Feature Summary of Hepatoid Tumors
Histologically similar to hepatocellular carcinoma (HCC) but arise outside the liver.
Most commonly arises in the gastrointestinal tract and pancreaticobiliary system.
Hepatocellular differentiation marked by positive immunostains for hepar-1, arginase-1, CD10 in canalicular pattern, and, to a greater extent, alfa-fetal protein and glypican-3
Largely classified as a form of adenocarcinoma rather than a specific entity.
In contrast to hepatocellular carcinoma, they are positive for SALL-4 and CK19.
Overall they are aggressive malignant neoplasms.
Hepatoid tumors encompass a heterogeneous group of neoplasms with hepatoid differentiation that is histologically similar to hepatocellular carcinoma (HCC) but is outside the liver. By immunohistochemistry, hepatoid tumors are also positive for Hep Par-1, arginase-1, alpha-fetoprotein, and CD10 in a canalicular pattern.
Hepatoid tumors are found in different anatomic sites including the lung, thymus, adrenal glands, ovary, and uterus, but the gastrointestinal-pancreaticobiliary system appears as the most common site. However, hepatoid tumors are often considered to be a variant of adenocarcinomas in these organs rather than a specific entity by the current WHO classification. Overall, hepatoid tumors are aggressive malignant neoplasms. They show different biological behaviors. For example, Hepatoid tumor of the colon is associated with a worse prognosis than a gastric hepatoid tumor. Hepatoid tumors also show phenotypical features different from hepatocellular carcinoma. Notably, the vast majority hepatoid tumors express alpha-fetal protein detectable by immunohistochemical stain compared to only 30% of hepatocellular carcinoma. Hepatoid tumors are positive for CK19 while hepatocellular carcinoma is not. Hepatoid tumor of the stomach and ovary expresses SALL4 while hepatocellular carcinoma does not. Conversely, hepatocellular carcinoma is positive for BSEP and MDR3 while hepatoid tumors are not. The importance of recognizing hepatoid tumors is at least three-fold. First, some so-called “hepatocellular carcinoma” found in non-cirrhotic liver is in fact metastatic hepatoid tumors. Second, hepatoid tumors should be kept in differential diagnosis for poorly differentiated tumors in a solid sheet of epithelioid cells with ample, often eosinophilic cytoplasm. Third, tumors with histological and immunohistochemical features of hepatocytes outside the liver are not necessarily metastatic hepatocellular carcinoma.
It is important to recognize that hepatoid differentiation of a tumor does not necessarily confer malignancy. For example, pancreatic neuroendocrine tumors (NETs) and solid pseudopapillary neoplasms (SPNs) may also show hepatoid differentiation. Hepatoid NETs show aggressive behavior, whereas hepatoid SPNs harbor CTNNB1 mutations and are characterized by an indolent clinical course.
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Key References
Mattiolo, Paola et al. “Hepatoid tumors of the gastrointestinal/pancreatobiliary district: morphology, immunohistochemistry, and molecular profiles.” Human pathology vol. 132 (2023): 169-175. doi:10.1016/j.humpath.2022.06.011
Fujikura, Kohei et al. “BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas.” The American journal of surgical pathology vol. 40,5 (2016): 689-96. doi:10.1097/PAS.0000000000000585 https://pubmed.ncbi.nlm.nih.gov/26735860/
Su, Jiann-Sheng et al. “Clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma: a literature review.” World journal of gastroenterology vol. 19,3 (2013): 321-7. doi:10.3748/wjg.v19.i3.321
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