Flowcharts for the management of biliary tract and ampullary carcinomas

No strategies for the diagnosis and treatment of biliary tract carcinoma have been clearly described. We developed fl owcharts for the diagnosis and treatment of biliary tract carcinoma on the basis of the best clinical evidence. Risk factors for bile duct carcinoma are a dilated type of pancreaticobiliary maljunction (PBM) and primary sclerosing cholangitis. A nondilated type of PBM is a risk factor for gallbladder carcinoma. Symptoms that may indicate biliary tract carcinoma are jaundice and pain in the upper right area of the abdomen. The fi rst step of diagnosis is to carry out blood biochemistry tests and ultrasonography (US) of the abdomen. The second step of diagnosis is to fi nd the local extension of the carcinoma by means of computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP). Because resection is the only way to completely cure biliary tract carcinoma, the indications for resection are determined fi rst. In patients with resectable disease, the indications for biliary drainage or portal vein embolization (PVE) are checked. In those with nonresectable disease, biliary stenting, chemotherapy, radiotherapy, and/or best supportive care is selected.

# Introduction
There have been no reports of a comprehensive clinical system to cover all entities of bile duct carcinoma, gallbladder carcinoma, and ampullary carcinoma. In addition, there is no clear consensus as to the best methods of diagnosis and treatment of biliary tract carcinoma. We therefore developed fl owcharts for the diagnosis and treatment of biliary tract carcinoma, on the basis of the best clinical evidence provided until 2007. Six levels of evidence were used (see defi nitions of levels in [fig_ref] Table 1: Levels of evidence 1 [/fig_ref] [bib_ref] Purpose, use, and preparation of clinical practice guidelines for the management of..., Takada [/bib_ref] , and the levels are noted here in parentheses after the citations of relevant references. The fl owchart for diagnosis consists of: (1) risk factors, [bib_ref] Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan, Tashiro [/bib_ref] clinical presentation, (3) the fi rst step of diagnosis, and (4) the second step of diagnosis. The fl owchart for treatment consists of: (1) resectable cases and (2) nonresectable cases.

## Flowchart for the diagnosis of biliary tract carcinoma
The fl owchart for the diagnosis of biliary tract carcinoma is shown in .

## Risk factors
Risk factors for bile duct carcinoma are a dilated type of pancreaticobiliary maljunction (PBM) and primary sclerosing cholangitis. Biliary tract carcinoma occurred in 10.6% of patients with a dilated type of PBM, and bile duct carcinoma occurred in 33.6% of such patients 2 (level IV). Bile duct carcinoma occurred in 5%-10% of patients with primary sclerosing cholangitis 3-6 (level V). No risk factor is known for ampullary carcinoma.

## Clinical presentation
Symptoms that may indicate biliary tract carcinoma are jaundice and pain in the upper right area of the abdomen.
For 90% of patients with bile duct carcinoma, the presenting symptom was jaundice [bib_ref] Cholangiocarcinoma: a review, Thuluvath [/bib_ref]. In patients without jaundice, the presenting symptom was pain in the abdomen, fever, anorexia, or lassitude 2,7-9 (level IV).
The symptom most often seen in gallbladder carcinoma is pain in the upper right area of the abdomen [bib_ref] Clinicopathological features and management of gallbladder cancer in Pakistan: a prospective study..., Malik [/bib_ref] (level IV). Other signs and symptoms are nausea, vomiting, loss of weight, jaundice, anorexia, a feeling of abdominal distension, pruritus, and black feces 10 (level IV).
Symptoms of ampullary carcinoma in many patients are jaundice, fever, and abdominal pain 12,13 (level IV).

## First step of diagnosis
The fi rst step of diagnosis is to carry out blood biochemistry tests and ultrasonography (US) of the abdomen. In blood biochemistry tests in patients with bile duct obstruction, rises in hepatobiliary enzymes are observed [bib_ref] Biliary tract cancers, De Groen [/bib_ref] (level III). Carbohydrate antigen (CA) 19-9 is elevated in 50%-79% of patients with biliary tract carcinoma [bib_ref] Carcinoma of the gallbladder, Misra [/bib_ref] [bib_ref] Increased levels of CA19-9, CA50 and CA125 in patients with benign disease..., Piantino [/bib_ref] [bib_ref] The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients..., Patel [/bib_ref] [bib_ref] Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary..., Nichols [/bib_ref] (levels II and III), and carcinoembryonic antigen (CEA) is elevated in 40%-70% of such patients [bib_ref] Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary..., Nichols [/bib_ref] [bib_ref] Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document, Khan [/bib_ref] [bib_ref] Clinical value of serum tumor markers CEA, CA50 and CA242 in the..., Pasanen [/bib_ref].
If there is a suspicion of biliary tract carcinoma, US is the fi rst diagnostic imaging to be applied. If dilation of the bile duct is found, it is possible to identify the obstructed region [bib_ref] Biliary tract cancers, De Groen [/bib_ref] (level III). For gallbladder carcinoma, the tumor is identifi ed by US in more than 50% of patients 14 (level III).

## Second step of diagnosis
Bile duct carcinoma Computed tomography (CT) and magnetic resonance imaging (MRI; including magnetic resonance cholangiopancreatography are useful to check on the location of bile duct carcinoma or to fi nd the local extension of such carcinoma. Contrast-enhanced CT is useful for fi nding the main local extension of cancer. In addition, examining whether there is invasion of the cancer into blood vessels by means of contrast-enhanced CT is important for deciding how to treat the cancer [bib_ref] Cholangiocarcinoma: pictorial essay of CT and cholangiographic fi ndings, Han [/bib_ref] [bib_ref] Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document, Khan [/bib_ref] [bib_ref] Preoperative evaluation of resectability of Klatskin tumor with 16-MDCT angiography and cholangiography, Chen [/bib_ref] (level II-IV). In bile duct carcinoma without thickening of biliary walls, it is diffi cult to identify local extension or depth only by means of CT [bib_ref] Cholangiocarcinoma: pictorial essay of CT and cholangiographic fi ndings, Han [/bib_ref] [bib_ref] Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document, Khan [/bib_ref] (levels II and IV).
MRCP is useful for identifying the obstructed region in the bile duct, for fi nding the local extension of the carcinoma, and for checking on PBM 25 (level IV). MRCP has a sensitivity of 70%-96% in determining whether a bile duct stricture is of benign/malignant nature, and is able to identify obstructed regions with a sensitivity of 94%-99% 26-28 (levels III and IV).
Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are useful for examining the horizontal invasion of nodular bile duct carcinoma, and for indicating nodular and invasive bile duct carcinoma 29,30 (level IV).
Examination of cells or tissues is carried out as required. The positive rate of bile cytology determined by means of endoscopic retrograde cholangiography (ERC) is about 30% 25 (level II). A combination of brush cytology and biopsy of the bile duct increases the positive rate to 40%-70% 25 (level II).
Percutaneous transhepatic cholangioscopy (PTCS) [bib_ref] Percutaneous transhepatic cholangiodrainage and cholangioscopy for the case of severe obstructive jaundice..., Takada [/bib_ref] [bib_ref] Cholangioscopic differentiation of biliary strictures and polyps, Nimura [/bib_ref] [bib_ref] Staging of biliary carcinoma: cholangiography and cholangioscopy, Nimura [/bib_ref] and peroral cholangioscopy (POCS) [bib_ref] Peroral cholangioscopic diagnosis of biliary-tract diseases by using narrow-band imaging (with videos), Itoi [/bib_ref] [bib_ref] Diagnostic utility of peroral cholangioscopy for various bile-duct lesions, Fukuda [/bib_ref] enable close examination of the lumen of the bile duct.
These modalities are useful in both differentiating benign and malignant biliary strictures and in diagnosing the superfi cial mucosal spread of bile duct carcinoma along the bile duct wall.

## Gallbladder carcinoma
In the diagnosis of gallbladder carcinoma, differential diagnosis and determination of the local extension of tumor are important. For these purposes, imaging modalities such as endoscopic ultrasonography (EUS), CT, MRI, and MRCP are useful. EUS has good sensitivity, of 92%-97%, in differentiating benign gallbladder diseases from gallbladder carcinoma [bib_ref] Endoscopic ultrasonography for differential diagnosis of polypoid gall bladder lesions: analysis in..., Sugiyama [/bib_ref] [bib_ref] Differential diagnosis of polypoid lesion of the gallbladder by endoscopic ultrasonography, Azuma [/bib_ref] [bib_ref] Contrast-enhanced endoscopic ultrasonography in gallbladder diseases, Hirooka [/bib_ref] (level IV). CT has a capability of diagnosis of tumorous lesions in the gallbladder with a sensitivity of 88%, a specifi city of 87%, and a correct diagnosis rate of 87% 39 (level IV). In a report that evaluated the diagnosis of the resectability of gallbladder carcinoma, accuracy of the diagnosis of resectability with CT was 93.3% 40 (level IV). According to some reports, in the diagnosis of direct invasion of tumor into the liver, MRI combined with MRCP had a sensitivity of 67%-100% and a specifi city of 89%; in the diagnosis of invasion of tumor into the bile duct, it had a sensitivity of 62%-100% and a specifi city of 89%; and in the diagnosis of cancer metastasis to lymph nodes, it had a sensitivity of 56%-92% and a specifi city of 89% 41,42 (level IV).

## Ampullary carcinoma
For the examination of ampullary carcinoma, endoscopic biopsy is used. For the examination of distant metastasis of cancer, e.g., to the liver, US, CT, and MRI are used. For the examination of invasion to the pancreas or the duodenum, EUS or intraductal ultrasonography (IDUS) is useful [bib_ref] Polypoid tumors of the major duodenal papilla: preoperative staging with intraductal US,..., Menzel [/bib_ref] [bib_ref] Intraductal ultrasonography in diagnosing tumor extension of cancer of the papilla of..., Itoh [/bib_ref] (level II).

## Flowchart for the treatment of biliary tract carcinoma
The fl owchart for the treatment of biliary tract carcinoma is shown in [fig_ref] Figure 2: Flowchart for the treatment of biliary tract and ampullary carcinomas [/fig_ref].

## Indications for resection
Resection is the only radical treatment for biliary tract carcinoma. Its possibility should, therefore, be considered fi rst. If such cancer involves metastasis to the liver, the lung or the peritoneum, it is not resectable [bib_ref] Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients, Weber [/bib_ref] [bib_ref] Regional and para-aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma, Kondo [/bib_ref] [bib_ref] The role of lymph node dissection in the treatment of gallbladder carcinoma, Shimada [/bib_ref] (level IV). On the other hand, there is a report which advocates surgery for patients with paraaoric lymph node metastasis, because the outcome is expected to be improved by surgery [bib_ref] Aggressive surgery for stage IV gallbladder carcinoma; what are the contraindications?, Nishio [/bib_ref] [bib_ref] Lymph node metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent..., Kitagawa [/bib_ref] (level IV). However, there is no consensus on standards for local extension factors or on the level of metastasis of lymph nodes that would determine whether the cancer is nonresectable.

## Resectable cancers
Preoperative management Biliary drainage. Many reports suggest that, except for patients with cholangitis or hepatic disorders, surgical operations that are as invasive as pancreatoduodenectomy do not need preoperative biliary drainage [bib_ref] Association of preoperative biliary drainage with postoperative outcome following pancreatoduodenestomy, Poveski [/bib_ref] [bib_ref] The effect of preoperative biliary drainage on postoperative complications after pancreatoduodenectomy, Sewnath [/bib_ref] [bib_ref] Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy, Martignoni [/bib_ref] [bib_ref] Effect of preoperative biliary decompression on pancreatoduodenectomy. Associated morbidity in 300 consecutive..., Pisters [/bib_ref] [bib_ref] Is preoperative biliary drainage necessary according to evidence-based medicine?, Takada [/bib_ref] (levels IV and VI). The mortality from complications in major hepatectomy is about 10%, and the main cause of death is hepatic failure 55 (level IV). In patients with severe jaundice, therefore, biliary drainage is carried out before surgical operation. For biliary drainage, it is, in principle, suffi cient to drain only the future remnant liver. However, there are no standards for indications for such drainage.

## Portal vein embolization (pve).
In patients who require right hemihepatectomy and more extended hepatectomy, or 50%-60% hepatectomy, particularly patients with obstructive jaundice, PVE may be performed. It may reduce postoperative complications or deaths related to the operations 56-62 (levels III and IV).

## Surgery
The results of surgical treatment of biliary tract carcinoma have been improved with various new procedures.
Bile duct carcinoma. For hilar cholangiocarcinoma and upper bile duct carcinoma, extrahepatic bile duct resection with hepatectomy is a standard surgical procedure; and for middle or lower bile duct carcinoma, pancreatoduodenectomy is a standard procedure. For many patients with hilar cholangiocarcinoma, combined resection of the caudate lobe is recommended [bib_ref] Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the..., Nimura [/bib_ref] [bib_ref] Surgery for hilar cholangiocarcinoma: Italian experience, Gazzaniga [/bib_ref] [bib_ref] One hundred and eleven liver resections for hilar bile duct cancer, Lee [/bib_ref] ; however, there is a report which describes that caudate lobe resection did not infl uence the outcome of patients with hilar cholangiocarcinoma [bib_ref] Factors infl uencing postoperative morbidity, mortality, and survival after resection for hilar..., Su [/bib_ref]. In patients with upper or middle bile duct carcinoma, resection of the extrahe- patic bile duct is indicated in those patients with papillary lesions localized in such regions, without clear metastasis to lymph nodes 67-69 (level IV). In addition, it is preferable to confi rm a negative surgical margin in intraoperative rapid pathological examination. Combined resection of the portal vein in patients with tumor invasion into the portal vein resulted in a more satisfactory outcome than that seen in nonresectable patients [bib_ref] Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive..., Ebata [/bib_ref] [bib_ref] Combined vascular resection in operative resection for hilar cholangiocarcinoma: does it work..., Miyazaki [/bib_ref] [bib_ref] Renal function is well maintained after use of left renal vein graft..., Suzuki [/bib_ref] [bib_ref] Portal vein resection for hilar cholangiocarcinoma, Hemming [/bib_ref] [bib_ref] Combined portal vein and liver resection for carcinoma of the biliary tract, Nimura [/bib_ref]. So this combined resection may be performed.
Gallbladder carcinoma. Gallbladder carcinoma involves various modes of extension to adjacent organs, such as invasion into the liver, hepatoduodenal ligament, duodenum, or transverse colon. So it is important to select the type of surgical operation according to the mode of extension on a case-by-case basis, aiming at no residual tumor [bib_ref] Radical surgery for advanced gallbladder carcinoma, Miyazaki [/bib_ref] [bib_ref] Extensive surgery for carcinoma of the gallbladder, Kondo [/bib_ref] (level IV).
Ampullary carcinoma. For this carcinoma, the standard operation is pancreatoduodenectomy. The indication for carcinoma in adenoma is minimally invasive surgery 77-79 (level IV).

## Adjuvant therapy
For chemotherapy, there are no recommendable regimens, so such therapy is used on a trial basis. For radiotherapy, some reports have stated that it was useful; however, there is no highly reliable evidence for standard therapy [bib_ref] Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder..., Todoroki [/bib_ref] [bib_ref] Benefi ts of combining radiotherapy with aggressive resection for stage IV gallbladder..., Todoroki [/bib_ref] [bib_ref] Results of radiation therapy in carcinoma of the proximal bile duct (Klatskin..., Gonzalez [/bib_ref] [bib_ref] Carcinoma of the extrahepatic bile ducts: results of an aggressive surgical approach, Langer [/bib_ref]. Accordingly, radiotherapy may be used in patients who have a positive surgical margin postoperatively 84 (level IV). However, one should be cautious in using radiotherapy in patients with curative resection.

## Nonresectable cancers biliary drainage and stenting
For patients with lower bile duct obstruction, biliary stenting is carried out. The stenting is preferably by an endoscopic route [bib_ref] Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice, Speer [/bib_ref] [bib_ref] Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile..., Smith [/bib_ref] (level II). For the type of stent, a metal stent is recommended for patients with lower bile duct obstruction [bib_ref] Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant..., Davids [/bib_ref] [bib_ref] Plastic or metal stents for malignant stricture of the common bile duct?..., Kaassis [/bib_ref] [bib_ref] Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents:..., Levy [/bib_ref] [bib_ref] Treatment of malignant biliary obstruction with polyurethane-covered Wallstents, Hausegger [/bib_ref] [bib_ref] A prospective randomised study of "covered" versus "uncovered" diamond stents for the..., Isayama [/bib_ref] [bib_ref] Plastic endoprostheses versus metal stents in the palliative treatment of malignant hilar..., Wagner [/bib_ref].
Chemotherapy, radiotherapy, and photodynamic therapy Chemotherapy. For patients in a good general state, chemotherapy is applied [bib_ref] Chemotherapy improves survival and quality of life in advanced pancreatic and biliary..., Glimelius [/bib_ref] [bib_ref] Prospective randomized trial of 5-fl uorouracil, doxorubicin, and mitomycin C for nonresectable..., Takada [/bib_ref] [bib_ref] Chemotherapy in the treatment of advanced gallbladder cancer, Ishii [/bib_ref] [bib_ref] Phase II study of single-agent gemcitabine in patients with advanced biliary tract..., Okusaka [/bib_ref] (levels II and IV). No standard chemotherapy has yet been established. A combination therapy regimen with gemcitabine hydrochloride is now in a phase II study.
Radiotherapy. It is reported that radiotherapy has a better effect in improving survival time than palliative therapy 97,98 (level IV). In addition, another advantage of radiotherapy is that the patency of the stent may be maintained and pain may be reduced by local control.
Photodynamic therapy. It is recognized that photodynamic therapy combined with biliary stenting has a signifi cantly better effect in improving survival time than biliary stenting only 99,100 (level II).

## Best supportive care
For patients in whom chemotherapy and radiotherapy are not indicated due to a poor general state or persistent jaundice, best supportive care, such as pain control, should be applied for the purpose of maintaining quality of life.
Acknowledgment. We would like to express our deep gratitude to the members of the the Japanese Association of Biliary Surgery, the Japanese Society of Hepato-Biliary-Pancreatic Surgery, and the Japan Society of Clinical Oncology, who provided us with great support and guidance in the preparation of the Guidelines. This process was conducted as part of the Integrated Research Project for Assessing Medical Technology 2005 and 2006 sponsored by the Japanese Ministry of Health, Labour, and Welfare.
We truly appreciate the following active working members who developed the draft of the evidencebased clinical practice Guidelines for the treatment of biliary tract cancer (Japanese version, 2007): Masahiro Kai , Yasutoshi Kimura (Sapporo), Shigeaki Sawada (Toyama), Hiroaki Shimizu (Chiba), Hisatoshi Nakagawara (Kanazawa), Kohei Nakachi (Kashiwa), and Hiroyuki Yoshitome (Chiba). We also appreciate very much the following members who reviewed and approved the fi nal Japanese version of the guidelines: Hiromitsu Saisyo (Ichikawa), Munemasa Ryu (Chiba), Satoru Shikata (Kyoto), and Yuji Nimura (Nagoya).
[fig] Fig: 1. Flowchart for the diagnosis of biliary tract and ampullary carcinomas. US, Ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; ERC, endoscopic retro- [/fig]
[table] Table 1: Levels of evidence 1 [/table]