Risk factors for biliary tract and ampullary carcinomas and prophylactic surgery for these factors

Curative resection is the only treatment for biliary tract cancer that achieves long-term survival. However, patients with advanced biliary tract cancer have only a limited prognosis even after radical surgical resection. Thus, to improve the longterm results, the early detection of biliary tract cancer and subsequent cure seem to be essential. The purpose of this study was to review the literature concerning the risk factors for cancerous and precancerous lesions of the biliary tract, and prophylactic surgery for these factors. It has been reported that pancreaticobiliary maljunction (PBM) with bile duct dilatation is a risk factor for gallbladder cancer and bile duct cancer, while PBM without bile duct dilatation is a risk factor for gallbladder cancer. Thus, in the former group, a prophylactic excision of the common bile duct and gallbladder should be recommended, while in the later group, a prophylactic cholecystectomy without bile duct resection may be the appropriate surgical procedure. It has also been reported that primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma. Patients with PSC often develop advanced cholangiocarcinoma with a poor prognosis. In patients with PSC, therefore, strict follow-up should be recommended. Adenoma and dysplasia have been regarded as precancerous lesions of gallbladder cancer. A polypoid lesion of the gallbladder that is sessile, has a diameter greater than 10 mm, and /or grows rapidly, is highly likely to be cancerous and should be resected. Although gallstones seem to be closely associated with gallbladder cancer, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Thus, a cholecystectomy is not advised for asymptomatic cholecystolithiasis. Controversy remains as to whether adenomyomatosis of the gallbladder and porcelain gallbladder are associated with gallbladder cancer. With respect to ampullary carcinoma, adenoma of the ampulla is considered to be a precancerous lesion. This article discusses the risk factors for cancerous and precancerous lesions of the biliary tract and prophylactic treatment for these factors.

# Introduction
One of the possible causes of biliary tract cancer may be chronic and continuous stimulation of the biliary tract, and cholangitis due to gallstones and the refl ux of pancreatic juice into the biliary tract. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] [bib_ref] Association between Helicobacter bilis in bile and biliary tract malignancies: H. bilis..., Matsukura [/bib_ref] The underlying diseases that potentially cause such a condition include pancreaticobiliary maljunction (PBM), [bib_ref] Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan, Tashiro [/bib_ref] primary sclerosing cholangitis (PSC), 4-7 chronic cholecystitis, [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] gallstones, [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] [bib_ref] Family history of gallstones and the risk of biliary tract cancer and..., Hsing [/bib_ref] and adenomyomatosis. [bib_ref] High risk of gallbladder carcinoma in elderly patients with segmental adenomyomatosis of..., Nabatame [/bib_ref] In such patients, chronic infl ammation potentially causes pathological changes of the biliary epithelium resulting in precursors of biliary tract cancer. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] Although curative resection is the only treatment for biliary tract cancer that achieves long-term survival, patients with advanced cancer have only a limited prognosis even after radical surgical resection. To improve the long-term results, therefore, the early detection of precancerous and cancerous lesions, and subsequent cure seem to be essential.
In this article, we discuss the predisposing factors for bile duct cancer, gallbladder cancer, and ampullary car-cinoma, using a format of clinical questions (CQs) and responses. In the responses to the CQs, recommendations for treatment are noted (grades of these recommendations are defi ned in [fig_ref] Table 1: Strength of recommendations10 [/fig_ref] [bib_ref] Purpose, use, and preparation of clinical practice guidelines for the management of..., Takada [/bib_ref]. Also, levels of evidence are given (in parentheses) for fi ndings in reference citations (see defi nitions of levels in [bib_ref] Purpose, use, and preparation of clinical practice guidelines for the management of..., Takada [/bib_ref].

## Risk factors for bile duct cancer
Pancreaticobiliary maljunction (see A retrospective nationwide survey (1990 to 1999) of PBM in Japan revealed that 10.6% of PBM patients with bile duct dilatation were complicated by biliary tract cancer, and 33.6% of these biliary tract cancers were bile duct cancer 3 (level IV). PBM with bile duct dilatation is considered as a risk factor for bile duct cancer.

## Primary sclerosing cholangitis (psc)
Patients wit PSC carry an increased risk of bile duct cancer. Five percent to 10% of PSC patients develop bile duct cancer 4-7 (level V). Bile duct cancer associated with PSC is often advanced with a poor prognosis. PSC, therefore, should be recognized as a risk factor for bile duct cancer.
Controversy remains as to whether bile duct cancer is related to chronic infl ammation due to gallstones or some gene mutations [bib_ref] Family history of gallstones and the risk of biliary tract cancer and..., Hsing [/bib_ref] [bib_ref] Expression of oncogene products HER2/Neu and Ras and fi brosisrelated growth factors..., Su [/bib_ref] [bib_ref] Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis, Matsumoto [/bib_ref] (level IV).

## Risk factors for gallbladder cancer
Pancreaticobiliary maljunction (see There have been many studies that reported PBM as a risk factor for gallbladder cancer. A nationwide survey (1990 to 1999) of PBM revealed that the prevalence rate of biliary tract cancer was 10.6% in the group with bile duct dilatation, while the prevalence rate was 37.9% in the group without bile duct dilatation 3 (level IV). With respect to the PBM patients who developed biliary tract cancer, the incidence of gallbladder cancer was 64.9% in those with PBM with bile duct dilatation, whereas the incidence was 93.2% in those with PBM without bile duct dilatation. Therefore, PBM is an evident risk factor for gallbladder cancer. Of note, the frequency of gallstones in patients with PBM associated with gallbladder cancer is low. [bib_ref] Cancer of the gallbladder associated with anomalous junction of the pancreatobiliary duct..., Tanaka [/bib_ref] Gallstones and porcelain gallbladder (see CQ [bib_ref] Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan, Tashiro [/bib_ref] It has been well established that gallstones are closely associated with gallbladder cancer 1,8 (level V). It has also been reported that a stone size of more than 3 cm, CQ 1 What are the risk factors for biliary tract and ampullary carcinomas?

## Pancreaticobiliary maljunction (pbm) with bile duct dilatation and primary sclerosing cholangitis (psc) are risk factors for biliary tract cancer (see side memos 1 and 2). pbm, particularly that without bile duct dilatation, is a risk factor for gallbladder cancer.
There are no evident risk factors for ampullary carcinoma.
The prevalence rate of biliary tract cancer varies in different geographical regions. Chile and Japan have the highest rate in the world, followed by East Asia and India (level V). 1,2 Also, there are age differences in the incidence of biliary tract cancer. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] It has been reported that the risk factors for biliary tract cancer are, possibly, chronic and continuous stimulation and infl ammation of the biliary tract. 1,2 Polypoid lesions of the gallbladder and adenomyomatosis have been regarded as a risk factors for gallbladder cancer. In this section, we review the respective risk factors for bile duct cancer, gallbladder cancer, and ampullary carcinoma. [fig_ref] more 3: Deductive diagnosis Exclude secondary sclerotic cholangitis as follows [/fig_ref] Adenomyomatosis has not been considered to have malignant potential. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] Nabatame et al. [bib_ref] High risk of gallbladder carcinoma in elderly patients with segmental adenomyomatosis of..., Nabatame [/bib_ref] studied the relationship between adenomyomatosis and gallbladder cancer by examining 4560 gallbladders (2031 from male patients and 2529 from female patients; age 14 to 94 years) resected for gallbladder cancer, gallstones, or other diseases. In that study, the incidence of gallbladder carcinoma was higher in patients with segmental adenomyomatosis (22/334; 6.6%) than in those without (181/4226; 4.3%; P = 0.049). This difference was more marked in patients equal to or older than 60 years of age (P < 0.001). However, the magnitude of risk for gallbladder cancer in patients with adenomyomatosis has not been clearly established. 1,26

## Risk factors for ampullary carcinoma
Kimura et al. [bib_ref] Neoplastic diseases of the papilla of Vater, Kimura [/bib_ref] histologically investigated the papilla of Vater in 576 autopsy cases of elderly people and revealed that the incidences of group 3 and 4 epithelia in the common channel were signifi cantly higher than those in the intraduodenal portion of the bile duct, pancreatic duct, or duodenal epithelia. They also investigated a family history of gallbladder cancer, and the duration of cholelithiasis are potential risk factors for developing gallbladder cancer. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] [bib_ref] An objective assessment of demography of gallbladder cancer, Kumar [/bib_ref] [bib_ref] Gallstone size and the risk of gallbladder cancer, Diehl [/bib_ref] [bib_ref] Treatment of gallstones, David [/bib_ref] However, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Gracie and Ransohoff 17 followed-up the subsequent history of 123 patients with asymptomatic gallstones for 10 years or longer, and revealed that there was no case of gallbladder cancer reported among that group. Controversy remains as to whether patients with "porcelain gallbladder" carry a risk of gallbladder cancer. It has been reported that porcelain gallbladder is often complicated by gallbladder carcinoma [bib_ref] Carcinoma in the porcelain gallbladder: a relationship revisited, Stephen [/bib_ref] [bib_ref] Carcinogenesis of malignant lesions of the gallbladder. The impact of chronic infl..., Tazuma [/bib_ref] (level IV), while another report suggests that porcelain gallbladder is not associated with gallbladder carcinoma 20 (level IV).

## Adenoma of the gallbladder (figs. 1 and 2; also see cq 4)
There is consensus regarding the existence of two models through which malignant transformation is produced: the adenoma-carcinoma sequence and the dysplasia-carcinoma sequence. Intestinal and gastric metaplasias appear to be the pathway through which epithelial dysplasia is produced. [bib_ref] Preneoplastic lesions in gallbladder cancer, Roa [/bib_ref] examined 110 cases of resected gallbladder carcinoma and found dysplasia adjacent to carcinoma in 46 of the 110 cases, and this change was frequently found in lesions at an early stage and in well-differentiated carcinoma (level V).
Kubota et al. [bib_ref] How should polypoid lesions of the gallbladder be treated in the era..., Kubota [/bib_ref] reported that in patients with polypoid lesions of the gallbladder, the respective diameters of adenomas and cancers were 6.9 mm (range, 4 to 13 mm) and 25.7 mm (range, 5 to 50 mm). In that study, 75% of the adenomas and 13% of the cancers had a diameter of less than 10 mm. It has also been reported that when a polypoid lesion of the gallbladder is sessile, has a diameter greater than 10 mm, and /or grows rapidly, it is highly likely to be cancerous. [bib_ref] How should polypoid lesions of the gallbladder be treated in the era..., Kubota [/bib_ref] [bib_ref] The difference in malignancy between pedunculated and sessile polypoid lesions of the..., Ishikawa [/bib_ref] [bib_ref] Endoscopic ultrasonography for differential diagnosis of polypoid gallbladder lesions: analysis in surgical..., Sugiyama [/bib_ref] In such cases, surgical resection should be recommended. . This Loupe image shows growing and dilating Rokitansky-Aschoff sinuses from the muscularis propria to the subserosa, and the growing smooth muscle fi ber and collagen fi ber surrounding them (H&E)

## Side memo 1 primary sclerosing cholangitis (psc)
Defi nition: recurrent or persistent chronic infl ammatory disease of extra-and intrahepatic bile ducts resulting in obliterative fi brosis. No effective treatment has been discovered to date, and liver transplant is required in the terminal stage. Although autoimmune abnormality is suspected, the underlying pathogenesis is still unknown.
Diagnostic criteria

## Typical radiological fi ndings
Typical radiological fi ndings of bile duct are; Multifocal stricturing -Beaded appearance; short or/and annular strictures interspersed among normal or slightly infl amed ducts. This appearance is thought to refl ect the fi brous stricture portions and the normal segments of the bile duct. One-fi fth of the cases present band-like strictures that are extremely short, and one-fourth present diverticulum-like outpouchings -Pruned-tree appearance; diminished arborization of the intrahepatic ducts -Shaggy appearance; diffuse mural irregularities of extrahepatic bile ducts 2. Typical clinical presentation Important clinical history: infl ammatory bowel disease, bile obstruction Blood examination: high alkaline phosphatase (ALP; two or three times upper limit of normal) for 6 months or resected specimens from the patients with carcinoma of the papilla of Vater and found tha the common channel was the most frequent site for the possible origin of carcinoma (level IV). These results suggest that the common channel is the most important site in the pathogenesis of carcinoma of the papilla of Vater. With regard to the incidence of "adenoma" surrounding carcinoma of the papilla of Vater, the values have been reported to range from 82% to 91% 27 (level IV). Therefore, the adenoma-carcinoma sequence is very important in the pathogenesis of carcinoma of the papilla of Vater. In addition, familial adenomatous polyposis (FAP) is notable for the risk of adenoma in the ampulla of Vater.

## Side memo 2 diagnostic criteria of pancreaticobiliary maljunction (pbm; see fig 6)
Defi nition: PBM is a congenital anomaly consisting of a union of the pancreatic and bile ducts located outside the duodenal wall.
Diagnostic criteria: PBM is diagnosed by either radiological or anatomical fi ndings

## 1) radiological fi ndings
It is necessary to confi rm the lack of sphincter action at the union of the pancreatic and bile ducts. However, because clarifi cation of the lack of sphincter action is often diffi cult, the following radiological fi ndings of endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTHC), intraoperative cholangiography, or similar methods are used to verify whether there is a long common channel or a complicated confl uence of the pancreatic and bile ducts.

## 2) anatomical fi ndings
Confi rm the abnormal anatomical confl uence of the pancreatic and bile ducts outside the duodenal wall or confi rm the complicated confl uence by surgery, autopsy, or other procedures.

## Cq 2 is prophylactic treatment necessary for pancreaticobiliary maljunction (pbm)?

## Pbm with bile duct dilatation is a risk factor for bile duct and gallbladder cancer. prophylactic excision of the gallbladder and common bile duct should be recommended for pbm with bile duct dilatation (recommendation grade c1) pbm without bile duct dilatation is a risk factor for gallbladder cancer. a prophylactic cholecystectomy is the appropriate surgical procedure for pbm without bile duct dilatation. (recommendation grade b)
As mentioned above, a retrospective nationwide survey (1990 to 1999) of PBM revealed that the incidence of biliary tract cancer was 10.6% in the group with bile duct dilatation; of these biliary tract cancers, 64.9% were gallbladder carcinoma and 33.6% were bile duct cancer. [bib_ref] Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan, Tashiro [/bib_ref] Therefore, PBM with bile duct dilatation should be considered as a risk factor for bile duct cancer and gallbladder cancer, and in these patients, prophylac-tic excision of the gallbladder and extrahepatic bile duct should be considered. Currently, standard prophylactic treatment of PBM with bile duct dilatation consists of cholecystectomy, extrahepatic biliary duct resection, and hepatocholangiojejunostomy. [bib_ref] Indications for surgery and optimal extent of resection of the bile duct:..., Sekido [/bib_ref] In the PBM patients without bile duct dilatation, the incidence of biliary tract cancer was 37.9%, and 93.2% of these patients had gallbladder cancer 3 (level IV). These reports suggest that PBM without bile duct dilatation should be considered as a risk factor for gallbladder cancer. Therefore, in these patients, excision of the gallbladder should be considered as a minimal prophylactic treatment. Controversy remains as to whether prophylactic bile duct resection is necessary in PBM patients without bile duct dilatation. It has been reported that the long-term results of a prophylactic cholecystectomy without bile duct resection for PBM patients without bile duct dilatation were acceptable 29,30 (level IV). Also, it has been reported that K-ras gene mutation is frequent in the mucosa of the bile duct in PBM patients with bile duct dilatation, while no mutation is observed in PBM patients without bile duct dilatation 31 (level IV). These reports support a prophylactic cholecystectomy without bile duct resection as being the best treatment option for PBM patients without bile duct dilatation. In contrast, it has been reported that the incidence of bile duct cancer in PBM patients without bile duct dilatation is lower than that in PBM patients with bile duct dilatation, but the incidence seems higher than that in healthy controls 3,32 (level IV). Moreover, it has been reported that K-ras and p53 gene mutations are found frequently even in the nondilated bile duct in patients with PBM 33 (level IV). These reports support the possibility that complete excision of the common bile duct may be needed to decrease the risk of bile duct cancer.
tionship between gallstones and gallbladder cancer. Maringhini et al. [bib_ref] Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in, Maringhini [/bib_ref] followed-up, for more than 31 000 person-years a total of 2583 residents of Rochester, Minnesota, who had gallstones. Gallbladder cancer developed in 5 patients after a median follow-up of 13.3 years. The incidence of gallbladder cancer was significantly higher than expected for men but not for women (153 vs 18 per 100 000 person-years). However, these authors do not recommend cholecystectomy, because the absolute incidence and the total numbers of men and women who developed gallbladder cancer were low. Moreover, Gracie and Ransohoff 17 followed up the subsequent history of 123 patients with asymptomatic gallstones for 10 years or longer, and revealed that there was no case of gallbladder cancer reported among that group. This low rate of cancer development in asymptomatic patients with gallstones is similar to that noted in other reports (0.01%/year-0.02%/year) [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] [bib_ref] The natural history of gallstones: the GREPCO experience. The GREPCO Group, Attili [/bib_ref] and, in general, this low rate has lent support to the practice of not performing prophylactic cholecystectomy in patients with asymptomatic cholelithiasis.
Controversy remains as to whether patients with calcifi cation of the wall of the gallbladder, referred to as "porcelain gallbladder" carry a risk of gallbladder cancer. It has been reported that porcelain gallbladder is often complicated by gallbladder carcinoma [bib_ref] Carcinoma in the porcelain gallbladder: a relationship revisited, Stephen [/bib_ref] [bib_ref] Carcinogenesis of malignant lesions of the gallbladder. The impact of chronic infl..., Tazuma [/bib_ref] (level IV). However, Towfi gh et al. [bib_ref] Porcelain gallbladder is not associated with gallbladder carcinoma, Towfi Gh [/bib_ref] have reported that porcelain gallbladder is not associated with gallbladder carcinoma (level IV). The pathogenic mechanism underlying the relationship of calcifi cation to gallbladder cancer also remains unknown.

## Cq 3 is a cholecystectomy required for asymptomatic cholecystolithiasis?

## A cholecystectomy is not advised for asymptomatic cholecystolithiasis (recommendation grade c2)
It has been well established that gallstones are associated with gallbladder cancer 1,8 (level V). Not only is there an increased prevalence of gallbladder cancer in patients with gallstones but up to 75% of patients with gallbladder cancer have been noted to have had gallstones. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] It has also been reported that a stone size of more than 3 cm, a family history of gallbladder cancer, and the duration of cholelithiasis are potential risk factors for the development of gallbladder cancer. [bib_ref] Primary gallbladder cancer: recognition of risk factors and the role of prophylactic..., Sheth [/bib_ref] [bib_ref] An objective assessment of demography of gallbladder cancer, Kumar [/bib_ref] [bib_ref] Gallstone size and the risk of gallbladder cancer, Diehl [/bib_ref] [bib_ref] Treatment of gallstones, David [/bib_ref] However, there is no evidence of a direct causal rela-

## Cq 4 is a cholecystectomy necessary for polypoid lesions of the gallbladder (see side memo 3)

## When a polypoid lesion of the gallbladder is sessile, has a diameter greater than 10 mm, and/or grows rapidly, it is highly likely to be cancerous and should be resected (recommendation grade b)
Currently, adenoma and dysplasia have been regarded as a precancerous lesions of the gallbladder. [bib_ref] Preneoplastic lesions in gallbladder cancer, Roa [/bib_ref] Intestinal and gastric metaplasia seems to be the pathway through which the epithelial dysplasia is produced. [bib_ref] Preneoplastic lesions in gallbladder cancer, Roa [/bib_ref] [bib_ref] Mucosal dysplasia of gallbladder: isolated and adjacent lesions to carcinoma, Yamagiwa [/bib_ref] Yamagiwa 22 examined 110 cases of resected gallbladder carcinoma and revealed that dysplasia adjacent to carcinoma was found in 46 of the 110 cases, and this change was frequently found in lesions at the early stage and in well-differentiated carcinoma (level V).
Kubota et al. [bib_ref] How should polypoid lesions of the gallbladder be treated in the era..., Kubota [/bib_ref] evaluated 72 patients who underwent cholecystectomy for polypoid lesions of the gallbladder. In that study, histological examination showed cholesterol polyps in 47 patients, adenoma in 8, cancers in 16, and an infl ammatory polyp in 1. The respective diameters of the adenomas and cancers were 6.9 mm (range, 4 to 13 mm) and 25.7 mm (range, 5 to 50 mm); 75% of the adenomas and 13% of the cancers had a diameter of less than 10 mm (level IV). Chijiiwa and Tanaka 36 also examined 44 patients who underwent cholecystectomy for polypoid lesions of the gallbladder, and reported that the sex ratio, symptoms, and the presence of gallstones were not signifi cantly different between patients with carcinoma and those with benign polypoid lesions, and that the size (>10 mm), number of polypoid lesions (single), and age (> or =60 years) were signifi cant indicators of carcinoma.
It has been reported that when a polypoid lesion of the gallbladder is sessile, has a diameter greater than 10 mm, and/or grows rapidly, it is highly likely to be cancerous [bib_ref] How should polypoid lesions of the gallbladder be treated in the era..., Kubota [/bib_ref] [bib_ref] The difference in malignancy between pedunculated and sessile polypoid lesions of the..., Ishikawa [/bib_ref] [bib_ref] Endoscopic ultrasonography for differential diagnosis of polypoid gallbladder lesions: analysis in surgical..., Sugiyama [/bib_ref] [bib_ref] Polypoid lesion of the gallbladder: indications of carcinoma and outcome after surgery..., Chijiiwa [/bib_ref] [bib_ref] Gallbladder polyps: epidemiology, natural history and management, Myers [/bib_ref] [bib_ref] Surgical management of polypoid lesions of the gallbladder, Mainprize [/bib_ref] [bib_ref] Can endoscopic sonography differentiate nonneoplastic from neoplastic gallbladder polyps?, Akatsu [/bib_ref]. In such cases, surgical resection should be considered.

## Side memo 3 polypoid lesions of the gallbladder (see figs. 7-10)
Defi nition: "Polypoid" is the general term for torous lesions protruding into the lumen of the gallbladder, no matter whether they are neoplastic or nonneoplastic. The majority of polypoid lesions are nonneoplastic lesions such as cholesterol polyp, adenomyomatosis, or infl ammatory polyp. Benign neoplastic lesions include adenoma and metaplastic polyp, while malignant neoplastic lesions include gallbladder cancer . Ultrasound image of a cholesterol polyp: sessile polyp that has a higher echoic signal than the liver
[fig] Figure 1: Macroscopic photograph of adenoma of the gallbladder a b,c Fig. 2a-c. Histological examination of adenoma of the gallbladder. a Low magnifi cation; b intermediate magnifi cation; c high magnifi cation (H&E) [/fig]
[fig] Fig: 3a-c. Findings in adenomyomatosis. [/fig]
[fig] more 3: Deductive diagnosis Exclude secondary sclerotic cholangitis as follows: -Infectious cholangitis due to AIDS -Malignant neoplasms or similar disease in the bile duct (excluding PSC accompanied by early-stage cholangiocarcinoma) -Previous surgery of the biliary tract (excluding cholecystectomy) -Bacterial cholangitis accompanying biliary tract stricturing or biliary calculus -Ischemic cholangitis due to fl oxuridine [/fig]
[table] Table 1: Strength of recommendations10 [/table]