Mucinous cholangiocarcinoma: Clinicopathological features of the rarest type of cholangiocarcinoma

Abstract Mucinous cholangiocarcinoma is extremely rare and its clinicopathological features remain unclear. The present study aimed to analyze published data on mucinous cholangiocarcinoma. Medical databases were searched from 1980 to 2016, and clinicopathological data for 16 mucinous cholangiocarcinoma patients were obtained. Characteristic imaging findings, including hypovascular tumor with peripheral enhancement on computed tomography and angiography, extremely high intensity on T2‐weighted magnetic resonance images, intratumoral calcification and luminal communication between the tumor and bile duct on cholangiography, were noted. Mucinous cholangiocarcinoma was correctly diagnosed in one patient only, with some patients diagnosed as low‐malignant biliary cystic tumors preoperatively. Five cases were followed up after the first medical examination, and three of these were initially diagnosed as biliary cystadenoma or intraductal papillary neoplasm of the bile duct. All five tumors showed marked enlargement within 4 months of follow up. Macroscopically, the resected tumors were non‐cystic/solid in seven cases, and cystic in seven. Tumor diameter ranged from 5 cm to 22 cm, and mucoid cut surface, lobulation, lack of capsule and papillary growth were observed. Microscopically, co‐existing intraductal papillary neoplasm of the bile duct was noted in three of five patients with available data. Nine of 10 cases in whom the pathological stage was reported had advanced disease with lymph node and/or distant metastasis, and 5‐year survival was achieved in one microinvasive case only. Overall 1‐ and 3‐year survival rates were 60.1% and 40.1%, respectively. The possibility of mucinous cholangiocarcinoma should be considered when biliary cystic tumors are detected on imaging modalities, despite the rarity of this tumor.


| INTRODUCTION
Mucinous carcinoma is defined in the presence of large extracellular mucus lakes containing floating carcinoma cells, accounting for more than 50% of neoplasm. 1 This entity has been well defined in the breast, colon, rectum, and pancreas. [1][2][3] However, the clinicopathological characteristics of mucinous cholangiocarcinoma have not been elucidated owing to the rarity of this tumor. In a series of cases reported by Nakajima et al., 4 there was only one mucinous cholangiocarcinoma among 102 consecutive cases of intrahepatic cholangiocarcinoma. In fact, most previous reports on mucinous cholangiocarcinoma were case reports, and no detailed review on this disease exists. Thus, we conducted a retrospective systemic review of mucinous cholangiocarcinoma cases, including one patient treated in our institution, to elucidate the clinicopathological characteristics of this rare tumor.

| Eligibility criteria
The current systemic review was carried out according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. 5 Observational studies written in English or Japanese were eligible for inclusion. However, articles in Japanese without an English abstract were excluded. All procedures carried out in studies involving human participants were in accordance with the ethics committee of the Kochi Health Sciences Center and with the Declaration of Helsinki.

| Literature search
A literature search was carried out using the following terms: "mucinous cholangiocarcinoma," "mucinous carcinoma of intrahepatic bile duct," and "colloid carcinoma in liver." The MEDLINE and Igakuchuo-Zashi database, a database of Japanese articles with English abstracts, were searched from 1980 to 2016. Studies in the reference lists of the retrieved articles were also searched. By reading the articles in detail, confusing biliary tumors such as biliary cyst adenoma or intraductal papillary neoplasm of the bile duct were carefully excluded. Cases in which mucus lakes were definitely described were considered eligible.

| Data collection and assessment
The following data were extracted from the identified studies: the patient characteristics, value of tumor markers, imaging findings, pretreatment diagnosis, treatment and prognosis.

| Statistical analysis
Survival rates were generated using the Kaplan-Meier method. Data were analyzed by using SPSS v.19 software (IBM, Armonk, NY, USA).

| Report of a case from our institution
A 49-year-old man presented with severely impaired consciousness and was admitted to our institution. Whole-body computed tomography (CT) scanning showed subarachnoid bleeding and a 5.4-cm-sized low-density tumor with peripheral calcification in the lateral segment of the liver ( Figure 1A). Carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9) levels were 2.9 ng/mL and 7.5 U/mL, respectively, which were within the normal ranges. After brain aneurysm clipping, the patient underwent several imaging tests for the liver tumor. Magnetic resonance imaging (MRI) showed low intensity on T1-weighted (T1W) images, extremely high intensity on T2W images, and high intensity on diffusion weighted images (DWI) ( Figure 1B, C). Endoscopic retrograde cholangiography showed communication between the intrahepatic bile duct and interior of the tumor ( Figure 1D). The extra-heptatic bile duct showed no dilatation, and neither mucus plug nor biliary stones were detected. Bile cytology showed no sign of malignancy. Biliary cystic tumor, especially intraductal papillary neoplasm of the bile duct (IPNB), was suspected. Although surgery was considered the most appropriate treatment option, close follow up was selected considering the need for rehabilitation for the aphasia and hemiparesis after the stroke. After 2 months of follow up, the CEA and CA19-9 values had increased from 2.9 ng/mL and 7.5 U/mL to 3.8 ng/mL and 9.7 U/mL, respectively. Contrastenhanced CT showed tumor growth from 5.4 cm to 7.6 cm in diameter over 2 months. Consequently, surgery was planned, and left hepatectomy concomitant with left caudate lobe resection and regional lymph node dissection was carried out. The cut surface of the resected specimen showed a well-demarcated, whitish-totranslucent, solid mucus mass ( Figure 1E). Microscopically, numerous mucinous lakes containing floating eosinophilic neoplastic cells were observed ( Figure 1F). IPNB was not observed in the involved bile duct. Multiple lymph node metastases were confirmed in the hepatic and suprapancreatic glands. According to the UICC-TNM classification system, the cholangiocarcinoma was classified as Stage IVA (T1N1M0). Oral S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) chemotherapy was given post-surgery and, at the latest follow-up (3 months post-surgery), the patient showed no sign of recurrence.

| Tumor markers
CEA and CA19-9 levels were most commonly measured, and elevated values of CEA and CA19-9 were noted in six of 11 (54.5%) and in six of nine patients (66.7%), respectively (Table S1). Values of CA19-9 >500 U/mL were noted in five of nine patients (55.5%).

| Imaging findings
Imaging findings of the mucinous cholangiocarcinomas are summarized in

| Prognosis
Lymph node metastases were noted in five of six patients (Table 4).
Distant metastases were noted in five of 10 patients. The site of distant metastasis was the lymph nodes in two patients, lungs in two, peritoneum in one, skin in one, and adrenal gland in one patient.
Nine of 10 cases in whom the pathological stage was disclosed were classified as Stage IV, whereas the remaining case was classified as