Cancers of the biliary tract could involve the intra- and extrahepatic ducts, gallbladder and ampulla [13]. The involved biliary segment has been described to vary among different countries, being the intrahepatic carcinoma more common in Asia and the gallbladder cancer in South America. Gallstones are the most important risk factor for the development of a gallbladder cancer and in 70-90% of cases of gallbladder cancer gallstones can be identified [14]. Chronic inflammation, Caroli’s disease, choledochal cysts, infectious diseases as well as a variety of biological and chemical toxins are further factors associated with biliary cancer development [14]. The carcinogenesis of biliary neoplasm is thought to be a multi-step process from metaplasia to malignant degeneration. Antral metaplasia, hyperplasia, non-neoplastic polyps represent non-neoplastic lesions and can be found in around 9 - 59.5% of cases after cholecystectomy [15,16]. The bile-type epithelium with columnar cells and round to oval uniform nuclei differ from the dysplastic changes that are characterized by the loss of epithelium architecture, increased height of cells and nuclear crowding with presence of mitotic figures (figure 3). While reactive changes blend gradually with the normal cells’ architecture, real dysplasia has sharp demarcated areas adjacent to the normal biliary epithelium [6].
Depending on the severity of atypia, dysplasia can be defined as either low- or high-grade. Terms like “moderate” or “severe” dysplasia, as well as “carcinoma in situ” are used to describe histological changes of biliary epithelium. Zen et al. [17] described two main types of premalignant dysplastic lesions: the biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasms (IPN-B). The latter is considered less common, it is associated with ectasia of extrahepatic biliary ducts and cysts formation with an exophytic proliferation of biliary epithelium. Moreover, it can be associated with abdominal pain and jaundice.
Zen et al. [17] originally described BilIN as microscopic alterations, asymptomatic and not appreciable with imaging studies. BilIN is frequently detectable in specimens with invasive carcinoma and is an incidental finding in 1% to 3.5% of cholecystectomies. BilIN was recently classified by the World Hospital Organization according to the degree of atypia in BilIN1, BilIN2 and BilIN3 [18]. Therefore, BilIN1 corresponds to low-grade, BilIN2 to intermediate grade and BilIN3 to a high-grade of dysplasia. Although this grading-system may be useful, in daily practice it is easier to apply a two-tiered system (low-grade and high-grade dysplasia).
The 5-year survival rate of patients with cholangiocarcinoma is thought to be around 5%-10%. An improved overall survival can only be achieved through a complete surgical resection with tumour-free margins [19] but, unfortunately, these surgical results are difficult to achieve as frequently an advanced disease is diagnosed [20]. Mizumoto et al. [21] reported a 5-year survival rate for early bile duct cancer of 100%. Kurosaki et al. [22] reported a 5-year survival rate for 7 patients with pT1 bile duct cancer of 86%. Therefore, in case of biliary dysplasia, strategies involving prophylactic surgical resections or detection of cancers at early stage could have a dramatic impact on patient’s prognosis.
Bickenbach et al. [10] reported a series of five patients with high-grade dysplasia at the cystic duct margin after cholecystectomy without preoperative evidence of malignancy. One of the five patients was found to have a carcinoma and deceased after 15 months despite proper surgery and adjuvant chemotherapy. From this small series, the authors concluded that the risk of underlying bile duct cancer in case of high-grade dysplasia at the cystic stump is not neglectable, as about 10% of biliary carcinomas are multifocal. So, high-grade dysplasia of the cystic stump could represent multifocal neoplastic changes of biliary ducts or express a wide extension of an underlying malignancy. In a recent case report, Moslim et al. [11] suggested the surgical intervention with excision and reconstruction of the main duct in case of positive cystic duct resection margins. More recently, Cianfarani et al. [12] reported a case of positive resection margins for low-grade dysplasia on the cystic duct that was successfully surgical treated with a cystic stump resection.
The lack of literature about the surveillance of cystic duct dysplasia makes difficult to draw conclusions. A possible management algorithm is shown in figure 2. Due to the known progression to carcinoma and the multifocality, a multidisciplinary board evaluation in case of dysplasia of the cystic duct is strongly advisable. The surgical treatment of positive resection margins after cholecystectomy with high-grade dysplasia should be considered mandatory. The treatment of cases with low-grade dysplasia should be tailored on patient’s age and general conditions, but a surgical resection can be a reasonable option. Due to the high rate of dysplasia multifocality, an optimal surveillance program should be considered in patient with low- and high-grade dysplasia. There is no evidence that supports one or the other method, so that its choice should be based on the local experience and resources. MRCP, ERCP with SpyGlass cholangioscopy, echoendoscopy and regular liver function tests can play a role in surveillance programs.
The main limitation of our study is the sparse data available in literature on positive resection margins for dysplasia after cholecystectomy. A case series and two case reports make difficult to draw proper conclusions. Nevertheless, literature on the gallbladder and the biliary tree dysplasia provides sufficient data to propose a possible treatment algorithm for this uncommon condition.