Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published March 17, 2021


Are there any molecularly targeted therapies for cholangiocarcinoma? 

In the United States, cholangiocarcinoma is rare, with approximately 8000 cases occurring per year, but the incidence is rising both in the United States and worldwide. Read the NEJM Case Records of the Massachusetts General Hospital here.

Clinical Pearls

Q: What are some of the risk factors for cholangiocarcinoma?

A: A variety of risk factors have been identified, including inflammatory liver diseases such as primary sclerosing cholangitis, congenital defects such as choledochal cysts, and parasitic infection such as from the liver flukes Opisthorchis viverrini and Clonorchis sinensis. However, cholangiocarcinoma usually arises when there are no clear risk factors.

Q: Are most patients with newly diagnosed cholangiocarcinoma eligible for surgical resection?

A: Cholangiocarcinoma is commonly manifested by abdominal pain, or by weight loss, nausea, poor appetite, or occasionally jaundice, particularly in patients with extrahepatic cholangiocarcinoma. Because of the lack of availability of a routine screening test and the nonspecific clinical features of cholangiocarcinoma, only 25 to 30% of patients present early, with resectable disease.

Morning Report Questions 

Q: How can one distinguish between intrahepatic cholangiocarcinoma and metastatic adenocarcinoma to the liver?

A: Distinguishing metastatic adenocarcinoma from intrahepatic cholangiocarcinoma can be challenging, since the immunohistochemical pattern that is typical of cholangiocarcinoma (CK7+, CK19+, and CK20−) is also seen in patients with metastatic cancers of the pancreas, stomach, small bowel, and less commonly, the colon. Because of the absence of a definitive diagnostic immunohistochemical biomarker, intrahepatic cholangiocarcinoma has historically been a diagnosis of exclusion when a dominant liver mass is identified and no alternative primary cancer is detected on PET-CT or on upper or lower endoscopy. Development of the albumin in situ hybridization assay has improved the ability of pathologists to establish the diagnosis of intrahepatic cholangiocarcinoma. A positive albumin in situ hybridization assay in the context of adenocarcinoma in the liver has a high specificity for intrahepatic cholangiocarcinoma. 

Q: Are there any molecularly targeted therapies for cholangiocarcinoma?

A: In the past several years, multiple actionable targets have been identified in intrahepatic cholangiocarcinoma, and the use of molecularly targeted therapies has resulted in substantial clinical improvement in select patients. In 2020, pemigatinib, an oral small-molecule inhibitor of fibroblast growth factor receptor (FGFR), became the first drug approved by the FDA specifically for the treatment of cholangiocarcinoma; the approval was based on a study that showed a response rate of 35.5% in patients with advanced refractory cholangiocarcinoma harboring an FGFR2 fusion or rearrangement. This molecular alteration is present in 13 to 14% of patients with intrahepatic cholangiocarcinoma, and given that FGFR2 fusions rarely occur with other adenocarcinomas, it can serve as both a diagnostic marker and a therapeutic target. Additional promising therapeutic agents for the treatment of intrahepatic cholangiocarcinoma are in development.

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