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Context.— The nature and associations of gallbladder (GB) “adenomyoma” (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.— To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.— Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.— Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3–5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive (“adenomyomatosis”). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma was arising from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.— AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component; (ie, the name “adeno-myoma” is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

Context.— Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. Objective.— To investigate their morphologic, immunohistochemical, and molecular features. Design.— Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. Results.— The mean age at diagnosis was 69 years (42–81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Conclusions.— Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

Pancreatobiliary tract lesions are increasingly being discovered because of more sensitive imaging modalities. Magnetic resonance imaging has identified incidental pancreatic cysts in 13.5% of patients of progressively increasing age. Pancreatobiliary tissue is more accessible through endoscopic ultrasound and magnetic resonance imaging–guided biopsy procedures, and is now an integral part of pathologists' routine practice. Accordingly, several new tumor categories have been recently recognized, including intraductal tubulopapillary neoplasm, a new addition to tumoral intraepithelial neoplasms. Other entities have been reclassified, including the recent transition to 2-tiered grading of preinvasive neoplasms, as well as new perspectives on the distinctive biologic behavior of oncocytic intraductal papillary mucinous neoplasms (IPMNs) compared with other IPMN subtypes. This has led to proposals for revised staging of virtually every segment of the pancreatobiliary tree, with theranostic markers becoming an integral part of workup. Ki-67 is now an integral part of the classification of neuroendocrine tumors, with new definitions of “high-grade neuroendocrine carcinoma.” Although bile duct brushings have opened new avenues for diagnosis, their sensitivity remains low and often requires concomitant fluorescent in situ hybridization to better define ambiguous cases. Various molecular pathways have been elucidated for pancreatic cysts, including KRAS for ductal neoplasia, GNAS for intestinal IPMNs, RNF3 for mucinous cysts, and VHL for serous cystic neoplasms, all key players in diagnostic workup. Integration of these updates into our understanding of pancreatobiliary disease requires active engagement of pathologists for appropriate specimen triage, judicious interpretation of results, and incorporation into reporting and staging. They also provide exciting opportunities for targeted therapy.

Context.—There are virtually no data in the literature regarding the incidence, patterns, and clinicopathologic characteristics of mucinous carcinomas (MCs) of the gallbladder (GB).Objective.—To determine the incidence of mucinous differentiation in invasive GB carcinomas and the clinicopathologic characteristics of those that qualify as MC.Design.—Primary invasive GB carcinomas (n = 606) were reviewed for mucinous differentiation. Some degree of mucin production was identified in 40 cases (6.6%); however, only 15 (2.5%) were qualified for the World Health Organization definition of MC (stromal mucin deposition constituting >50% of the tumor).Results.—The mean age was 65 years, and the female to male ratio was 1.1 (versus 3.9 for conventional pancreatobiliary-type GB adenocarcinomas; P = .04). A significant proportion of the cases (8 of 12, 67%) presented with the clinical picture and intraoperative findings that were interpreted as acute cholecystitis. Mean and median tumor sizes were larger than those of conventional adenocarcinomas (4.8 and 3.4 cm versus 2.9 and 2.5 cm, respectively; P = .01). Most (13 of 15, 87%) cases presented with pT3 tumors (versus 48% for ordinary GB carcinomas; P = .01). Two cases had almost an exclusive colloid pattern (>90% composed of well-defined stromal mucin nodules that contained scanty carcinoma cells, most of which were floating within the mucin). Eight cases were of mixed-mucinous type, showing a mixture of colloid and noncolloid patterns. Five others had prominent signet-ring cells, both floating within the mucin (which constituted >50% of the tumor by definition) and infiltrating into the stroma as individual signet-ring cells in some areas. Immunohistochemical analysis performed on the 7 cases that had available tissue revealed CK7 in 4 of 7 (57%), CK20 in 2 of 7 (29%), MUC1 in 4 of 7 (57%), MUC2 in 6 of 7 (86%), CDX2 in 1 of 7 (14%), MUC5AC in 6 of 7 (86%), MUC6 in 0 of 7 (0%), and loss of E-cadherin in 6 of 7 (86%). The MLH1 and MSH2 were retained in 6 of 7 cases (100%). Follow-up information was available for 13 cases: 11 (85%) died of disease (1–37 months) and 2 (15%) were alive (23 months and 1 month). Overall survival of MCs was significantly worse than that of conventional adenocarcinomas (13 versus 26 months; P = .01); however, that did not seem to be independent of stage.Conclusions.—Mucinous carcinomas constitute 2.5% of GB carcinomas. They present with an acute cholecystitis-type picture. Most MCs are a mixed-mucinous, not pure colloid, type. They are typically large and advanced tumors at the time of diagnosis and thus exhibit more-aggressive behavior than do ordinary GB carcinomas. Immunophenotypically, they differ from conventional GB adenocarcinomas by MUC2 positivity, from intestinal carcinomas by an often inverse CK7/20 profile, from pancreatic mucinous carcinomas by CDX2 negativity, and from mammary colloid carcinomas by a lack of MUC6. Unlike gastrointestinal MCs, they appear to be microsatellite stable.