Update on Pathologic and Radiologic Diagnosis of Combined Hepatocellular-Cholangiocarcinoma

Abstract

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a malignant primary liver carcinoma characterized by the unequivocal presence of both hepatocytic and cholangiocytic differentiation within the same tumor. Recent research has highlighted that cHCC-CCAs are more heterogeneous than previously expected. In the updated consensus terminology and WHO 2019 classification, "classical type" and "subtypes with stem-cell features" of the WHO 2010 classification are no longer recommended. Instead, it is recommended that the presence and percentages of various histopathologic components and stem-cell features be mentioned in the pathologic report. The new terminology and classification enable the exchange of clearer and more objective information about cHCC-CCAs, facilitating multi-center and multi-national research. However, there are limitations to the diagnosis of cHCC-CCA by imaging and biopsy. cHCC-CCAs showing typical imaging findings of HCC could be misdiagnosed as HCC and subjected to inappropriate treatment, if other clinical findings are not sufficiently considered. cHCC-CCAs showing at least one of the CCA-like imaging features or unusual clinical features should be subjected to biopsy. There may be a sampling error for the biopsy diagnosis of cHCC-CCA. An optimized diagnostic algorithm integrating clinical, radiological, and histopathologic information of biopsy is required to resolve these diagnostic pitfalls.

Keywords: Biopsy; Diagnosis; Liver neoplasm; Magnetic resonance imaging; Stem cell.

Figure 1

A 57-year-old male with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) in the background liver of hepatitis B-virus and alcohol related chronic hepatitis. A 3.4-cm infiltrative mass lesion in the liver segment 7 shows low-signal intensity in precontrast T1-weighted image (A), peripheral enhancement in the arterial phase (B), absence of washout in portal phase (C) and 2-minute delay phase (D), decreased hepatobiliary uptake in hepatobiliary phase (E), and high-signal intensity in T2-weighted image (F) of gadoxetate-enhanced magnetic resonance imaging. It is categorized as Liver Imaging Reporting and Data System M based on targetoid appearance. On pathologic examination (G–I), the tumor shows cholangiocarcinoma (CCA) component in whitish and fibrotic area of gross specimen and hepatocellular carcinoma (HCC) component in more yellowish area of resected specimen, and there are transitional differentiation zones between them (G, gross feature of resected specimen; H, scanning view of hematoxylin-eosin stain; I, map of histological components). HCC and CCA areas are not distinguishable in magnetic resonance imaging.

Figure 2

A 58-year-old male showing combined hepatocellular-cholangiocarcinoma (cHCC-CCA) with cholangiolocellular (CLC) and intermediate-cell carcinoma components, developed in cirrhosis of unknown etiology. A 3.2-cm lobulated mass lesion in the liver segment 4 shows low-signal intensity in precontrast T1-weighted image (A), peripheral enhancement in the arterial phase (B), absence of washout in portal phase (C) and delayed central enhancement in hepatobiliary phase (D) of gadoxetate-enhanced magnetic resonance imaging (MRI). The lesion also shows nodule-in-nodule appearance: the inner nodule exhibited hypervascularity in arterial phase, absence of washout in portal phase, and low-signal intensity in T2-weighted image (E). As the lesion shows peripheral arterial enhancement and delayed central enhancement, it is categorized as Liver Imaging Reporting and Data System M. On pathologic examination (F–L), the tumor shows complex mixture of hepatocellular carcinoma (HCC) (I), intermediate-cell carcinoma (J), CLC (K), and cholangiocarcinoma (CCA) (L) components. On MRI, the CCA component, corresponding the inner nodule, was more hypervascular than other components including HCC ([F] gross feature of resected specimen; [G] scanning view of hematoxylin-eosin [H–E] stain; [H] map of histological components; [I–L] H–E stain, original magnification, ×100).

Figure 3

A 50-year-old female showing combined hepatocellular-cholangiocarcinoma (cHCC-CCA), developed in B viral cirrhosis. A 1.7-cm tumor in the liver segment 2 shows low-signal intensity on precontrast T1-weighted image (A), non-peripheral enhancement in the arterial phase (B), washout and enhancing capsule on portal phase (C) and 2-minutes delay phase (D) of gadoterate meglumine-enhanced magnetic resonance imaging (white arrows). The lesion also shows high signal intensity in T2-weighted image (E) and diffusion-weighted image (F, b=800). Since the lesion exhibits three major features of Liver Imaging and Reporting and Data System, it is categorized as HCC (LR-5). On pathologic examination, the tumor is composed of two histologic components (G–L), showing large area of HCC (J) and small area of CCA (K) on hematoxylin-eosin (H–E) staining. Alcian-blue staining shows mucin, stained as blue color, at CCA (L, red arrows) ([G] gross feature of resected specimen; [H] scanning view of H–E stain; [I] map of histological component; [J, K] H–E stain, original magnification, ×100; [L] scanning view of Alcian-blue stain).

Figure 4

A 67-year-old male with combined hepatocellular-cholangiocarcinoma (cHCC-CCA), developed in C viral cirrhosis with matched biopsied and resected specimen. The gadoxetate-enhanced magnetic resonance imaging shows approximately 2.4 cm mass lesion with low-signal intensity in precontrast T1-weighted image (A), peripheral enhancement in the arterial phase (B), absence of washout in portal phase (C) and decreased hepatobiliary uptake in hepatobiliary phase (D), high signal intensity in T2-weighted image (E), and targetoid restriction in diffusion-weighted image (F, b=800). The patient has past history of distal common bile duct cancer (26 years ago), and recently diagnosed squamous cell carcinoma of oral cavity. To determine whether the lesion is metastasis, percutaneous liver biopsy was performed. The biopsy specimen shows adenocarcinoma without other component (G, H). The patient underwent hepatic resection and the tumor reveals cHCC-CCA (I, J). There is large area of cholangiocarcinoma (approximately 90%) and small area of hepatocellular carcinoma (approximately 10%) with transitional differentiation zones between them ([G] hematoxylin-eosin stain [H–E], original magnification, ×100; [H, I] scanning view of H–E stain; [J] H–E stain, original magnification, ×40).