Diagnosis of biliary tract and ampullary carcinomas

Diagnostic methods for biliary tract carcinoma and the efficacy of these methods are discussed. Neither defi nite methods for early diagnosis nor specifi c markers are available in this disease. When this disease is suspected on the basis of clinical symptoms and risk factors, hemato-biochemical examination and abdominal ultrasonography are performed and, where appropriate, enhanced computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) is carried out. Diagnoses of extrahepatic bile duct cancer and ampullary carcinoma are often made based on the presence of obstructive jaundice. Although rare, abdominal pain and pyrexia, as well as abnormal fi ndings of the hepatobiliary system detected by hemato-biochemical examination, serve as a clue to making a diagnosis of these diseases. On the other hand, the early diagnosis of gallbladder cancer is scarcely possible on the basis of clinical symptoms, so when this cancer is found with the onset of abdominal pain and jaundice, it is already advanced at the time of detection, thus making a cure diffi cult. When gallbladder cancer is suspected, enhanced CT is carried out. Multidetector computed tomography (MDCT), in particular -one of the methods of enhanced CT -is useful for decision of surgical criteria, because MDCT shows fi ndings such as localization and extension of the tumor, and the presence or absence of remote metastasis. Procedures such as magnetic resonance imaging, endoscopic ultrasonography, bile duct biopsy, and cholangioscopy should be carried out taking into account indications for these procedures in individual patients. However, direct biliary tract imaging is necessary for making a precise diagnosis of the horizontal extension of bile duct cancer.

# Introduction
Of biliary tract cancers, extrahepatic bile duct cancer and carcinoma of the papilla are often diagnosed with the onset of obstructive jaundice. In only a few cases is a diagnosis of these cancers made prior to the onset of jaundice, based on a detailed examination of symptoms of cholangitis. Also, a diagnosis of biliary tract cancer is occasionally made in a patient without symptoms, on the basis of abnormal results on hemato-biochemical examination of the hepatobiliary system. Although some risk factors for biliary tract cancer have been indicated, neither an algorithm for early diagnosis nor hemato-biochemical examinations, nor clinical symptoms and tumor markers that are specifi c to this disease are available. As far as gallbl adder cancer is concerned, it is already advanced at the time when its diagnosis has been made, based on the presence of abdominal pain and jaundice. The fi rst step in the diagnostic imaging of biliary tract cancer is abdominal ultrasonography; enhanced computed tomography (multidetector CT where available) is carried out for patients with suspected biliary tract tumors. Magnetic resonance imaging (MRI, including magnetic resonance cholangiopancreatography has come into increased use as an alternative procedure for direct biliary tract imaging, and is indispensable in making a precise diagnosis of horizontal extension. Other excellent diagnostic procedures include endoscopic ultrasonography, bile duct biopsy (cytologic diagnosis), and cholangioscopy. These should be used with care as test procedures prior to treatment while paying attention to the symptoms of individual patients. As guidelines for the diagnosis of gallbladder cancer, this article poses fi ve clinical questions (CQs), in addition to a providing a literature review related to each of these questions. 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 recommendations 1 [/fig_ref]. Also, levels of evidence are given (in parentheses) for fi ndings in reference citations (see defi nitions of levels in [fig_ref] Table 1: Strength of recommendations 1 [/fig_ref].

## Cq 1 by which clinical symptoms is biliary tract cancer suspected?

## When jaundice, right upper abdominal pain, and abnormal fi ndings detected by hemato-biochemical examination of the hepatobiliary system have been observed, examination should be carried out, bearing biliary tract carcinoma in mind (recommendation b).
In 90% of patients with bile duct cancer, the initial symptom is jaundice 2 (level VI). Other symptoms, including pruritus, mild upper abdominal pain, and weight loss are found in more than half of the patients with this cancer 2-4 (level VI). There is a report that, in patients without jaundice, abdominal pain is present in 44% of these patients, pyrexia in 17%, anorexia in 11%, and general lassitude in 11% as initial symptoms, but that 27% of the patients (level IV) have no symptoms. [bib_ref] Bile duct carcinoma without jaundice: clues to early diagnosis, Sugiyama [/bib_ref] The clinical symptom observed most frequently in gallbladder cancer is right upper abdominal pain, in 79%-89% of the patients, 6-8 followed by nausea/vomiting, in 52%-53%, [bib_ref] Is carcinoma of the gallbladder a curable lesion, Wanebo [/bib_ref] [bib_ref] Clinicopathological features and management of gallbladder cancer in Pakistan: a prospective study..., Malik [/bib_ref] and other signs and symptoms, such as weight loss, jaundice, anorexia, abdominal distention, pruritus, and tarry stools 6 (level IV). Many of these patients have such complications as cholecystoli-CQ 2 What is the fi rst step in the diagnosis of biliary tract cancer?

## Noninvasive abdominal ultrasonography and hematological examination can be the fi rst step in diagnosis (recommendation b).

## Hemato-biochemical examination
Liver dysfunction is present in patients with bile duct obstruction.(increases in alkaline phosphatase, glutamyl transpeptidase, and total bilirubin) 12,13 (level III), but no specifi c hemato-biochemical examination to diagnose biliary tract carcinoma is available.

## Abdominal ultrasonography (abdominal us; see figs 1-3)
The diagnostic imaging to be performed in the fi rst place is abdominal US when biliary tract cancer is suspected. Particularly, this procedure facilitates the detection of dilated intrahepatic bile ducts , thus enabling assessment of the obstructed site 12,13 (level III). Fifty percent of gallbladder cancers cases are depicted as tumors on abdominal US . [bib_ref] Clinicopathologic features of ampullary carcinoma without jaundice, Kamisawa [/bib_ref] The detectability of bile duct cancer varies from 21% to 90% (Figs. 1b, 2) 2,5,14,16 and the detectability of distal Opinions of expert panels and individual experts not based on patient's data thiasis and anomalous arrangement of pancreaticobiliary ducts, so it cannot be denied that the above mentioned clinical symptoms have occurred due to these complications. Thus, it may be diffi cult to conclude that they are specifi c symptoms induced by gallbladder cancer.
The clinical symptoms frequently encountered in ampullary carcinoma are jaundice, pyrexia, abdominal pain followed by general lassitude, weight loss, anorexia, and back pain. Jaundice is reported to be observed in 72%-90% of these patients 9-11 (levels IV, VI), but it is characterized by occasional fl uctuation 11 (level VI). There is a report that pyrexia is present in 44% 11 (level IV) and abdominal pain occurs in 45% of patients 10 (level IV).

## Carbohydrate antigen 19-9 (ca19-9) 17-21 (levels ii, iii)
CA19-9 is not evident to confi rm of diagnosis in patients with suspected biliary tract cancer. However:
- It is increased in 50%-79% of patients with biliary tract cancer. - It also increases in patients with cholestasis.
- It does not increase in patients with biliary tract cancer if sialyl Le a is negative.

## Carcinoembryonic antigen (cea) 17,21-23 (level iii)
- CEA is increased in 40%-70% of patients with biliary tract cancer. - Cholestasis has no impact on CEA.

## Cancer antigen 125 (ca125) 21,24 (level iv)
- CA125 is increased in 58% of patients with gallbladder cancer (17 U/ml as the cutoff point). - It tends to increase in patients with ascites.
Although the values of other markers, including DUPAN-2, CA195, CA242, and interleukin (IL)-6 are occasionally measured, their clinical usefulness is not clear [bib_ref] British Society of Gastroenterology. Guidelines for the diagnosis and treatment of cholangiocarcinoma:..., Khan [/bib_ref] 

## Ct and mri (including mrcp) are useful for localization of the lesion and assessment of the degree of its extension (recommendation b). also, direct cholangiography is useful for the diagnosis of the horizontal extension of bile duct cancer (recommendation c1).
bile duct carcinoma is low. When dilatation of the intrahepatic bile duct without extrahepatic bile duct dilatation is observed, stricture of the hilar bile duct is suspected , but middle and lower bile duct stricture is suspected when both intrahepatic and extrahepatic bile ducts are dilated 2,5,14-16 (level IV).

## Tumor markers
No tumor markers specifi c to biliary tract cancer are available. Improved diagnostic ability can be achieved with a combination of tumor markers and other procedures, but early diagnosis using tumor markers alone is diffi cult 12,13,17-24 (levels II, III, IV).
with primary sclerosing cholangitis (PSC), in which it is demonstrated that, in regard to sensitivity and specifi city, three-dimensional CT (3 D-CT) is as useful as cholangiography in assessing this cancer 27 (level IV). On the other hand, it is also known that the diagnosis of bile duct cancer associated with PSC is diffi cult. The presence of lymph node enlargement, which is useful for making a diagnosis of cancers, does not mean that there is malignancy, because lymph node enlargement also occurs in infl ammatory changes in PSC 28 level IV). Enhanced CT detect the lymph node swelling, however it is not effective in differentiating whether the swelling indicates an infl ammatory or a malignant change [bib_ref] CT evaluation of paraaortic lymph node metastasis in patients with biliary cancer, Noji [/bib_ref] [bib_ref] Impact of integrated positron emission tomography and computed tomography on staging and..., Petrowsky [/bib_ref] (level IV).

## Mrcp, endoscopic cholangiopancreatography (ercp), and percutaneous transhepatic cholangiography (ptc) (fig. 7)
MRCP is useful in identifying the site of bile duct stricture, in diagnosing the extension of invasion, and in confi rming the presence or absence of abnormal pancreas and bile duct confl uence 31 (level IV). The sensitivity of MRCP in differentiating between benign and malignant bile duct strictures is 70%-96% and that in identifying the site of obstruction is 94%-99%. [bib_ref] Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease, Romagnuolo [/bib_ref] [bib_ref] Magnetic resonance cholangiopancreatography, Barish [/bib_ref] [bib_ref] Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: fi ndings at..., Park [/bib_ref] Therefore, MRCP is a recommendable procedure. Although direct cholangiography modalities, such as ERCP and cholangiography using percutaneous transhepatic biliary drainage (PTBD), are associated with a risk of incidental disease and are not necessarily required 35 (level IV), these modalities are useful for the diagnosis of the horizontal extension of nodules or the nodular invasive type of bile duct cancer [bib_ref] The pattern of infi ltration at the proximal border of hilar bile..., Sakamoto [/bib_ref] [bib_ref] Invasive growth patterns of hepatic hilar ductal carcinoma. A histologic analysis of..., Hayashi [/bib_ref] (level IV) .
A cytologic diagnosis of bile can be carried out with the use of endoscopic retrograde cholangiography where available) enables the assessment of blood-fl ow dynamics in the bile duct wall and it is useful for making a diagnosis of the main invasion site . However, there are cases in which no association of thickening of the bile duct wall is observed, so the use of CT alone is not suffi cient for a diagnosis of the precise degree of extension and depth of mural invasion [bib_ref] Clinical value of serum tumor markers CEA, CA50 and CA242 in the..., Pasanen [/bib_ref] Ductal tapering due to cancer infi ltration is seen from the hepatic confl uence to the left hepatic duct (arrows). Right hepatectomy is required for curative resection; however, right trisectionectomy is necessary. B2, B3, and B4 indicate the segmental ducts of S2, S3, and S4, respectively (ERC), but the rate of accurate diagnosis using this procedure is approximately 30%. The rate increases by 40%-70% by using brush biopsy 22 (level II).

## Cholangioscopy
Percutaneous transhepatic cholangioscopy (PTCS) enables the detailed examination and direct-vision biopsy of the lumen of the bile duct. PTCS is useful in both differentiating benign and malignant biliary strictures and in diagnosing the superfi cial mucosal spread of cholangiocarcinoma along the bile duct wall. [bib_ref] Cholangioscopic differentiation of biliary strictures and polyps, Nimura [/bib_ref] [bib_ref] Staging of biliary carcinoma: cholangiography and cholangioscopy, Nimura [/bib_ref] Peroral cholangioscopy (POCS) is useful in differentiating benign and malignant stenotic lesions of the bile duct; 40,41 however, it is not so feasible for close examination of the hilar bile duct due to its relatively poor operational performance. [bib_ref] Diagnostic utility of peroral cholangioscopy for various bile-duct lesions, Fukuda [/bib_ref] Intraductal ultrasonography (IDUS) has advantages in both diagnosing the depth of invasion, including vascular invasion, and the intramural spread of cholangiocarcinoma along the bile duct wall. [bib_ref] Assessment of hepatic artery invasion by bile duct cancer using intraductal ultrasonography, Tamada [/bib_ref] [bib_ref] Transpapillary intraductal US prior to biliary drainage in the assessment of longitudinal..., Tamada [/bib_ref] Positron emission tomography (PET)
Although there are no defi nite opinions about the role of PET in the diagnosis of bile duct cancer, there is a report describing its usefulness in making a diagnosis of distant metastasis 44 (level III). The diagnostic capability of PET/CT is superior to that of CT alone with respect to distant metastatic lesions, but it is similar with respect to primary lesions 30 (level IV). Although PET/CT shows excellent diagnostic ability in detecting the mass-forming type of tumor, its usefulness in detecting the invasive type is poor 45 (level IV). There are almost no reports proving the usefulness of PET in differentiating PSC and bile duct cancer 46 (level III).

## Cq 4 what is the second step in the diagnosis of gallbladder cancer?

## In gallbladder cancer, the differential diagnosis and the diagnosis of the degree of extension of the cancer are of importance. endoscopic ultrasonography (eus) and ct (including mdct) are recommended for both of these diagnoses (recommendation b).

## Endoscopic ultrasonography (eus)
Endoscopic ultrasonography (EUS) is an excellent procedure for depicting a protruded lesion in the gallbladder and the procedure can be conducted in an outpatient clinic. Its sensitivity in differentiating benign gallbladder disease from gallbladder cancer is reported to be excellent, ranging from 92% to 97% 47,48 (level IV). It is reported that it is also useful for the diagnosis of the depth of mural invasion, the rate of accurate diagnosis being 100% for invasion limited to the mucosa (m) and muscularis propria (mp), and 75% for invasion limited to the subserosa (ss) and invasion of the serosal surface (se) or more; also, a diagnosis of the depth of mural invasion was possible in 13 of 14 patients receiving EUS 49 (level IV). Furthermore, there is also a report that in a case of pedunculated lesions (Ip), according to the classifi cation based on gross appearance, EUS showed that all of these lesions were cancers with invasion limited to the mucosa 50 (level IV).

## Ct
There is a report showing that the sensitivity, specifi city, and accuracy of CT for a protruded lesion in the gallbladder is 88%, 87%, and 87%, respectively, 51 these values being lower than those of EUS. According to another report, the accuracy of diagnosis of invasion depth by helical CT is 86% for T1, 71% for T2, 81% for T3, and 95% for T4 tumors 52 (level IV). The accuracy of diagnosis of hepatic infi ltration was 81% for cases in which the tumor had infi ltrated the hepatic parenchyma less than 2 cm in length and 100% for cases with infi ltration of more than 2 cm 53 (level V). The rate of detection 53 of lymph node metastasis with CT is reported to be 38%-65% 54,55 (level IV). As criteria for decisions on metastasis, Ohtani et al. [bib_ref] Carcinoma of the gallbladder: CT evaluation of lymphatic spread, Ohtani [/bib_ref] indicated that the metastasis should be, in anterior and posterior diameter, larger than 10 mm and that the images achieved should be ring-like in shape or heterogeneous (level IV).
CT is inferior to EUS in its rate of accurate diagnosis of individual factors in the extension of the lesion. However, CT makes possible the assessment of images of all the surroundings of the lesion, and according to a report on resectability, the accuracy of diagnosis was 93.3% 56 (level IV).

## Erc
ERC is useful for assessing the invasion of tumor to the cystic duct and common hepatic duct 57,58 (level IV). As for the diagnosis of gallbladder cancer with ERC, the positive rate with the use of cytologic diagnosis is reported to be 45%-67% [bib_ref] Gallbladder and biliary tract carcinoma: a comprehesive update, Rajagopalan [/bib_ref] [bib_ref] Cytologic examination as an adjunct to laparoscopy and guided biopsy in the..., Verma [/bib_ref] [bib_ref] The usefulness of saline irrigated bile for the intraoperative cytologic diagnosis of..., Ishikawa [/bib_ref] [bib_ref] Cytologic diagnosis in the management of gallbladder carcinoma, Akosa [/bib_ref].

## Mri, mrcp
It is reported that the sensitivity of the diagnosis of hepatic infi ltration with MRI is 67%-100% and the specifi city is 89%; the sensitivity of invasion to the bile duct is 62%-100% and the specifi city is 56%-92%; and the sensitivity for lymph node metastasis is 56%-92% and the specifi city is 89% 63,64 (level IV).

## Pet
The assessment of PET or PET/CT in gallbladder cancer is similar to that noted above for the second step in bile duct cancer. [bib_ref] Impact of integrated positron emission tomography and computed tomography on staging and..., Petrowsky [/bib_ref] [bib_ref] Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma, Anderson [/bib_ref] CQ 5 What is the second step in the diagnosis of ampullary carcinoma?

## Tissue biopsy is conducted for tumor of the papilla (recommendation b). ct and mri are performed for the diagnosis of distant metastasis and lymph node metastasis (recommendation b). intraductal ultrasonography (idus) and eus are useful for diagnosis of pancreatic and duodenal invasions (recommendation c1).
The rate of resection of ampullary carcinoma is high and the number of patients in whom this disease is unresectable due to local extension is small (level IV). According to the gross appearance (endoscopic characteristics) of the tumor [fig_ref] Figure 9, Figure 10a-g.: Macroscopic types of ampullary tumors [/fig_ref] , an ulcerative type tumor is often an advanced cancer, 65 so this type of tumor is not indicated for limited surgery. Therefore, a diagnosis should be made only concerning the suitability of resection. The diagnosis of distant metastasis, including liver metastasis, is now being made by US, CT, and MRI. Recent MDCT techniques 66 (level IV) enable the production of three-dimensional images, which make clear the anatomical relationship (the presence or absence of invasion ) of a tumor with the bile duct and vessels.
Although ampullary carcinoma presents with symptoms such as jaundice, fever, and abdominal pain, tumor of the papilla is often suspected based on endoscopic and ultrasonographic fi ndings on the occasion of medical examination, which are followed by detailed examination. The second step in the diagnosis of a mass-forming type of tumor is to make a diagnosis of the presence or absence of cancer. Adenoma is indicated for resection because a cancer in adenoma, [bib_ref] Endoscopic biopsy has limited accuracy in diagnosis of ampullary tumors, Yamaguchi [/bib_ref] in which cancer exists in a small region, is not infrequent (level IV). Biopsy is helpful in performing limited surgery for resection or endoscopic resection of the papilla. Many of the tumors for which endoscopic resection of the papilla 68 has been performed are adenomas. Although there are reports of cases of cancer in adenoma, they are concerned with discussions of only a small number of cases. A good outcome cannot be achieved for an advanced cancer with the use of limited surgery (level IV).
There are many reports comparing preoperative and postoperative stages with respect to diagnosis of the degree of local extension. It is consistently accepted that depicting tumors by means of US and CT is diffi cult, but that tumors can be depicted with the use of EUS or IDUS 69,70 (level II). EUS is an excellent procedure to determine pancreatic invasion, but it is unable to determine histological pancreas invasion pPanc 1a [fig_ref] Table 3: Histopathological fi ndings of primary tumor invasion to the pancreas and the... [/fig_ref]. There are also a number of reports demonstrating that determination of histological duodenal invasion (pDu 1; [fig_ref] Table 3: Histopathological fi ndings of primary tumor invasion to the pancreas and the... [/fig_ref] by EUS is also diffi cult. In the present guidelines, histological determination was made according to the Japanese Society of Biliary Surgery Classifi cation of biliary tract carcinoma. Second English edition (Tokyo: Kanehara; 2004). Although IDUS is superior for making a diagnosis of extension to the pancreas duct or bile duct, pancreatic invasion, and duodenal invasion, the rate of accurate diagnosis being 80%-90%, the number of institutions employing EUS and IDUS is small. The use of IDUS has not been taken up widely yet. and/or pancreatic parenchyma pPanc1a: Invasion beyond Oddi's sphincter or the duodenal wall, but not to pancreatic parenchyma pPanc1b: Invasion of the pancreatic parenchyma, which invasion is not more than 5 mm in depth pPanc2: Invasion of the pancreatic parenchyma, which invasion is 5 mm or more but not more than 20 mm in depth pPanc3: Invasion of the pancreatic parenchyma, which invasion is 20 mm or more in depth 2. Duodenum pDu0: Invasion limited to Oddi's sphincter pDu0: Invasion limited to the duodenal mucosa pDu0: Invasion limited to Oddi's sphincter pDu1: Invasion beyond Oddi's sphincter, but not to the duodenal muscularis propria pDu1: Invasion limited to the major duodenal papilla pDu1: Invasion beyond the major duodenal papilla pDu2: Invasion of the duodenal muscularis propria pDu3: Invasion of the duodenal serosa
[fig] Figure 1, Figure 2, Figure 3: Extracorporeal ultrasonography (US) images of a case of cancer in the hepatic hilar bile duct, showing dilated right intrahepatic bile duct (a), but imaging of hepatic hilar tumor is poor (indirect fi ndings showing the presence of tumor) (b) Extracorporeal US image of a case of middle bile duct cancer, showing blockage of the bile duct due to the tumor in the superior margin of the pancreas head (direct fi nding of tumor) Extracorporeal US image of an advanced gallbladder cancer (wall-thickness type), showing advanced gallbladder cancer with circumferential wall thickness CQ 3 What is the second step in the diagnosis of bile duct cancer? [/fig]
[fig] Figure 5, Figure 4: MDCT intersection image of the same patient as inFig. 4(arterial phase) the right hepatic artery is adjacent to the tumorFig. 6. MDCT intersection image of the same patient as in Fig. 4 (venous phase) reconstructed along the left and right confl uence of the hepatic duct. The portal vein runs parallel with the tumor Multidetector computed tomography (MDCT) image of cancer of the hilar bile duct reconstructed along the left and right confl uence of the hepatic duct. It suggests invasion as well as thickening of the hepatic duct as far as the anterior and posterior segment branching CT Enhanced CT (multidetector computed tomography [MDCT] [/fig]
[fig] Figure 7, Figure 8: 25 (levels IV, II). A diagnosis of vascular invasion with the use of enhanced CT (MDCT where available) is of importance for decision-making in diagnostic policies (Figs. 5, 6) 22,25,26 (levels II-IV). In Western countries, there are many studies of the diagnosis and treatment of bile duct cancer associated Percutaneous transhepatic cholangiography of cancer of the hilar bile duct (BD): the stricture has extended as far as the upper bile duct and the confl uence of the left and right hepatic duct. The middle and lower bile ducts and gallbladder are almost normal. Ant., anterior; post., posterior; B2, B3, and B4 indicate the segmental ducts of S2, S3, Percutaneous transhepatic biliary drainage (PTBD) cholangiography for nodular-infi ltrating type cholangiocarcinoma. [/fig]
[fig] Figure 9, Figure 10a-g.: Macroscopic types of ampullary tumors (with permission from the Japanese Society of Biliary Surgery. Classifi cation of biliary tract carcinoma. Second English edition. [/fig]
[table] Table 1: Strength of recommendations 1 [/table]
[table] Table 3: Histopathological fi ndings of primary tumor invasion to the pancreas and the duodenum a 1. Pancreas pPanc0: Invasion limited to Oddi's sphincter or the duodenal wall pPanc1: Invasion of Oddi's sphincter or the duodenal wall, [/table]