Discussion
The World Health Organization (WHO) classifies mucus-producing bile duct tumors of the liver into intraductal papillary neoplasm of the bile duct (IPNB) or MCN-L [
1]. These concepts were established as counterparts to intraductal papillary mucinous neoplasm (IPMN) of the pancreas and mucinous cystic neoplasm of the pancreas (MCN-P). IPNBs become papillary inside the bile duct and secrete mucin in approximately one-third of all cases. They show communication with the bile duct and do not exhibit OLS. As in the case of IPMN of the pancreas, four phenotypes are known to exist––pancreatobiliary, intestinal, oncocytic, and gastric. On the other hand, MCN-Ls are cyst-forming epithelial tumors that are composed pathologically of mucus-producing cuboidal or columnar epithelium. They usually have no communication with the bile duct and exhibit OLS.
MCN-Ls have been traditionally called biliary cystadenomas or biliary cystadenocarcinomas [
2,
3]. The definitions of these tumors have been controversial; however, in recent years, OLS has been considered necessary for a MCN-L diagnosis, and therefore the disease concept is now being established. Thus, tumors that have been referred to as biliary cystadenomas or biliary cystadenocarcinomas in previous reports could be classified into tumors with and without OLS. Most biliary cystic neoplasms that have been reported previously as biliary cystadenomas or cystadenocarcinomas without OLS are currently thought to be IPNBs [
2,
4‐
8]. Based on the 2010 WHO classifications, biliary cystic neoplasm with OLS should be diagnosed as MCN-L.
Zen et al. [
9] investigated 54 cases of MCN-L and reported the following characteristics: MCN-Ls often occurred in the left hepatic lobe (72 %), the mean age of onset was 52.5 years, and they rarely developed in men (over 90 % of the patients were women). In addition, MCN-Ls are often large, with a mean size of 100 mm (29–240 mm). There is little correlation with viral hepatitis, intrahepatic cholelithiasis, or liver cirrhosis, and malignancy is uncommon, with 1 out of 54 cases exhibiting micro-invasive carcinoma. Although rare, MCN-Ls have the potential to be malignant. Even for asymptomatic cases, surgery is generally preferable for MCN-L. MCN-Ps, the same type of tumor but located in the pancreas, are known to have relatively low malignant potential, but invasive carcinomas have been reported to account for approximately 10 % of cases [
10]. Zen et al. suggested that both MCN-Ls and MCN-Ps exhibit low malignant potential; however, of the two, MCN-Ls exhibit lower malignant potential [
9].
Preoperative differentiation of benign and malignant MCN-Ls is difficult. Previous reports of malignant MCN-Ls indicate nodular components with contrast enhancement effects within the cyst, ductal invasion, and metastasis to other organs [
2,
11]. In our cases, contrast CT showed no nodules inside the cyst, no ductal invasion, and no metastasis to other organs. There were no findings indicating malignancy in the bile cytology. The above findings suggested the presence of benign MCN-L preoperatively. However, a definitive diagnosis can only be made based on postoperative pathological findings.
Kubota et al. [
12] investigated 119 cases of IPNB and 9 cases of MCN-L, all of which occurred in females, and most MCN-L cases were asymptomatic in comparison with the IPNB cases. They suggested that patients with IPNBs may be more likely to develop symptoms such as cholangitis and liver dysfunction due to communication with the bile duct. However, the tumors of the 2 patients in the present report had prolapsed into the bile duct and exhibited expansive growth. Obstructive jaundice was therefore observed.
We searched the literature for MCN-L cases in which the tumor grew expansively in the bile duct over the past 10 years (from 2004 to 2014). In our literature search, we used the keywords “biliary cystadenoma”, “biliary cystadenocarcinoma”, and “mucinous cystic neoplasm of the liver” to search PubMed and extracted cases with growth in the bile duct. We only diagnosed cases with OLS as MCN-Ls and excluded cases that did not exhibit OLS or for which no mention of OLS was made. We also excluded any cases that were complicated by IPNB.
As a result, 15 cases were extracted [
13‐
27] and are listed in Table
1. The mean age of these patients was 44.5 years (25−62 years), all of the patients were female, and all showed the following symptoms: jaundice (9 patients), abdominal pain (9 patients), and liver dysfunction (2 patients); some patients had multiple symptoms. Tumor size was recorded in 11 of the 15 patients. The mean size was 49.5 mm (18−79 mm); the primary tumor sites included the left hepatic lobe (10 patients: 8 cases of S4, 1 case of S3, 1 case of unknown), the common bile duct (3 patients), and the left hepatic duct (2 patients). The tumor spread to both the left hepatic duct and the common bile duct in 7 patients, only the common bile duct in 5 patients, and only the left hepatic duct in 3 patients. ERCP images were recorded for 7 patients. In all of the patients, the images revealed the same characteristic oval-shaped filling defects in the bile duct, as seen in the 2 patients in our study. A hepatectomy and bile duct resection were performed to completely remove the lesions. Pathological examination indicated that none of tumors was malignant.
13 | 62 | F | Jaundice | 41 mm | Common bile duct | Common bile duct | Oval-shaped filling defect | Bile duct resection | Cystadenoma of the common bile duct |
14 | 34 | F | Recurrent episodes of obstructive jaundice | 45 mm | Left lobe (S4) | Left hepatic duct, common bile duct | – | Bile duct resection | Biliary cystadenoma |
15 | 41 | F | Epigastric pain and obstructive liver enzymes | 30 mm | Left lobe (S4) | Left hepatic duct | Oval-shaped filling defect | Left lobectomy, bile duct resection | Hepatobiliary cystadenoma |
16 | 37 | F | Abdominal bloating | 29 mm | Left lobe (S4) | Left hepatic duct, common bile duct | Oval-shaped filling defect | Left lobectomy, bile duct resection | Biliary cystadenoma |
17 | 39 | F | Obstructive jaundice | – | Left lobe (S4) | Left hepatic duct, common bile duct | Oval-shaped filling defect | Left lobectomy, bile duct resection | Biliary mucinous cystadenoma |
18 | 25 | F | Hypochondrial pain | 55 mm | Left lobe (S4) | Left hepatic duct, common bile duct | – | Left lobectomy | Biliary cystadenoma |
19 | 62 | F | Dysuria and hyperpigmentation of urine | – | Left hepatic duct | Common bile duct | – | Extended left lobectomy, bile duct resection | Extrahepatic cystadenoma |
20 | 28 | F | Upper abdominal pain | 73 mm | Left lobe (S4) | Common bile duct | Oval-shaped filling defect | Segmentectomy (left medial section), bile duct resection, cholecystectomy | Hepatobiliary cystadenoma |
21 | 56 | F | Right hypochondrial pain, spontaneously remitted jaundice | 55 mm | Left lobe (S4) | Left hepatic duct, common bile duct | – | Left lobectomy | Biliary cystadenoma |
22 | 57 | F | Right hypochondrial pain, jaundice | 50 mm | Left lobe (S4) | Left hepatic duct | – | Left lobectomy, bile duct resection, cholecystectomy | Hepatobiliary cystadenoma |
23 | 42 | F | Jaundice | – | Common bile duct | Common bile duct | Oval-shaped filling defect | Bile duct resection | Biliary cystadenoma |
24 | 54 | F | Abdominal pain, abnormal liver function tests | 18 mm | Common bile duct | Common bile duct | – | Bile duct resection | Biliary cystadenoma |
25 | 58 | F | Hypochondrial pain, jaundice | – | Left hepatic duct, common bile duct | Left hepatic duct, common bile duct | Oval-shaped filling defect | Bile duct resection | Biliary cystadenoma |
26 | 40 | F | Epigastric pain, jaundice | 70 mm | Left lobe | Left hepatic duct | – | Left lobectomy | Biliary cystadenoma |
27 | 32 | F | Abdominal pain, jaundice | 79 mm | Left lobe (S3) | Left hepatic duct, common bile duct | – | Left lobectomy | Biliary cystadenoma |
The MCN-Ls that spread to and grew in the bile duct developed in patients who were younger than those described in the report by Zen et al., and the tumors tended to be smaller. This may have been because the spread of the tumors to the bile duct is more likely to cause symptoms, such as jaundice or cholangitis, leading to early detection. The characteristic oval-shaped filling defects that are observed with ERCP may be extremely useful in diagnosing this tumor. The most common primary tumor site was S4 of the liver. The primary tumor site was also S4 of the liver in the 2 patients in our reports, suggesting that MCN-Ls that develop from this site may be prone to prolapse into the bile duct. This may be because the most common primary site of MCN-L is S4 of the liver [
2], but it is potentially an interesting phenomenon. We hypothesize that because S4 of the liver is near the hepatic portal region and close to the relatively thick central side of the bile duct, the tumors originating from this site may be prone to prolapse into the bile duct. MCN-Ls in the 15 cases that we reviewed were all benign. Prolapse into the bile duct may be a finding which suggests that the tumor is benign. However, as malignant MCN-Ls are relatively uncommon, we have not reviewed enough cases to date to make such conclusions.
In addition, we will discuss bile duct lesions of other liver tumors and compare them with MCN-L. Bile duct invasion of hepatocellular carcinomas (HCCs) is clinically rare, but reports suggest that it has been observed in 5 % of HCCs in autopsies [
28]. Such cases exhibit irregular stenosis and exclusion of the bile duct. There are three main categories of cholangiocellular carcinoma (CCC): mass-forming (MF), periductal infiltrative (IF), and intraductal growth (IG). Of these, the IG type overlaps the IPNB concept proposed in recent years, with irregular papillary tumors developing in the bile duct. The frequency of the IG type is reported to be 4 % of CCC cases [
29]. Papillary tumors are confirmed on cholangiography and cholangioscopy. Growth of other tumor-related lesions into the bile duct (focal nodular hyperplasia, hepatic adenoma, lymphoma, hepatoblastoma, and mesenchymal tumor) is exceptionally rare.
The occurrence of MCN-Ls prolapsing into the bile duct is unclear as it is an extremely rare tumor. Prolapse into the bile duct has a strong impact, making it likely to be reported. Examination of further cases is required. In MCN-L, expansive growth is shown by prolapse into the bile duct so that the smooth, round tumor occupies the lumen of the bile duct. This development of the tumor, which is completely different from HCC invasion into the bile duct and the IG type of CCC, can be said to be a characteristic behavior of MCN-L.
MCN-L is basically considered to be a non-invasive, benign tumor that does not grow invasively but grows expansively. This tumor can prolapse into the bile duct and then grow to fill the bile duct. ERCP can be used to confirm the characteristic oval-shaped filling defect in the bile duct. Even if the entire oval shape is not revealed, as in case 2, careful attention should be paid to the fact that the margins of the filling defect are oval. In addition, cholangioscopy, IDUS, and EUS are useful for differentiating these tumors from stones.
We described 2 MCN-L cases that exhibited extremely interesting spread patterns. Prolapse into the bile duct and expansive growth may be a characteristic behavior of MCN-L. Additional data from more cases needs to be collected for further elucidation of MCN-L’s pathophysiology.