Although a unified criteria for combined HCC-CC is still not available, it is generally accepted that a firm diagnosis of combined HCC-CC requires evidence of HCC differentiation (Fig. 2a), such as trabecular growth

pattern, bile production, or bile canaliculi as well as clear evidence of CC (Fig. 2b), such as true glandular structures formed by biliary-type epithelium, mucin production or prominent desmoplastic stoma.4,14 In addition, ideally, an interface of these two components showing they intermingle intimately with each other should also be appreciated (Fig. 3). Practically, a definitive diagnosis always requires the use of immunohistochemical and special stains to demonstrate LDE225 both hepatocytic and biliary phenotypes. Commonly used stains include Hep Par 1 (Fig. 4a), polyclonal NVP-BKM120 concentration carcinoembryonic antigen (Fig. 4b), or CD10 for the hepatocytic differentiation, and mucin (Fig. 4c), CK7, and CK19 (Fig. 4d) stains for the biliary differentiation. Combined HCC-CC often expresses both biliary cytokeratins and markers of HCC, and is an important diagnosis to consider when there is an apparently conflicting or overlapping immunophenotype.15 While fibrolamellar carcinoma, a variant of HCC, very rarely occurs in association with CC, a single case of combined fibrolamellar HCC-CC has been reported previously.16 Studies with a series of combined fibrolamellar HCC-CC

are needed to further characterize this rare neoplasm. Glypican-3 (GPC3) is a novel serological and immunohistochemical marker of hepatocellular carcinoma.17–19 A recent study to examine GPC3 immunoreactivity MCE in combined HCC-CC shows the expression is sensitive and specific to the HCC component of combined HCC-CC but few cases also show weak immunoreactivity in the cholangiocarcinoma component of combined HCC-CC.20 While the positivity of GPC3 in the cholangiocarcinoma component may be a drawback, this antibody may offer as an additional immunohistochemical stain in diagnosing combined HCC-CC, if used along with

other antibodies and in careful correlation with morphology. The cell of origin of combined HCC-CC has been a matter of dispute. Overall three possibilities may be postulated regarding its cell of origin: (i) collision (double) tumor of HCC and CC that incidentally coexist in the same liver; (ii) subsequent differentiation of HCC or CC into the other component; and (iii) the cancer derives from the hepatic progenitor cells (Fig. 5). The fact that the HCC and CC elements intermingle with each other in a transitional area in most combined HCC-CC makes the first hypothesis less likely. Depending on various investigations, patients with combined HCC-CC share similar clinical and pathological features with patients with HCC4,21 or CC12,15,22 or the tumors are clinicopathologically different from those of CC11 or HCC.