Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results

The differential diagnoses of hepatic cystic lesions include simple cysts, parasitic cysts, mucinous cystic neoplasms, congenital cystic dilatation, degenerated metastatic tumors, mucin producing metastatic tumors, cystic hemangioma, lymphangioma, hepatic foregut cyst, and mesenchymal hamartoma and teratoma [5‐7]. Mucinous cystic neoplasms including intrahepatic biliary cystadenoma and cystadenocarcinoma, account for approximately 5 % of hepatic cystic lesions [3]. They are being discovered more frequently due to advances in abdominal imaging modalities and improved awareness of this disease entity. Although benign, intrahepatic biliary cystadenomas have the potential for malignant transformation and the prognosis of intrahepatic biliary cystadenocarcinomas is poor [8, 9].

The World Health Organization (WHO) in 2010 had re-categorized biliary cystadenoma into mucinous cystic neoplasms with low-, intermediate, or high-grade intraepithelial neoplasia and biliary cystadenocarcinoma into mucinous cystic neoplasms with an associated invasive carcinoma [2]. However, most authors in the recent literature continue using cystadenoma/cystadenocarcinoma to describe this rare disease. For the convenience of further literature review, we adopt the terms cystadenoma/cystadenocarcinoma in the current study. Readers should be aware that these terms should be avoided in the future.

The cause of intrahepatic biliary cystadenoma remains unknown. The almost exclusive female predominance of biliary cystadenoma (>85 %) suggests a strong hormonal influence [10]. Our study, in which 84.2 % of the biliary cystadenoma patients are female, corresponds to this published result. The mean age of diagnosis in our study is 57, which is similar to most of other series [11, 12]. This feminine hormonal influence might explain the older age on diagnosis in male population (69.3 year-old in male and 54.7 year-old in female patients, respectively), of whom masculine hormone decreases with aging.

Intrahepatic biliary cystadenomas are rare. Few large series have been reported in the literature [1, 6, 12‐18]. Our study is by far one of the largest series in the English literature. The clinical presentations of intrahepatic biliary cystadenomas could vary widely, as evidenced from the literature [1, 12, 16, 17]. In contrast to the previous series, in which most patients were symptomatic before operation, only 11 patients (57.9 %) were symptomatic upon presentation in the current study and 8 patients (42.1 %) were found incidentally. The most common presenting symptom was abdominal pain whereas fever, abdominal mass/distension, jaundice, dyspnea and diarrhea were the less common symptoms. The nonspecific nature of these symptoms rendered clinical diagnosis difficult and laboratory/radiologic examinations imperative. Numerous efforts were taken in the past to develop a sensitive and specific diagnostic modality for intrahepatic biliary cystadenoma. Koffron A. et al. suggested that cystic fluid analysis could be used to differentiate intrahepatic biliary cystadenomas from simple cysts, of which cystic fluid CEA and CA19-9 were usually normal [16]. Intrahepatic biliary cystadenomas, on the other hand, usually had elevated cystic fluid CEA and CA 19–9 levels. However, another study indicated that cystic fluid CEA and CA 19–9 levels were not useful in differentiating biliary cystadenoma from simple cysts [12]. They reported that both hepatic simple cysts and biliary cystadenoma could have elevated cystic fluid CEA and CA 19–9 levels. Our study did not compare the difference between those hepatic simple cysts and intrahepatic biliary cystadenomas. Nevertheless, among patients with available data, we found that serum and cystic fluid CA 19–9 levels were invariably elevated in the intrahepatic biliary cystadenomas. In addition, cystic fluid CA 19–9 level was significantly higher than that in serum. These findings could be explained by part the biliary origin of intrahepatic cystadenomas. As a result, we suggest preoperative serum and cystic fluid CA 19–9 determination to exclude intrahepatic biliary cystadenomas.

Since there are neither sensitive nor specific clinical or laboratory findings suggestive of intrahepatic biliary cystadenomas, preoperative imaging studies are thus indispensable for the evaluation of patients with hepatic cystic mass. In the current study, every patient received either contrast-enhanced CT or MRI for preoperative evaluation. Among other features, loculations and internal septations were the two most common radiologic characteristics in patients with intrahepatic biliary cystadenoma, with 87 % and 56 % of patients having these features, respectively. Our finding was in accordance with previous reports, in which septations and/or septal thickening were the common radiologic features in intrahepatic biliary cystadenomas [1, 12]. Therefore, preoperative contrast-enhanced radiologic study, including CT or MRI, should be carried out and intrahepatic biliary cystadenomas should be highly suspected if loculations and/or internal septations are demonstrated. It is noteworthy, however, that these radiologic features are not specific for intrahepatic biliary cystadenomas and the definitive diagnosis should be based on final pathologic finding.

Preoperative pathologic diagnosis remains difficult for intrahepatic biliary cystadenomas. In our series, 6 patients received preoperative percutaneous aspiration cytology or biopsy. The interpretation did not give any specific diagnosis. The reason for these false negative results may be attributed to inadequate tissue sampling upon percutaneous biopsy/aspiration since intrahepatic biliary cystadenomas usually have rather thin walls, as demonstrated by our study in which only 25 % of biliary cystadenomas had thickened wall/mural nodules. As a result, we do not suggest routine preoperative aspiration/biopsy only if the cystic neoplasm has apparent wall thickening or mural nodules and the biopsy is carried out by experienced hands.

The treatment of intrahepatic biliary cystadenomas remains controversial among literatures. Most authors suggested complete surgical removal by either liver resection or enucleation to prevent recurrence or potential malignant transformation [1, 5, 6, 11, 15, 17, 19]. Nevertheless, there have been other authors indicating that marsupialization of the hepatic cysts could result in optimal outcome without tumor recurrence [16]. In our study, none of the 11 patients who received radical resection developed recurrence postoperatively, while more than 60 % of patients who underwent liver-preserving surgery developed postoperative recurrence. Given the possibility of malignant transformation, we suggest radical resection by either hepatic resection or enucleation for suspected intrahepatic biliary cystadenomas. The emergence of laparoscopic techniques in recent decades renders the surgeons more options regarding hepatic surgery and should also be considered. Since most patients with intrahepatic biliary cystadenomas are non-cirrhotic in the absence of viral hepatitis, hepatic resection should be relatively safe, provided that adequate future liver remnant is reserved. On the other hand, in the cases of hepatic viral infection and/or cirrhosis, liver functions, particularly indocyanine green 15 min retention test (ICG-15), should be taken into consideration before performing radical hepatic resection. The result after well-planned radical hepatic resection is usually good and patients can achieve satisfactory long-term outcome.

As for intrahepatic biliary cystadenocarcinoma, a recent study has shown that older age, male gender, and shorter symptom duration were the major differences from biliary cystadenoma [18]. The current study, although with limited cases, agreed to that publication. In addition, a septated cystic mass with a solid mural component on image study should also raise our suspicion of this diagnosis [9]. As for treatment, we suggest radical resection with negative resection margin for suspected intrahepatic biliary cystadenocarcinomas. This approach has been the only potentially curative treatment proposed by most other authors [1, 17]. Reported survival rates for intrahepatic biliary cystadenocarcinomas ranged from 25 % to 100 % at 5 years [1]. Despite its poor prognosis, our patients survived for at least 2 years after the operations.