Combined hepatocellular cholangiocarcinoma: A rare hepatic malignancy exhibiting concurrent imaging features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Abstract

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary hepatic neoplasm characterized by the coexistence of hepatocellular and cholangiocellular differentiation within the same tumor. The diagnosis is challenging because imaging characteristics may resemble those of hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC), depending on the dominant histologic component. We present a case of cHCC-CC demonstrating discrete regions with imaging features of both HCC and ICC, along with elevation of both alpha-fetoprotein and carbohydrate antigen 19-9. Recognition of discrete imaging features of HCC and ICC in the same mass should raise suspicion for cHCC-CC when evaluating primary liver neoplasms. Accurate diagnosis of cHCC-CC is important for prognostication and to guide clinical decision-making.

Introduction

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary hepatic neoplasm characterized by the unequivocal presence of both hepatocellular and cholangiocellular differentiation in the same tumor, excluding collision tumors. There is no minimum proportion required for either tumor component and the transition between the hepatocellular and cholangiocellular components can be abrupt or gradual [1]. It accounts for 0.4%-14% of all primary liver malignancies, with a male to female predominance of 7:3 [2]. The median age at diagnosis is in the seventh decade of life [2,3]. Known risk factors include cirrhosis, chronic hepatitis, alcohol consumption, and metabolic syndrome [3]. Patients typically present with nonspecific symptoms such as abdominal discomfort, weight loss, fatigue, and pruritus [2].

The prognosis of cHCC-CC is variable and is generally considered intermediate between that of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) [2]. However, the prognosis is overall poor, with 5-year survival rates ranging from 24% to 30% [3]. Due to its rarity, there is no standardized treatment approach. Surgical resection offers the best chance of cure; however, only a minority of patients are eligible [3]. For unresectable disease, locoregional treatments including transarterial chemoembolization, transarterial radioembolization, and radiofrequency ablation have been explored and may serve as initial strategies for tumor downstaging [2,3]. Treatment decisions may be individualized or guided by the presumed dominant histologic component of the tumor [3].

Case report

An 82-year-old woman presented to her primary care physician with vague right upper quadrant pain and diarrhea. Her past medical history was significant for type 2 diabetes mellitus, chronic kidney disease, and coronary artery disease. Initial laboratory investigations showed mildly elevated alanine aminotransferase (ALT) at 41 U/L (normal <40 U/L) and aspartate aminotransferase (AST) at 39 U/L (normal <35 U/L). Complete blood counts, alkaline phosphatase, bilirubin, and electrolytes were within normal limits. An initial ultrasound showed an irregular avascular hypoechoic mass in the liver near the porta hepatis (Fig. 1A and B). A subsequent computed tomography (CT) scan of the abdomen and pelvis confirmed a lobulated, irregular enhancing mass involving hepatic segment 4A and 4B (Fig. 1C and D).

Fig. 1.

Ultrasound of the liver in the sagittal plane (A) and transverse plane (B) shows a lobulated hypoechoic mass (white arrows). CT of the segment 4A/4B mass (white arrows) shows heterogenous arterial phase enhancement (C) and subtle portal venous phase enhancement (D).

Magnetic resonance imaging (MRI) of the abdomen showed the mass to be hypointense on T1-weighted images (Fig. 2C), moderately hyperintense on T2-weighted images (Fig. 2A), and diffusion restricting (Fig. 2B). Following gadobutrol contrast administration, the anterior portion of the mass exhibited heterogeneous nonrim arterial phase enhancement with central washout on portal venous and delayed phases, consistent with HCC-like features (Fig. 2D-F, red arrow). In contrast, the larger posterior portion showed rim-like arterial enhancement with delayed central enhancement, more consistent with ICC-like features (Fig. 2D-F, green arrow). The mass did not have an enhancing capsule. LI-RADS classification was not prospectively applied because the liver did not have obvious cirrhotic morphology on imaging. The differential diagnosis for the liver mass at the time of the MRI report included HCC and ICC but did not explicitly mention cHCC-CC.

Fig. 2.

MRI of segment 4A/4B liver mass (white arrows). The mass is lobulated and T2 hyperintense (A), diffusion restricting (B), and T1 hypointense (C). After gadolinium administration, the anterior component of the mass (red arrows) demonstrates nonrim arterial phase hyperenhancement (D) with portal venous (E) and delayed phase (F) nonperipheral washout. The posterior component of the mass (green arrows) demonstrates rim-like arterial phase enhancement (D) with progressive central enhancement on portal venous and delayed phases (E and F).

The patient was referred to hepatobiliary surgery and underwent an extended left liver lobectomy for definitive management. The liver mass was not biopsied preoperatively. The patient’s Alpha-fetoprotein (AFP) was elevated at 68 μg/L (normal <9 μg/L) and carbohydrate antigen 19-9 (CA 19-9) was elevated at 37 kU/L (normal <36 kU/L). Pathologic examination of the resected liver revealed diffusely micronodular liver contour with background steatosis and F3 to F4 fibrosis, nearing cirrhosis. The mass was diagnosed as a poorly differentiated cHCC-CC, composed of approximately 25% hepatocellular and 75% cholangiocellular components. Immunohistochemical studies showed that hepatocytic markers were more intensely expressed in the morphologically hepatocytic differentiated areas; whereas, glandular/cholangiocytic markers were more intensely expressed in the morphologically cholangiocellular areas.

The patient was subsequently referred to medical oncology but was not a candidate for chemotherapy because of medical comorbidities. Four months after surgery, new enhancing liver lesions and a new enlarged portocaval lymph node were identified on routine postoperative follow-up CT. The lymph node was biopsied via endoscopic ultrasound and was positive for metastatic disease. Since the patient was not a candidate for chemotherapy, she was transitioned to palliative care. The patient ultimately passed away 8 months after surgery, 13 months after presentation, from complications of pneumonia.

Discussion

The diagnosis of cHCC-CC is challenging because of its heterogeneous imaging characteristics. Reflecting its mixed cellular composition, cHCC-CC may demonstrate imaging features of both HCC and ICC, often resembling the dominant pathologic component [4,5]. cHCC-CCs with a predominant HCC component typically exhibit MRI features of HCC, including nonrim arterial phase enhancement, delayed phase nonperipheral washout, and enhancing capsule. cHCC-CCs with a predominant ICC component typically exhibit MRI features of ICC, including targetoid enhancement with progressive central enhancement on delayed phases [5]. In this case, the tumor exhibited features of both HCC and ICC in distinct regions of the tumor, which correlated with the pathologic findings of distinct regions of hepatocytic and cholangiocytic morphology and immunohistochemistry. These pathologic findings were not correlated spatially with the HCC-like and ICC-like regions seen on MRI at time of pathologic analysis. However, the sizes of the described hepatocellular and cholangiocellular components were consistent with the sizes of the HCC-like and ICC-like regions of the mass seen on MRI. This suggests that critically assessing MRI of liver tumors for distinct imaging patterns can help with the diagnosis of cHCC-CC. However, these well-delineated imaging features may not be present in tumors with a more admixed form of cHCC-CC.

The pathological composition of cHCC-CC has been linked to its imaging features. cHCC-CCs that are pathologically HCC-predominant are known to be more often categorized as LR-4 or LR-5 [6] using the Liver Imaging Reporting and Data System Version 2018 (LI-RADS 2018) categorization [7]. The LR-4 and LR-5 categories are more specific for HCC. The LR-5 category is specific for HCC such that patients with LR-5 disease do not have to undergo liver biopsy before initiating treatment. Similarly, pathologically ICC-predominant cHCC-CC are more often categorized as LR-M [6], a category that suggests liver malignancy other than HCC. cHCC-CC classified as LR-4 and LR-5 has shown better survival compared to cHCC-CC classified as LR-M, suggesting that radiology classifications can have prognostic implications [4,6,8].

Although biopsy was not attempted in this case, preoperative pathologic diagnosis of cHCC-CC is known to be challenging because tumor heterogeneity increases the risk of sampling error. As in this case, the hepatocellular and cholangiocellular components of cHCC-CC may not be uniformly distributed throughout the tumor. As a result, percutaneous needle biopsy demonstrates limited sensitivity for cHCC-CC, ranging from 11% to 48%, because it samples only a small portion of the mass [2]. Even core biopsies may fail to capture adequate histologic representation of both tumor components. In cases with disparate MR imaging features, the biopsy targets can be even more precisely identified. If there are defined regions in the tumor with MRI features of HCC and ICC, each of these regions can be targeted to ensure adequate sampling. Even without distinctive MR features, obtaining multiple core biopsies from different regions of the tumor has been suggested to improve diagnostic accuracy [2,5,9].

Serum tumor markers may further support the diagnosis. AFP and CA 19-9 levels have been shown to correlate with the relative histological composition of cHCC-CC, with higher AFP levels observed in HCC-predominant tumors and higher CA 19-9 levels in ICC-predominant tumors [2,4,5,10]. In this case, the patient had concurrent elevated AFP and CA 19-9 levels, which would be atypical for HCC and ICC, and should prompt the consideration of cHCC-CC. cHCC-CC should be considered when AFP and CA 19-9 levels are discordant with the presumed imaging-based diagnosis [5].

As demonstrated in this case, the presence of concurrent features of HCC and ICC within distinct regions of the same primary tumor should raise suspicion for cHCC-CC. Careful assessment of intratumoral heterogeneity in combination with serum AFP and CA 19-9 levels may improve diagnostic accuracy for this rare malignancy. In addition, identification of distinct imaging patterns may help guide targeted sampling of both HCC-like and ICC-like regions, increasing the likelihood of adequate pathologic representation of both tumor components. Given its aggressive behavior and poor prognosis, particularly in ICC-predominant cHCC-CC, early recognition may facilitate more accurate diagnosis and inform treatment decisions.

Patient consent

Written patient consent was not required as per our institution’s ethics board as no personal patient identifiers were included. Patient anonymity was maintained throughout.