Cholangioblastic Cholangiocarcinoma (NIPBL::NACC1 Cholangiocarcinoma)

The cholangioblastic variant of intrahepatic cholangiocarcinoma is a distinctive neoplasm that typically affects young women without underlying liver disease. Morphologically, it demonstrates solid, trabecular, and tubulocystic architecture, biphasic small cell-large cell cytology, and immunoreactivity for inhibin, neuroendocrine markers, and biliary but not hepatocellular markers. In 2021, our group identified a characteristic NIPBL::NACC1 gene fusion in cholangioblastic cholangiocarcinoma, and since then ~20 genetically confirmed cases have been reported in the literature. We report 2 additional cases, both of which caused diagnostic challenges. The first was previously published as a "biliary adenofibroma with malignant features" which we now show recurred as a high-grade adenocarcinoma. Re-review of the original lesion demonstrated the morphologic and immunohistochemical features of highly cystic cholangioblastic cholangiocarcinoma, whereas the high-grade recurrence lacked many of these features. In addition to the characteristic NIPBL::NACC1 gene fusion, the recurrence demonstrated loss of the RB1 and PTEN genes which were found in the highly cystic, bland areas of the original tumor, suggesting that the recurrence was derived from this bland component. The second case was originally misclassified as metastatic well-differentiated neuroendocrine neoplasm and only focally demonstrated the characteristic biphasic small cell-large cell cytology. In addition, a review of 7 cholangioblastic cholangiocarcinomas in our files demonstrates that loss of chromosome 13q14.2 (where the RB1 gene resides) and loss of chromosome 6q15-q16.3 are recurrent secondary changes in these neoplasms. Expression profiling demonstrated alterations in the transforming growth factor receptor beta superfamily, and overexpression of MYC which was validated by immunohistochemistry. Our findings expand the morphologic and genetic spectrum of this neoplasm and provide insight into secondary genetic changes associated with progression.