Cholangiohepatoma

Cholangiohepatoma, also referred to as mixed hepatocellular cholangiocarcinoma (HCC-CC) or combined hepatocellular-cholangiocarcinoma (cHCC-CC) or hepatocholangiocarcinoma, refers to synchronous cholangiocarcinoma and hepatocellular carcinoma (HCC) in the same tumor. It is a rare and aggressive primary hepatic tumor combination. The origin of cholangiohepatoma is closely linked to the origin of cholangiocarcinoma rather than hepatocellular carcinoma.

Terminology

A cholangiohepatoma is defined when both histological types are found within the same hepatic tumor. Therefore, it does not apply to synchronous separated hepatocellular and cholangiocellular carcinomas. Furthermore, fibrolamellar hepatocellular carcinoma and hepatoblastoma are not included in the current definition of cholangiohepatoma ³.

Epidemiology

The incidence of cholangiohepatoma varies between 0.4% and 4.7%.

Clinical presentation

Most commonly, these tumors develop asymptomatically until they become more advanced. They can then manifest with right upper quadrant pain, weight loss, and obstructive jaundice.

Both alpha-fetoprotein (AFP), a serum marker for hepatocellular carcinoma, and carbohydrate antigen 19-9 (CA 19-9), a serum marker for cholangiocarcinoma, may be elevated. AFP levels tend to be lower in cholangiohepatoma when compared to hepatocellular carcinoma ³. 

Pathology

Etiology

Histogenesis of the tumor is thought to occur at the canal of Hering:

• the canals of Hering (CoH) or intrahepatic bile ductules are found near the outer edge of a liver lobule
• they are lined partially by cholangiocytes and partly by hepatocytes
• hepatic stem cell niches (hepatic progenitor cells) have been identified in the canals of Hering
• they can differentiate into hepatocytes and cholangiocytes and can, therefore, give rise to hepatocellular carcinoma, cholangiocarcinoma, and cholangiohepatoma, which shares features of both hepatocellular carcinoma and cholangiocarcinoma

Microscopic appearance

• conventional histology may be inconclusive
• the 2010 WHO classification divides cholangiohepatoma tumors into two types ³:
  • classical: histologically characterized by typical areas of hepatocellular carcinoma together with those of cholangiocarcinoma in the same tumor
  • with stem cell features

Immunophenotype

Glypican-3 is highly sensitive and specific for identification of the hepatocellular carcinoma component and only weakly reactive with cholangiocarcinoma. Biliary cell stains are mucin, CK7, and CK19, whereas hepatocellular stains comprise polyclonal CEA, Hep Par 1, and CD10. 

Radiographic features

Imaging features are a combined spectrum of intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

Ultrasound

Seen as a heterogeneous iso-to-hyperechoic mass with a peripheral hypoechoic halo of the compressed liver. Capsular retraction and lobulated appearance with infiltration of the biliary system are usually seen. Ultrasound appearance is non-specific and usually parallels that of conventional cholangiocarcinoma.

CT

The lesion is usually lobulated and well delineated, although a well-defined capsule is not seen. Hepatic capsular retraction and infiltration of the biliary tree are usually present. Biliary obstruction is often disproportionate to that expected for the tumor size.

On post-contrast imaging, progressive delayed enhancing regions mixed with regions of arterial enhancement and washout is very suggestive of cholangiohepatoma.

MRI

MRI features of cholangiohepatoma have not been described extensively. 

Signal characteristics:

• T1: low signal
• T2: intermediate-to-high signal intensity +/- central hypointense focus
• DWI/ADC: marked restricted diffusion ³
• T1 C+ (Gd): progressive delayed enhancing areas mixed with areas arterial enhancement and washout

MR imaging with a hepatocyte-specific agent like gadoxetic acid may also be useful to differentiate cholangiohepatoma and cholangiocarcinoma. 

Capsular retraction has shown to be much less common when compared to a intrahepatic cholangiocarcinoma ⁶. Intralesional fat, intralesional hemorrhage and tumor thrombus has been uncommonly reported ⁶.

Treatment and prognosis

The prognosis of cholangiohepatoma is poor, even with resection. 

Differential diagnosis

Possible differential considerations include:

• hepatocellular carcinoma (HCC)
  • tumor thrombus more common
  • capsular retraction uncommon
  • may appear very similar
• cholangiocarcinoma: especially intrahepatic cholangiocarcinoma
  • peripheral location
  • biliary obstruction
  • delayed enhancement
• liver metastases: central necrosis (high T2 signal) is more common
• hepatic abscess