Cystic duct dysplasia after cholecystectomy: a systematic review of the literature

Purpose Approximately 1 to 3.5% of cholecystectomies are found to have incidental dysplasia on histological examination. Cases of positive resection margins on the cystic stump are rare and evidence lack. The aim of this article was to systematically review the literature and to suggest a possible management algorithm. Methods We searched PubMed, Cochrane Library and Google Scholar databases by combining “cholecystectomy” AND “dysplasia” AND “cystic” according to PRISMA guidelines. Studies providing information about cystic duct dysplasia with positive resection margin after cholecystectomy were included. Results The searches identi�ed 109 articles from PubMed and 4 articles from Cochrane Library and Google Scholar, of which three were eligible. Five were found to have post-operative high-grade dysplasia, one patient had a carcinoma and one had a low-grade dysplasia. Median follow-up was of 10.5 months (range: 0.5 – 26.6 months), no evidence of recurrence was found in patients with dysplasia, while the patient with diagnosis of cholangiocarcinoma died during follow-up. Conclusions Patients with positive resection margins for dysplasia after cholecystectomy should be considered for a surgical treatment. The latter depends on several factors related to the patient and the grade of dysplasia itself. Simple cystic duct stump excision has been suggested and it seems to be safe and effective with no evidence of recurrence during follow-up when a R0 resection is achieved. A multidisciplinary approach and a surveillance program should be always taken into account.


Background
Gallstone disease is an extremely widespread disease, being the estimated prevalence around 10-15% in adult population.Symptoms leading to cholecystectomy can be identi ed in up to 35% of patients with cholecystolithiasis [1], making the laparoscopic cholecystectomy one of the most commonly performed surgical operations in developed countries [2].
Approximately 1 to 3.5% of cholecystectomies are found to have incidental dysplasia on histological examination [3][4][5].Biliary dysplasia is considered a risk factor for the development of an invasive carcinoma [6].Usually, dysplasia does not reach the resection margin, so that no further treatment is needed after cholecystectomy [7].The clinical implications and management of the resection margin involvement by dysplastic changes are unknown.
In this article, we discuss this matter and suggest a possible management algorithm.

Search strategy
Two researchers independently searched the PubMed, Cochrane Library and Google Scholar databases by combining "cholecystectomy" AND "dysplasia" AND "cystic" (last update: June 1 2019) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8].

Inclusion and exclusion criteria
Were included studies providing adequate information about the cystic duct or stump dysplasia after cholecystectomy on the histopathological examination.Studies were excluded in case of a proved diagnosis of gallbladder or cystic duct cancer.

Study selection and quality assessment
Two reviewers independently evaluated titles and abstracts to choose potential studies.If data were duplicated or overlapping, only the most recent data were included.Studies not matching inclusion and exclusion criteria were discarded.Studies potentially suitable for inclusion were evaluated in full-text.Disagreements were resolved by discussion.The evidence quality of was assessed with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE approach) [9].In particular, it was rated from 4 to 1, corresponding 4 to a high level of evidence, 3 to moderate, 2 to low and 1 to very low.With this methodology, the risk of bias, inconsistency, indirectness, imprecision and publication bias were considered to possibly reduce the quality of evidence by 1 or 2 points according to the importance of the factor itself.

Results
The searches identi ed 109 articles from PubMed and 4 articles from Cochrane Library and Google Scholar.After removing duplicates, 110 studies remained.Abstracts and titles were screened and 12 articles were considered potentially eligible.Full texts of these studies were retrieved and analysed.Nine studies were excluded because did not match inclusion and exclusion criteria.Finally, three studies were found eligible and considered in this systematic review [10][11][12] (Figure 1).The characteristics of the included studies are given in Table 1.
Seven patients were found in the medical literature.Median age at the moment of the diagnosis was 61 years old (range: 36 -77).Pre-operative radiographic abnormalities were detected only in 2 out of 7 patients.Four patients had simple cystic duct resection with one 1 case of bile duct exploration for gallstone, 1 patient had cystic duct resection with lymphadenectomy and IV and V segments hepatectomy, 2 patients had bile duct resection with lymphadenectomy , in 1 case with associated IV and V segments hepatectomy.Five patients were found to have post-operative high-grade dysplasia, one patient had a carcinoma and one had a low-grade dysplasia.Median follow-up was of 10.5 months (range: 0.5 -26.6 months), no evidence of recurrence was found in patients with dysplasia.The patient with pathological diagnosis of cholangiocarcinoma died during follow-up after 15.3 months after surgery.Based on these considerations the proposal for a therapeutic algorithm is presented in gure 2.
According to the GRADE approach, due to sparse data and other limitations in the quality of selected studies, the overall quality of evidence of this systematic review was judged "very low" (level of evidence 5).

Discussion
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 identi ed [14].Chronic in ammation, 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 gures ( gure 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 de ned 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 nding in 1% to 3.5% of cholecystectomies.BilIN was recently classi ed 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 di cult to achieve as frequently an advanced disease is diagnosed [20].Mizumoto et al. [21] reported a 5-year survival rate Tables Table 1: Flow chart of the literature search according to PRISMA Guidelines.
Histologic exam showing a low-grade dysplasia on the cystic duct stump.

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