Cases of Mixed Hepatocellular Carcinoma–Cholangiocarcinoma Emerging

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We found that 11.4% [of specimens] actually had mixed hepatocellular carcinoma–cholangiocarcinomas. Not much is known about them. The patients were treated as if they had liver cancer, since there is no protocol for the mixed entity.
— Varun ­Kapur, MD

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Combined hepatocellular carcinoma–cholangiocarcinoma is a histopathologically distinct tumor for which no formal treatment guidelines exist. It is also a malignancy that is being diagnosed more often, according to researchers from Mount Sinai Beth Israel Medical Center, New York, who reported their case series at the 2016 Annual Conference of the National Comprehensive Cancer Network (NCCN).1 Varun ­Kapur, MD, explained that advances in immunohistochemistry and the availability of numerous tumor markers have led to more observations of this “mixed entity,” which was first identified in 1940.

“We went back and looked at specimens and scanned for cholangiocarcinoma markers, and we found that 11.4% actually had mixed hepatocellular carcinoma–cholangiocarcinomas,” he said. “Not much is known about them. The patients were treated as if they had liver cancer, since there is no protocol for the mixed entity.”

The researchers reviewed all primary hepatocellular tumors at Beth Israel Medical Center between 2008 and 2013. They identified eight combined hepatocellular carcinoma–cholangiocarcinomas using the immunohistochemical hepatocellular carcinoma markers (HepPar1, CD10, pCEA, arginase-1), biliary markers (CK7, CK19), and mucin. Additional immunostaining was performed for liver fatty acid binding protein, CA19.9, glypican-3, CD117 (c-kit), epithelial adhesion molecule, beta-catenin, and C-reactive protein.

The charts of the eight patients with the mixed tumor type were also reviewed to collect sociodemographic, clinical, radiologic, and outcomes data. Seven of the eight patients were male. Five patients had cirrhosis of the liver, including four cases of viral hepatitis.

Study Findings

“Using different treatment approaches, survival was unexpectedly high,” Dr. Kapur noted. “Six of eight patients (75%) were still alive at follow-up.” The mean follow-up was 22.4 months, and the median follow-up was 24 months (range, 2–50 months). He added that survival with this mixed tumor type appears to be better than is typically seen with either hepatocellular carcinoma or cholangiocarcinoma.

Tumor Markers for Mixed Liver Cancer–Cholangiocarcinoma

  • With the availability of multiple tumor markers, more cases of mixed hepatocellular carcinoma–cholangiocarcinoma are being detected.
  • There are no guidelines for tailored treatment of this mixed entity.
  • In a case series from Mount Sinai Beth Israel Medical Center, survival of these patients appears to be better than survival for either liver cancer or cholangiocarcinoma.

Two patients are alive and apparently disease-free, including one patient 4 years after laparoscopic radiofrequency ablation and another one 3 years after radiofrequency ablation plus liver transplant. One patient was unresectable and has stable disease more than 2 years after five courses of transarterial chemobolization. Two patients recurred after hepatectomy plus chemotherapy and radiofrequency ablation/transarterial chemobolization. One metastatic patient is alive at 2 months, and two unresectable patients died.

Dr. Kapur concluded that multicenter data are needed to better understand the clinical behavior of this tumor and determine tailored treatment, “rather than treating it like hepatocellular carcinoma or cholangiocarcinoma.” ■

Disclosure: Dr. Kapur reported no potential conflicts of interest.


1. Kapur V, Iskandar ME, Brower ST, et al: Combined hepatocellular-cholangiocarcinoma: A case series at a North American Center. 2016 NCCN Annual Conference. Breakfast Session. Presented March 31, 2016.