Intrahepatic Cholangiocarcinoma Arising from Biliary Hamartomas in Patients with Recurrent Acute Cholangitis: A Case Report and Literature Review

Abstract

Biliary hamartomas are tumor-like malformations of the liver. Biliary hamartomas are a type of fibrocystic disorder originating from ductal plate malformation and are typically considered benign, but with the risk of malignant transformation. In this case report, we present a rare occurrence of intrahepatic cholangiocarcinoma (ICC) that developed from biliary hamartomas, along with a literature review. A 76-year-old man with a diagnosis of biliary hamartomas had a history of recurrent cholangitis for 12 years, necessitating cholecystectomy, ERCP, and repeated antibiotic treatments. During his last episode, imaging studies revealed a hypervascular infiltrative mass in the right posterior liver segment. A liver biopsy confirmed adenocarcinoma and subsequent surgical pathology revealed ICC originating from biliary hamartomas. Chronic inflammation in the bile duct associated with biliary hamartomas may serve as a potential trigger for malignant transformation, as observed in this case. Therefore, close surveillance is essential for patients with biliary hamartomas presenting with infectious complications.

INTRODUCTION

Intrahepatic cholangiocarcinoma (ICC) arising from biliary hamartomas is very rare.¹ Biliary hamartomas, characterized by fibrocystic changes arising from ductal plate malformation, are generally considered benign. However, they do carry the potential risk of malignant transformation.² This case report highlights the development of early-stage ICC in a man previously diagnosed with biliary hamartomas and recurrent acute cholangitis, shedding light on the importance of establishing surveillance strategies for such cases. Given the scarcity of reported cases, our clinical experience is crucial in contributing to the understanding of this condition. Additionally, we present a comprehensive literature review on the subject.

CASE REPORT

A 76-year-old man with a 12-year history of biliary hamartomas under clinical surveillance presented to the emergency room with complaints of chills and general weakness. He had a medical history of acute cholangitis and acute cholecystitis, successfully managed with cholecystectomy, ERCP, and repeated use of broad-spectrum antibiotics. He also had a medical history of diabetes mellitus for 30 years, hypertension for 27 years, and had undergone prostatectomy for prostate cancer eight years ago. Upon examination, his blood pressure was 126/66 mmHg, heart rate was 79 beats/min, respiratory rate was 20 breaths/min, and body temperature was 36.5°C. Abdominal tenderness in the right upper quadrant was noted during the physical examination. Laboratory tests revealed normal values, except for an elevated CRP level of 18.40 mg/dL. Viral markers of hepatitis B or C were negative.

Previous abdominal imaging studies, including abdominal CT and MRI of the liver conducted five years ago, had shown multiple ill-defined tiny low-density lesions throughout the liver (Fig. 1). The recent abdominal CT scan revealed an indeterminate hypervascular lesion, prompting a recommendation for a liver MRI. The liver MRI findings suggested a tumorous condition resembling an infiltrative hepatocellular carcinoma (HCC) (Fig. 2). A liver biopsy was performed, confirming the presence of adenocarcinoma. Subsequently, the patient underwent a right posterior sectionectomy of the liver. The gross examination revealed a 4.0×3.2×2.0 cm-sized mass confined to the hepatic parenchyma. The histopathological diagnosis confirmed ICC. Microscopic examination showed diffuse nodularity and fibrosis, numerous biliary hamartomas, discrete periportal cysts embedded in a fibrous stroma, lined by a low columnar or cuboidal epithelium, and containing bile-stained material. Additionally, dilated ductal proliferations exhibiting adenocarcinoma were observed, indicating neoplastic changes within the biliary hamartomas (Fig. 3). Immunohistochemical analysis demonstrated positive staining for cytokeratin-19 (CK-19) and tumor protein p53 (p53), but negative staining for CK20. At the two-year follow- up after the surgery, the patient remained in good health with no evidence of tumor recurrence.

Fig. 1.

(A) An abdominal CT image showing multiple variable-sized, well-defined cystic lesions in the liver. (B) A T2-weighted MR image showing multiple variable-sized, high signal intensity lesions in the liver.

Fig. 2.

(A) An abdominal CT image showing ill-defined enhancing lesions in the right posterior segment of the liver (arrow). (B–D) A liver MR image showing an ill-defined arterial enhancing (B) and delayed washout (C, D) lesion in the right liver (arrows).

Fig. 3.

(A) A well-demarcated irregular mass is identified (arrow). Its cut surface is pinkish-white, firm, and granular. Multiple nodules are observed in the peritumoral area (arrowheads). (B) Liver parenchyma showing a well-demarcated lesion with small to medium-sized, irregularly shaped dilated glands lined by cuboidal epithelium with intervening fibrous stroma and surrounding inflammatory cells consistent with biliary hamartomas (Hematoxylin and eosin [H&E], ×100). (C) Dysplasia (arrow) adjacent to biliary hamartoma (right lower) is accompanied by chronic inflammation (H&E, ×100). (D) The tumor shows uneven gland distribution and infiltrative borders with tissue destruction (arrow) (H&E, ×40). (E) The tumor forms aberrant glands accompanied by desmoplastic reactions and inflammation (H&E, ×200).

DISCUSSION

Biliary hamartomas, also known as "von Meyenburg complexes" (VMC), are a malformation of the small interlobular bile ducts that result from incomplete embryonic bile duct involution.³ It falls under the category of fibrocystic disorders originating from ductal plate malformation, which include congenital hepatic fibrosis and Caroli's disease, sometimes presenting as an overlap syndrome.³

The demographics of biliary hamartomas show a mean age of 55 years (ranging from 17 to 88 years) at the time of diagnosis, with a slight male predominance (63.3% of cases being males).² The average size of the lesions was 1.0 cm.² Clinical manifestations range from asymptomatic cases to symptoms such as fever, jaundice, abdominal pain, and portal hypertension.^2,4,5 Infectious complications in the liver are a result of superinfection of the cystic content,⁶ and portal hypertension may be caused by the displacement of the portal vein due to dilated bile ducts.⁴ However, the most common comorbidity associated with biliary hamartomas is malignancies, with 12.9% of cases linked to malignancies, two-thirds of which are gastrointestinal cancers. Other cancers, such as breast, prostate, lung, and thyroid cancers, have also been reported to be present in patients with biliary hamartomas.²

ICC is the most common cancer arising from biliary hamartomas,⁷ and the occurrence of HCC is less frequent.⁸ The ICCs arising from biliary hamartomas are typically well-differentiated adenocarcinomas. There is histological evidence of progression from hyperplasia to invasive cancer,⁹ and molecular evidence to support this transformation, with a shared immunostaining pattern between bile duct cancer and biliary hamartomas.^1,10 Immunohistochemical staining for the Ki-67 or mitotic index and CK-19 aid in the diagnosis of ICC arising in biliary hamartomas.¹¹

We analyzed 34 cases of ICC arising in biliary hamartomas reported in the literature (Table 1).^12-31 The mean age of patients at the time of the ICC diagnosis was 67 years (ranging from 35 to 88 years). Among these cases, there was a male predominance, accounting for 73% of the reported cases. Biliary hamartomas tended to develop slightly more frequently in the right lobe of the liver, and the average size of the ICC tumors was approximately 4.9 cm.

Table 1.

Case Reports Documenting the Association of Biliary Hamartomas with Intrahepatic Cholangiocarcinoma

References	Year	Sex	Age (yr)	Tumor size (cm)	Location	Risk factors	Combined cancers
Lindgren et al.12	1961	M	74	4
Homer et al.13	1968	M	75	0.8
Homer et al.13	1968	M	71	0.3
Homer et al.13	1968	M	70	0.2
Börnfors14	1984	M	80	4	Rt & Lt
Honda et al.15	1986	F	61	0.3
Dekker et al.16	1989	F	61	4	Lt
Burns et al.17	1990	M	35	18.5	Rt
Hasebe et al.18	1995	M	59	5.5	Lt
Papadogiannakis et al.19	1996	F	49	1.5	Lt
Yaziji et al.20	1997	M	68	10	Rt	Hemochromatosis
Kim et al.21	1999	M	74	2	Rt		HCC
Blanc et al.22	2000	M	61	4	Rt	Hemochromatosis	HCC
Jain et al.10	2000	M	81	15	Lt	HCV
Jain et al.10	2000	F	66	4.5	Lt		Breast
Jain et al.10	2000	M	63	3	Lt		HCC
Röcken et al.23	2000	F	59	10	Rt
Wisniewsk et al.24	2002	M	63			Hemochromatosis
Orii et al.25	2003	M	72	3	Lt
Zimpfer et al.26	2007	M	73	4	Rt
Song et al.27	2008	M	68	8	Rt	Alcoholics
Song et al.27	2008	M	69	3.5	Lt	HBV
Song et al.27	2008	M	75	4.5	Rt	HCV, alcoholics
Song et al.27	2008	M	59	2.7	Rt		Colon
Li et al.28	2009	F	73	9	Rt	HBV
Xu et al.29	2009	F	65	8	Rt	HCV
Xu et al.29	2009	M	88	4	Rt
Kim and Jin30	2011	M	66	7.6	Rt
Parekh and Peker1	2015	F	76	4.2	Rt
Parekh and Peker1	2015	F	77	3.1	Rt
Yang et al.5	2017	M	41	5.8	Rt	HBV
Sugawara et al.16	2018	M	55	2.5	Rt	Liver abscesses
Yuan et al.31	2022	M	63	1.5	Rt
Present case	2023	M	76	4	Rt	Cholangitis	Prostate

Rt, right liver; Lt, left liver; HCC, hepatocellular carcinoma.

Among the 34 cases, 35.3% showed potential risk factors associated with ICC development. Specifically, three cases were associated with a hepatitis B virus infection, three cases with a hepatitis C virus infection, and three cases with hemochromatosis. Additionally, two cases were linked to chronic alcohol consumption, and two cases were associated with either liver abscess or recurrent cholangitis. These findings highlight the relevance of these risk factors in patients with ICC arising in biliary hamartomas. Additionally, there were reports of other types of cholangiocarcinoma, such as hilar bile duct cancers,^32,33 common bile duct cancer,³⁴ and intraductal papillary cholangiocarcinoma,³⁵ occurring in patients with biliary hamartomas.

Although the precise mechanisms of malignant transformation in congenital bile duct cysts, including biliary hamartomas, remain unclear, chronic inflammation caused by chemical or mechanical irritation, cholestasis, or hepatolithiasis has been suggested as the probable cause for the transformation.⁷ Biliary hamartomas do contain inspissated bile and a chronic inflammatory infiltrate. The presence of persistent chronic inflammation, such as a liver microabscess³⁶ or recurrent cholangitis as confirmed in the current patient, might explain the malignant transformation based on the concept of the adenoma- carcinoma sequence.³⁶

Treatment guidelines for biliary hamartomas are not standardized, and management becomes challenging in cases of persistent or recurrent cholangitis. The patient in the present case had long-term recurrent acute cholangitis and was treated by cholecystectomy, ERCP, and broad-spectrum antibiotics during the period. Earlier reports indicate that some patients underwent surgical treatment for the condition.³⁷ Further research is needed to understand the pathophysiology of cholangitis in patients with biliary hamartomas and the bacterial colonization associated with numerous foci of biliary stasis. Although regular monitoring is not indicated due to its benign nature, long-term follow-up is essential, especially in patients with biliary hamartomas and associated risk factors for ICC.