Intrahepatic Cholangiocarcinoma in Wilson’s Disease: A Case Report

Background

Wilson’s disease (WD) is characterized by the accumulation of excessive copper in vital organs such as the liver, brain, and kidneys [1]. This autosomal recessive disorder, which affects copper metabolism, occurs in approximately 1 in 30 000 individuals [2]. It causes progressive liver damage and neurological impairment [3]. WD presents a wide spectrum of clinical manifestations related to hepatic disease, ranging from asymptomatic patients to acute liver failure [4,5]. Hepatobiliary malignancies are common in other chronic liver diseases. Hepatobiliary malignancies appear to be uncommon in WD, even among patients with cirrhosis, although the exact reasons for this finding are unclear. Contradictory theories exist regrading copper accumulation in the liver: some propose it has a protective effect against carcinoma through chromatin stabilization, while others associate it with elevated hepatic malignancy risk [6–8].

There have been occasional reports of hepatocellular carcinoma (HCC) in WD. However, the incidence of intrahepatic cholangiocarcinoma (IHCC) is even rarer in this condition [1]. Here, we report a case of successful treatment of IHCC in a 39-year-old woman and discuss IHCC in WD.

Case Report

A 39-year-old woman diagnosed with IHCC was referred for surgery. She was first diagnosed with WD at the age of 17 years and had been prescribed D-penicillamine for 10 years and had been taking zinc acetate, without any specific findings. A 19-mm intrahepatic mass was suspected on follow-up ultrasonography 22 years after the WD diagnosis.

Further evaluation was conducted with computed tomography (CT) and magnetic resonance imaging (MRI). CT showed an ill-defined, 4.3-cm, hypodense lesion in the liver in segment (S) 3/4, heterogenous hypodense on arterial phase and portal venous phase, heterogenous hyperdense on delayed phases, encasement of umbilical portion of the left portal vein, mild dilation of the bile duct(B)3 and B4, and no enlarged lymph nodes in the abdomen (Figure 1). MRI showed a 4.3-cm mass in the liver S3/S4, delayed centripetal enhancement, invasion of the umbilical portion of the left portal vein, mild dilatation of the B3/B4, and targetoid diffusion restriction. These findings were indicative of infiltrative intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma (Figure 2).

The laboratory findings were as follows: alanine transaminase, 45 (normal range: 0–35 U/L); aspartate transaminase, 46 (normal range: 0–35 U/L); alkaline phosphatase, 96 (normal range: 30–120 U/L); total bilirubin, 0.8 (normal range: 0.2–1.2 mg/dL); prothrombin time (INR) 1.11 (normal range: 0.85–1.2 INR); alpha-fetoprotein, 9.32 (normal range: 0–7 ng/mL); carcinoembryonic antigen, 0.546 (normal range: 0–5 ng/mL); and carbohydrate antigen 19–9, 46.6 (normal range: 0–27 U/mL). There was no evidence of metastasis on chest CT or positron emission tomography, and left hepatectomy was the first treatment of choice.

Left hepatectomy was performed for 120 min, and the IHCC was located in segments 2, 3, and 4 grossly, with minimal liver cirrhosis. During surgery, there was no evidence of metastasis, significant lymph node involvement, or intraoperative complications. The patient was discharged after 7 days without any postoperative complications. Upon histological examination, the mass was diagnosed as a cholangiocarcinoma, moderately differentiated. Grossly, it was an ill-defined mass with dimensions of 42 mm×26 cm with low- to high-grade biliary intraepithelial neoplasia. Clear bile and parenchymal resection margins were also observed (margin of clearance: 0.9×0.8 cm). Immunochemical studies showed positive results for cytokeratin 7, 19, and P53 (Figure 3).

As adjuvant chemotherapy, 8 cycles of capecitabine were administered postoperatively, and the patient remained healthy without recurrence for 15 months after surgery (Figure 4).

Discussion

Hepatic malignancy, including HCC and IHCC, is common in patients with liver disease, regardless of whether they have cirrhosis [9]. Although chronic liver damage is a potential risk factor for primary liver cancer, it appears to be rare in WD, accounting for approximately 1.2% of cases [1]. The incidence of HCC and IHCC in individuals with WD is 0.7% and 0.5%, respectively. Although the exact reasons for the low incidence of primary liver cancer in WD remain unclear and controversial, some theories suggest that the accumulation of excessive copper in the liver protects against carcinoma development, and this mechanism is related to the stabilization of cellular chromatin [1,6–8]. However, other studies have demonstrated that accumulation of copper increases susceptibility to HCC, a risk that can potentially be prevented through the administration of D-penicillamine. This research suggests that carcino-genesis may arise from liver damage, subsequently leading to chronic inflammation and cirrhosis due to chronic copper accumulation [10,11]. Recent research indicates that certain genetic variations, particularly the c.3972C > T variant at exon 28 of the ABCC2 gene, may play a role in enhancing susceptibility to primary liver cancer, including both HCC and IHCC [12].

Among the hepatic malignancies, there are fewer IHCC cases in WD, with only 14 cases reported to date, including the present study. Two of the reports were cohort studies [3,13], whereas the others were case reports [1,14–16]. Although details for these cases were not included, 7 of the 14 cases were treated surgically, including our case, and various treatments for the remaining cases were applied, including liver transplantation, radiofrequency ablation, and chemotherapy according to the tumor and liver condition at the time of diagnosis (Table 1).

Generally, IHCC is the second most common malignancy arising from the liver, accounting for 3% of all cases of gastrointestinal cancer [17]. Liver resection is a fundamental component of any curative treatment approach for IHCC, although only approximately 20% of cases are eligible for resection at the time of diagnosis [18]. The primary objective of surgery is to achieve a complete margin-negative resection (R0) while considering the functional capacity of the liver and ensuring oncologic radicality. These factors, along with the patient’s performance status, are crucial determinants of surgical intervention success. In the present case, the tumor was resectable by the time of diagnosis, and the sufficient residual liver volume and oncologic radicality were obtained for successful treatment. Oncological radicality pertains to the goal of achieving complete removal of the tumor, often including the removal of surrounding tissues and lymph nodes to minimize the risk of cancer recurrence.

Approximately 50% of patients with WD have liver nodules detected on imaging, most of which are typically benign [19]. Although it is a very low probability, the livers of patients with WD should be carefully followed up owing to the possibility of hepatic malignancy. Close observation enables early detection, which, in turn, facilitates timely surgical intervention and contributes to favorable outcomes, as observed in the present case.

Conclusions

In summary, despite the limited understanding of the causes and rarity of hepatic malignancy in WD, owing to the possibility of IHCC, careful monitoring should be implemented and appropriate treatment plans established by the time of diagnosis for good outcomes.