronous or metachronous pancreatic and gallbladder epithelial tumors

Ref.	Sex/age	Pancreatic lesion	Gallbladder lesion	Timing	Molecular/genetic evidence	Possible mechanism or key finding
Ueda et al[14]	Male/58	Papillary adenocarcinoma	Papillary adenocarcinoma of the gallbladder and CBD	Synchronous	Not mentioned	Associated with anomalous arrangement of the pancreaticobiliary ductal system; gallbladder, CBD, and pancreatic duct tumors were not continuous
Sato et al[15]	Male/74	Mucinous cystadenocarcinoma	Well-differentiated tubular adenocarcinoma of the gallbladder; poorly differentiated tubular adenocarcinoma of CBD	Synchronous	p53-positive nuclei were detected only in the pancreatic tumor	Triple synchronous tumors with different histopathology; findings suggested different oncogenic mechanisms rather than a single DNA-repair abnormality
Minami et al[16]	Female/50	Moderately differentiated ductal adenocarcinoma	Moderately differentiated tubular adenocarcinoma	Metachronous; pancreatic cancer 10 years after cholecystectomy	Not mentioned	Associated with PBM without bile duct dilatation; emphasized long-term surveillance of the pancreas and biliary tract after biliary diversion
Lahmar et al[17]	Female/68	Adenosquamous carcinoma	Moderately differentiated adenocarcinoma of the gallbladder invading CBD	Metachronous; pancreatic cancer 4 years after cholecystectomy	Not mentioned	Associated with PBM and cystic dilatation of the CBD; pancreatobiliary or biliopancreatic reflux was proposed as a carcinogenic mechanism
Chen et al[18]	Female/56	Ductal adenocarcinoma	Well-differentiated adenocarcinoma	Metachronous; pancreatic cancer 3 years after cholecystectomy	Not mentioned	No recurrence after 33 months of follow-up after pancreaticoduodenectomy; mechanism not specified
Rungsakulkij and Boonsakan[19]	Female/46	Well-differentiated ductal adenocarcinoma	Well-differentiated adenocarcinoma	Synchronous	Not mentioned	Associated with PBM and pancreaticobiliary reflux; authors emphasized the possibility of double primary cancer in PBM
Mori et al[20]	Female/72	Moderately differentiated ductal adenocarcinoma	Well-differentiated tubular adenocarcinoma	Synchronous	Not mentioned	Associated with congenital biliary dilatation and PBM; reported as an extremely rare synchronous primary gallbladder-pancreatic cancer case in this setting
Ikeda et al[21]	Female/71	IPMN with invasive carcinoma	Gallbladder cancer arising in polypoid lesions; histological not specified	Metachronous; pancreatic cancer 5 years after cholecystectomy	IHC: Pancreatic tumor MUC1+, MUC5AC+, MUC2-	Associated with non-dilated PBM; supports surveillance for pancreatic as well as biliary tract cancer in PBM
Kuhara et al[22]	Female/65	First well-differentiated adenocarcinoma in pancreatic head; later moderately differentiated adenocarcinoma in remnant pancreas	Advanced papillary adenocarcinoma	Metachronous; pancreatic cancers 6.2 and 12.5 years after cholecystectomy	Not mentioned	Associated with PBM; bile pigment and marked inflammation in non-cancerous pancreatic ducts supported chronic inflammation and reflux-related carcinogenesis
Sato et al[23]	Male/72	IPMN	Adenocarcinoma	Synchronous	IHC: MUC6-positive pyloric gland metaplasia in both the dilated pancreatic duct and gallbladder background mucosa	Associated with PBM; authors suggested a possible common phenotypic origin and recommended comprehensive pancreaticobiliary evaluation
Kato et al[24]	Female/77	ITPN with invasive carcinoma	Papillary adenocarcinoma	Metachronous; pancreatic cancer 2 years after cholecystectomy	IHC: MUC1 focal weak+, MUC2-, MUC5AC-	Associated with PBM; supports careful long-term follow-up after diversion surgery because pancreatic or biliary cancers may still occur
Kogure et al[25]	Female/in her 80s	Adenosquamous carcinoma	Carcinoma; histological not specified	Synchronous	Not mentioned	Associated with PBM; co-occurrence of pancreatic adenosquamous carcinoma and gallbladder carcinoma was described as extremely rare
Miyazawa et al[26]	Male/63	Adenocarcinoma	Gallbladder cancer; histological not specified	Metachronous; pancreatic cancer 5 years after cholecystectomy	Not mentioned	PBM was diagnosed after cholecystectomy; progressive pancreatic changes suggested biliopancreatic reflux-related pancreatic carcinogenesis
Present case	Female/30	ITPN with multifocal invasive carcinoma	ICPN with high-grade dysplasia	Synchronous	No pathogenic variant identified by germline WES; somatic sequencing was not performed	No PBM was evident on available imaging; synchronous gallbladder ICPN and pancreatic ITPN suggest a possible field effect or shared epithelial susceptibility

CBD: Common bile duct; PBM: Pancreaticobiliary maljunction; IPMN: Intraductal papillary mucinous neoplasm; IHC: Immunohistochemistry; MUC1: Mucin 1; ICPN: Intracholecystic papillary-tubular neoplasm; ITPN: Intraductal tubulopapillary neoplasm; WES: Whole-exome sequencing.