January 2023 – Gastroenterology

TP53.

The patient’s initial presentation is highly concerning for cholangiocarcinoma arising above the level of the common bile duct as indicated by the lack of obstructive jaundice and the location of post-obstructive bile duct dilation.  

The gross and histologic findings demonstrate an interesting presentation of colloidal carcinoma (mucinous adenocarcinoma) arising from perihilar bile ducts. Colloidal carcinoma is a rare histologic subtype of cholangiocarcinoma that most often arises in association with intraductal papillary neoplasia of the bile ducts (IPNB). Colloidal bile duct carcinomas may be widely disseminated at the time of diagnosis; however, in this case, the lesion showed minimal invasion into the bile duct wall and adventitial fat. 

Cholangiocarcinomas share many molecular features with pancreatic ductal adenocarcinomas (PDAC), with several common alterations factoring prominently into the mutational landscapes of both tumors. Of note, FGFR2 and FGFR3 rearrangements can act as driver mutations in cholangiocarcinomas, while FGFR rearrangements have not been reported in PDAC. FGFR aberrations represent an alternative pathway of oncogenesis, and as a result, the frequency of KRAS mutations is diminished at the population level to a level below that of TP53, the most commonly mutated tumor suppressor gene in both malignancies and most commonly mutated gene in cholangiocarcinoma.

It is important to note that there may be significant differences in mutational frequencies depending on intra vs. extrahepatic locations. In general, it appears that extrahepatic cholangiocarcinomas have a more diverse profile of driver mutations than intrahepatic carcinomas; however, this remains difficult to assess due to the relatively low frequency with which cholangiocarcinomas occur. As a whole, GNAS mutations in PDAC and cholangiocarcinoma are rare; however, in the subset of cancers arising from intraductal papillary neoplasms, GNAS mutations are more frequent. Fewer than half of IPNBs carry a GNAS mutation, and a small minority of these cases progress to cholangiocarcinoma. SMAD4 is frequently mutated in cholangiocarcinoma as well. In this capacity, it functions as driver mutation; however, at a frequency of 10%, SMAD4 mutations are far less common than both KRAS and TP53. 

References

1. Nakamura, H Arai, Y Totoki, Y et al. Genomic spectra of biliary tract cancer. Nature Genetics. 2015; 47(9):1003-10.
2. Arend MJ, Fukayama M, Klimstra DS, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IRAC; 2019.
3. The Cancer Genome Atlas Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell; 32(2):185-203.