A Case of Cholangiolocellular Carcinoma Preoperatively Diagnosed With Typical Imaging Findings

A 70-year-old female with inactive chronic hepatitis C was referred to our hospital for an assessment of an asymptomatic liver mass that was detected by routine abdominal ultrasonography (US). She had never smoked or drunk alcohol. Laboratory data and tumor markers were within normal range, whereas anti-hepatitis C virus antibody was positive (Table 1). Abdominal US showed a well-defined, 30-mm diameter, hypoechoic mass with heterogeneous hyperechoic area inside, in segment 4 of the liver (Fig. 1a). In the Doppler mode of US, vessels penetrating the tumor were observed (Fig. 1b).

Abdominal contrast-enhanced (CE) –CT revealed an inhomogeneous thick ring-enhancement in the peripheral area of the tumor in the arterial phase (Fig. 2b). The enhancement prolonged until the delayed phase, becoming homogeneous except for the central area (Fig. 2c and 2d). Another CE–CT slice revealed vessel penetration through the tumor in the arterial phase (Fig. 2e). In addition, no dilatation of peripheral intrahepatic bile duct was observed. ¹⁸F-fluorodeoxyglucose-positron emission tomography/CT (¹⁸F–FDG–PET/CT) revealed a weak uptake of FDG in the tumor, and the maximum standardized uptake value (SUV) was 2.83 (Fig. 2f).

In the magnetic resonance imaging (MRI) examination, the tumor showed low intensity on T1-weighted images (Fig. 3a), and heterogeneous high intensity on T2-weighted images (Fig. 3b). Dynamic MRI using the contrast agent ethoxybenzyl diethylenetriamine (EOB–MRI) revealed a pattern of tumor enhancement similar to that in the CE–CT. Namely, a thick ring enhancement appeared during the early phase (Fig. 3d), which prolonged until the late phase (Fig. 3e). Moreover, a dot-/band-like internal enhancement during the early and late phases (Fig. 3d and 3e) and a target appearance during the hepatocyte phase (Fig. 3f), which have been reported as typical MRI findings of CoCC,⁸  were detected.

All the imaging findings mentioned already were typical of CoCC,^5–8  but were atypical of CCC or hepatocellular carcinoma (HCC). Therefore, we diagnosed the tumor as CoCC preoperatively, and a possible differential diagnosis was atypical CCC. The extended left hepatectomy, including the resection of the middle hepatic vein, was performed. The operating time was 285 minutes, and blood loss was 243 mL.

The resected tumor measured 45 by 30 by 20 mm and was pale yellow (Fig. 4a and 4b), and a vascular penetration through the tumor was macroscopically observed (Fig. 4b). Microscopically, the tumor comprised small tubular, acinar, or cord-like structures (Fig. 5b and 5c). The interface between the tumor and surrounding non-tumorous liver shows a replacing growth pattern of the tumor cells forming continuous tumor cords with normal liver cell cords (Fig. 5a–5c). Inside the tumor, the cells showed an “antler-like” anastomosing pattern with marked fibrous stroma that continued to the central hyalinized fibrotic stroma (Fig. 5d). In addition, retained Glisson's sheath structures were often detected in the tumor (Fig 5a and 5b). Immunohistochemical study revealed the tumor cells were positive for cytokeratin 7 (Fig. 6b) and negative for CK 20 (Fig. 6d). Epithelial membrane antigen (EMA) was also positive on the luminal surface of tubules of tumor cells (Fig. 6c). According to these pathologic findings of the tumor, CoCC was diagnosed. No complications occurred after operation, and the patient was discharged on postoperative day 10. She is alive without recurrence for 15 months after the operation.

CoCC belongs to subtype of a combined HCC–CCC (CHC) with stem cell features “cholangiolocellular subtype” in the fourth version of the World Health Organization classification,⁹  and it accounts for less than 1% of all liver carcinomas. According to its classification, CoCC possibly possesses dual histologic components of HCCs and CCCs: thus, heterogeneous imaging characteristics with overlapping features of both tumors were sometimes reported.^10–13 

Meanwhile, recent extensive investigations of CoCC have revealed that CoCC has several characteristic image findings, and each finding closely corresponds to this tumor's histologic characteristic.^5–8  In the present case, CE–CT revealed thick ring enhancement in the peripheral area of the tumor in the early phase. The enhancement prolonged until the delayed phase, becoming homogeneous except for the central area. These imaging signs are different from those observed in CCC or HCC and are thought to reflect the characteristic histologic features of CoCC (i.e., many retained Glisson's sheath structures in the tumor because of replacing growth, abundant fibrous stroma in the tumor, and the central hyalinized fibrotic stroma). Replacing growth pattern of CoCC is also associated with no dilatation of peripheral intrahepatic bile ducts and the vessel-penetrating sign through the tumor. EOB–MRI revealed an enhancement pattern similar to that in the CE–CT. In addition, dot-/band-shaped internal enhancement during the arterial and portal phases was also detected. The latter findings are thought to correspond to the tumor cell nest with vascular proliferations and retained Glisson's sheath structures.⁸ 

Among the case reports of CoCC, FDG PET has been performed in only 5 cases (Table 2). In the present study, the accumulation of FDG in the tumor was relatively low, and the SUV max was 2.83. This finding was compatible with several cases reported previously,^14–16  and the low density of tumor cells with abundant fibrous stroma in this tumor is possibly associated with the low uptake of FDG. However, a strong accumulation of FDG into the CoCC was reported in other cases,^11,17  suggesting the diversity of tumor cell activity of CoCC. Further investigation of the relationship between FDG accumulation and tumor histology in each CoCC case is required to address these discrepancies.

Prognosis of CoCC has been reported to be better than that of CCC,^18,19  indicating this tumor's relatively low malignant potential, while prognosis of the whole combined HCC–CCC (CHC) including a classical type, a subtype of CHC with stem cell features, an intermediate cell type, and cholangiolocellular subtype⁹  is similar to that of CCC.^20,21  These data may indicate that CoCC and other CHC tumors belong to a distinct category.²²  Indeed, a recent integrative genomic analysis has revealed that CoCC belongs to a distinct biliary molecular entity with a biliary molecular profile, low chromosomal instability, and enrichment of TGF–β and immune-related signaling.⁴  Thus, accurate preoperative diagnosis of CoCC is important for surgical planning, and adequate resection possibly leads to good prognosis.

Preoperative diagnosis of CoCC was difficult because of its rarity, but recent data concerning imaging findings of CoCC have suggested its characteristic imaging features as mentioned already. Accordingly, we could strongly suspect a liver tumor preoperatively as CoCC, a rare liver tumor. In conclusion, cautious investigation of preoperative characteristic imaging findings possibly leads to accurate diagnosis of CoCC, despite its rarity.

Our article is a case report concerning one patient, and ethics approval was not required. Meanwhile, a written informed consent was obtained from the patient for publication of this case report and accompanying images.