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Hilar Cholangiocarcinoma
PIERRE F. SALDINGER, MD WILLIAM R. JARNAGIN, MD LESLIE H. BLUMGART, MD, FACS, FRCS (ENG, EDIN, GLAS)

Malignant tumors of the bile ducts remain a major management challenge. They occur most commonly in the proximal bile duct, at the hepatic duct confluence (hilar cholangiocarcinoma), or in the distal common bile duct near the papilla (distal cholangiocarcinoma) (Fig. 91). Resection offers the best chance of long-term survival, but many patients present with advanced disease that is not amenable to extirpation. The assessment and treatment of distal bile duct cancers is similar to that of cancers of the head of the pancreas. This chapter focuses on management issues specific to hilar cholangiocarcinoma. EPIDEMIOLOGY Cholangiocarcinoma is an uncommon disease. The annual incidence in the United States is 1 to 2 per 100,000, and it accounts for approximately 2 percent of all cancers.1 Men and women are affected in nearly equal proportions. Although occasionally seen in young patients, cholangiocarcinoma is primarily a disease of the elderly. The majority of patients are over 65 years of age, and the peak incidence occurs in the eighth decade of life.1 Untreated, hilar cholangiocarcinoma generally results in death within 12 months, from liver failure or from complications arising from biliary tract obstruction. ETIOLOGY Cholangiocarcinoma usually occurs sporadically, and most patients have no obvious risk factors. While the etiology of cholangiocarcinoma is unknown,

there are several conditions that are associated with an increased risk. Primary Sclerosing Cholangitis Perhaps the most common associated condition in Western countries is primary sclerosing cholangitis (PSC), an autoimmune disease characterized by

Figure 91. Diagram illustrating the anatomy of the extrahepatic biliary tree. (CD = cystic duct; GB = gallbladder; LHD = left hepatic duct; RHD = right hepatic duct.)

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inflammation of the periductal tissues, ultimately resulting in multifocal strictures of the intrahepatic and extrahepatic bile ducts.2,3 The natural history of PSC is quite variable, and the true incidence of cholangiocarcinoma is unknown. The reported incidence in PSC ranges from 8 to 40 percent.2,3 Unlike most patients with sporadic cholangiocarcinoma of the extrahepatic biliary tree, patients with PSC are at risk for multifocal disease that is often not amenable to resection. Congenital Biliary Cystic Disease The increased risk of cholangiocarcinoma in patients with congenital biliary cystic disease (choledochal cysts, Carolis disease) is well described.4 Malignant degeneration is uncommon in choledochal cysts that have been completely excised early. However, the incidence of cancer increases substantially (approximately 15 to 20%) in patients who are not treated until after the age of 20 years or in those previously treated by cyst drainage.5,6 The reason for the high incidence of cancer in patients with cystic diseases appears to be related to an abnormal choledochopancreatic duct junction that predisposes to reflux of pancreatic secretions into the biliary tree, bacterial contamination, and chronic inflammation.57 An increased incidence of cholangiocarcinoma has also been reported in patients subjected to transduodenal sphincteroplasty,8 and a similar mechanism may be responsible. Hepatolithiasis and Biliary Parasites Hepatolithiasis, also known as recurrent pyogenic cholangiohepatitis or Oriental cholangiohepatitis, is prevalent in Japan and parts of Southeast Asia. Obstruction of intrahepatic ducts leads to chronic recurrent episodes of cholangitis and stricture forma-

tion.911 Approximately 10 percent of patients will develop cholangiocarcinoma.10 Biliary parasites (Clonorchis sinensis and Opisthorchis viverrini) are also prevalent in parts of Asia and are similarly associated with an increased risk of cholangiocarcinoma.3 LOCATION Although cholangiocarcinoma can arise anywhere within the biliary tree, hilar cholangiocarcinoma or tumors involving the biliary confluence are the most common (see Fig. 91). In most large series, the proportion of patients with tumors involving the hilus ranges from 40 to 60 percent (Table 91).1214 Tumors of the distal bile duct are somewhat less common, accounting for 20 to 30 percent of all cholangiocarcinomas and 5 to 10 percent of all periampullary tumors.13,15,16 Approximately 10 percent of cholangiocarcinomas arise within the intrahepatic biliary tree.1719 These tumors usually present as an intrahepatic mass, and although uncommon, jaundice may result from intrabiliary tumor extension (Fig. 92). HISTOPATHOLOGY The overwhelming majority of cholangiocarcinomas are adenocarcinomas, often well differentiated and mucin producing.1,20 There are three well-described macroscopic subtypes of cholangiocarcinoma: sclerosing, nodular, and papillary.20 Sclerosing tumors account for the majority of cases. Sclerosing tumors are very firm and cause an annular thickening of the bile duct, often with diffuse infiltration and fibrosis of the periductal tissues (Fig. 93). Nodular tumors are characterized by a firm irregular nodule of tumor that projects into the lumen of the duct. Features of both types are often seen, hence the frequently used

Institution UCLA (1981) Mayo Clinic (1993)12 Johns Hopkins (1996)13 MSKCC (1998)14

Table 91. INCIDENCE OF HILAR CHOLANGIOCARCINOMA IN SELECTED SERIES Years* Patients with Cholangiocarcinoma Patients with Hilar Cholangiocarcinoma 24 9 23 6 96 171 294 225 47 79 197 90 (49%) (46%) (67%) (40%)

MSKCC = Memorial Sloan-Kettering Cancer Center; UCLA = University of California, Los Angeles. *Time interval over which patients were accumulated. Reported in Tompkins RK, Thomas D, Wile A, Longmire WP Jr. Prognostic factors in bile duct carcinoma: analysis of 96 cases. Ann Surg 1981;194:44757.

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descriptor nodular-sclerosing. The papillary variant accounts for approximately 10 percent of all cholangiocarcinomas and is more common in the distal bile duct.21 A polypoid mass that expands rather than contracts the duct is a characteristic feature (Fig. 94). Although papillary tumors may grow to significant size and appear surgically unapproachable (based on radiographic studies), they often arise from a well-defined stalk and histologically may be confined to the superficial layers of the duct wall (Fig. 95). Recognition of papillary cholangiocarcinomas is important since they are more often resectable and have a more favorable prognosis than the other types.3 Longitudinal spread along the duct wall and periductal tissues is an important pathologic feature

of cholangiocarcinomas.20 There may be substantial extension of tumor beneath an intact epithelial liningas much as 2 cm proximally and 1 cm distally.22 The full tumor extent may thus be underestimated by radiographic studies and may not be fully appreciated by palpation at the time of resection. This feature underscores the importance of checking all resection margins with frozen-section histology at operation. STAGING According to the American Joint Commission on Cancer (AJCC), the staging of extrahepatic cholangiocarcinomas is based on the extent of the primary tumor (T stage), the extent of regional lymph node

B
Figure 92. Images from a patient with an intrahepatic cholangiocarcinoma and jaundice. A, Cross-sectional computed tomography image showing dilated left biliary tree (arrow) but no clearly defined mass. B, Cross-sectional magnetic resonance cholangiopancreatography (MRCP) image showing a heterogeneous mass in segment IV (arrow). Dilated bile ducts appear as white areas. C, Coronal MRCP reconstruction showing the tumor growing down the left hepatic duct and extending across the right hepatic duct and into the common hepatic duct (arrow). The dilated bile ducts again appear as white areas. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

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involvement (N stage), and the presence of distant metastases (M stage) (Table 92). An alternative staging system proposed by Bismuth and Corlette classifies cholangiocarcinomas on the basis of their location with respect to the hilus and on the extent of

ductal involvement.23 The AJCC staging is based largely on pathologic criteria and has little clinical applicability. The majority of patients in our practice have T3 (stage 4A) tumors based on invasion into the liver, but this alone says very little about their resectability. Moreover, this finding does not correlate with survival, provided that complete resection

B
Figure 93. A, Endoscopic cholangiogram showing the typical irregular biliary stricture characteristic of sclerosing adenocarcinomas (arrow). These tumors cause a circumferential thickening of the duct wall and periductal fibrosis, which ultimately obliterates the lumen. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.) B, Coronal magnetic resonance cholangiopancreatography reconstruction showing an infiltrating tumor involving the hepatic duct confluence (arrow). The right and left intrahepatic ducts, which appear white, are dilated.

B
Figure 94. A, Transhepatic cholangiogram showing a markedly dilated bile duct from the confluence of the right and left hepatic ducts to the ampulla of Vater. Filling defects are apparent throughout the length of the duct (black arrows). A percutaneous biliary stent is in place (white arrow). B, Cross-sectional computed tomography image of the same patient. The stent (white arrowhead) is seen within the duct, adjacent to a large tumor mass (white arrow). The underlying portal vein (black arrow) is free, and there is no evidence of lobar atrophy.

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Figure 95. A, Excised bile duct from the patient discussed in Fig. 94. The duct has been opened longitudinally to reveal two separate polypoid masses (arrows). B, View looking down the incised bile duct, with one of the tumors seen arising from the mucosal surface. Most of the tumor mass extends into the bile duct lumen. C, Photomicrograph showing the malignant cells largely confined to the mucosa of the duct wall (arrow) (hematoxylin-eosin stain, low power view).

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Table 92. CURRENT AMERICAN JOINT COMMISSION ON CANCER STAGING SYSTEM FOR CANCER OF EXTRAHEPATIC BILE DUCTS Stage 0 1 2 3 4A 4B Tumor Tis T1 T2 T1 or 2 T3 Any T Node N0 N0 N0 N1 or 2 Any N Any N Metastasis M0 M0 M0 M0 M0 M1

Tis = carcinoma in situ; T1 = tumor invades subepithelial connective tissue or fibromuscular layer; T2 = tumor invades perifibromuscular connective tissue; T3 = tumor invades adjacent organs (liver, pancreas, duodenum, gallbladder, colon, stomach). N0 = no regional lymph node metastases; N1 = metastasis to lymph nodes within the hepatoduodenal ligament (cystic duct, pericholedochal, and/or hilar lymph nodes); N2 = metastasis to peripancreatic, periduodenal, periportal, celiac, superior mesenteric, and/or posterior pancreaticoduodenal lymph nodes. M0 = no distant metastasis; M1 = distant metastasis.

hepatic duct) or segmental ductal obstruction. Patients with papillary tumors of the hilus may have a history of fluctuating jaundice, which may be the result of loose tumor fragments intermittently obstructing the bile duct. In patients with cholangiocarcinoma and no previous biliary intervention, cholangitis is uncommon at initial presentation despite a 30 percent incidence of bacterial contamination (bacterbilia).11,25 The physical findings are often nonspecific. Jaundice will usually be obvious. The gallbladder is usually decompressed and nonpalpable with hilar obstruction; thus, a palpable gallbladder suggests a more distal obstruction or an alternative diagnosis. Patients with long-standing biliary obstruction and/or portal vein involvement may have findings consistent with portal hypertension. Alternative Diagnoses The vast majority of patients with proximal biliary obstruction and jaundice have cholangiocarcinoma. However, alternative diagnoses are possible and can be expected in 10 to 15 percent of patients.26 Gallbladder carcinoma, Mirizzi syndrome, and idiopathic benign focal stenosis (malignant masquerade) are the most common conditions that may be mistaken for cholangiocarcinoma. Over a 28-month period at Memorial Sloan-Kettering Cancer Center, we evaluated 109 patients with obstruction involving the biliary confluence consistent with hilar cholangiocarcinoma. In 90 patients, this diagnosis was confirmed while 19 patients were found to have other conditions (9 with gallbladder cancer, 6 with malignant masquerade, 3 with neuroendocrine tumor of the bile duct, and 1 with Mirizzi syndrome). Distinguishing gallbladder carcinoma from hilar cholangiocarcinoma can be difficult. A thickened and irregular gallbladder with infiltration into segment IV, selective involvement of the right portal pedicle, and obstruction of the common hepatic duct with occlusion of the cystic duct on endoscopic cholangiography are all suggestive of gallbladder carcinoma. Mirizzi syndrome is a benign condition resulting from a large gallstone impacted in the neck of the gallbladder (Fig. 96).21,27 Benign focal strictures (malignant masquerade) can occur at the

can be achieved.14 In the AJCC system, patients with involvement of N1- and N2-lymph nodes are staged similarly. This is inappropriate since patients with metastatic disease to N2-level lymph nodes (celiac, periduodenal, or retroperitoneal) are not candidates for resection and should be considered to have M1 disease. The Bismuth-Corlette system is more clinically relevant but is too simplified and, like the AJCC system, correlates poorly with resectability and survival.14 None of the current staging systems takes into account local factors such as vascular invasion or hepatic lobar atrophy, which are important determinants of resectability, which (in turn) is a major determinant of outcome. A more reliable and systematic method of selecting candidates for resection is clearly needed (see below). DIAGNOSIS Symptoms and Physical Examination The early symptoms of hilar cholangiocarcinoma are nonspecific. Abdominal pain or discomfort, anorexia, weight loss, and pruritus are the most common symptoms and are seen only in one-third of patients.3,11,13,24 Most of these tumors come to attention because of jaundice or abnormal liver function tests. Jaundice is not present initially in cases of incomplete biliary obstruction (ie, right or left

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Figure 96. Endoscopic retrograde cholangiography (ERCP) and cross-sectional computed tomography (CT) scan images of a patient with Mirizzi syndrome. Left, The ERCP shows a characteristic large gallstone (arrow) impacted in the neck of the gallbladder, causing obstruction of the hepatic duct just below the biliary confluence. Right, The CT scan confirms the presence of a large gallstone (arrow). In most cases, the diagnosis of Mirizzi syndrome is not as clear-cut since the stone is usually not visualized. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

hepatic duct confluence but are uncommon (Fig. 97).26,28,29 Relying on the results of percutaneous needle biopsy or biliary brush cytology is dangerous since they are often misleading and because one may miss the opportunity to resect an early cancer.30,31 It is often impossible to establish the diagnosis unequivocally before operation, and this is indeed unnecessary in nearly all cases since lesions at the biliary confluence (including benign strictures) are best assessed and treated at operation. We firmly

believe that in the absence of clear contraindications (see below), exploration is indicated in all patients with suspicious hilar lesions. TREATMENT Preoperative Evaluation Evaluation of patients with hilar cholangiocarcinoma is principally an assessment of resectability,

Figure 97. A, Endoscopic cholangiogram in a patient with a benign focal stricture of the common hepatic duct (white arrowhead). The smooth, tapered appearance of the stricture suggests a benign process but is by no means conclusive. The cystic duct is shown partially filled (black arrowhead). B, Photomicrograph of the common hepatic duct in the same patient. The duct lumen is severely narrowed by the surrounding scar tissue (arrowhead) (hematoxylin-eosin stain, low power view).

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since resection is the only effective therapy. First and foremost, the patients general health and fitness for major surgery (possibly including partial hepatectomy) must be examined. The presence of significant comorbid conditions, chronic liver disease, and/or portal hypertension generally precludes resection. Patients with potentially resectable tumors may develop biliary tract sepsis, often after intubation of the biliary tree. These patients require resuscitation and treatment of the infection before surgery is undertaken. The preoperative evaluation must address four critical determinants of resectability: (1) tumor extent within the biliary tree, (2) vascular invasion, (3) hepatic lobar atrophy, and (4) metastatic disease.14 Tumors that extend into the second-order biliary radicles bilaterally are not amenable to resection with clear margins, but this is often difficult to determine before operation. Likewise, the presence of metastatic disease (to distant sites or N2-level lymph nodes) is a contraindication to resection. Lobar atrophy is an often overlooked but important factor in assessing the resectability of these tumors32 (see below). Long-standing biliary obstruction may cause moderate atrophy whereas concomitant portal venous compromise induces rapid and severe atrophy of the involved segments. On cross-sectional

imaging, atrophy is characterized by a small and often hypoperfused lobe, with crowding of the dilated intrahepatic ducts14 (Fig. 98).
Radiographic Studies

High-quality radiographic studies are critical in selecting patients for resection. In the past, computed tomography (CT), percutaneous transhepatic cholangiography (PTC), and angiography were considered the standard investigations. Currently, we rely almost exclusively on magnetic resonance cholangiopancreatography (MRCP), and duplex ultrasonography (US). These noninvasive studies provide the same information regarding the extent of disease as the aforementioned studies but with less risk. Magnetic resonance cholangiopancreatography has emerged as a powerful investigative tool, and we prefer it to the more invasive endoscopic retrograde cholangiography (ERCP) or PTC. Several studies have demonstrated the utility of MRCP in evaluating patients with biliary obstruction.3335 It may identify the tumor and level of obstruction and may also reveal obstructed and isolated ducts not seen by PTC. It also provides information regarding the patency of hilar vascular structures, the presence of nodal or distant metastases, and lobar

Figure 98. Left, Cross-sectional computed tomography image of a patient with cholangiocarcinoma involving the left hepatic duct. The left lobe, clearly demarcated from the right, is shrunken and hypoperfused (arrows). The bile ducts, which appear black, are dilated and crowded. Right, T1-weighted gadolinium-enhanced cross-sectional magnetic resonance image of a different patient with hilar cholangiocarcinoma involving the left hepatic duct. The left lobe is small, and the bile ducts (which appear black) are dilated and crowded. There is evidence of hypoperfusion of the left lobe, which appears darker. There is also evidence of hypoperfusion of the right posterior sector, which also appears darker and is clearly demarcated from the well-perfused right anterior sector (arrowheads) but does not as yet show evidence of atrophy. These radiographic features suggest that the tumor involves the left hepatic duct and the left portal vein and is beginning to involve the right portal pedicle. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

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Figure 99. A, T1-weighted gadolinium-enhanced magnetic resonance image of a patient with hilar cholangiocarcinoma. In this image, the bile ducts appear black. A hilar tumor (T) is seen, apparently adherent to or encasing the right portal vein branch (PV) (white arrowhead). The tumor has occluded the right anterior sectoral branch of the portal vein, and the anterior sector appears atrophic (indicated by the black lines), with crowded dilated ducts. Intrahepatic metastases are also noted (arrow). B, Cross-sectional magnetic resonance cholangiopancreatography image through the same area of the liver. Similar findings are shown in this image, in which the bile ducts appear white. The vascular findings seen on magnetic resonance imaging were confirmed on duplex ultrasonography. Biopsies of the main tumor and the intrahepatic metastases confirmed adenocarcinoma. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

atrophy (Figs. 99 and 910). Furthermore, unlike direct cholangiography, MRCP does not require biliary intubation. Potential infectious complications, which may increase operative morbidity, are thus avoided. Duplex US is a valuable study in patients with hilar obstruction; in experienced hands, US rivals all other modalities for assessing extent of disease and vascular involvement3638 (Fig. 911). In our practice, MRCP and duplex US have become the preferred investigations.
Patient Selection

Despite improvements in radiologic techniques, only 20 to 50 percent of patients submitted to exploration have tumors that can be resected.13,14,39 We have therefore proposed a preoperative staging system aimed at improving patient selection.14 Based on the radiographic interpretation of local tumor

Distinguishing resectable from irresectable tumors demands careful consideration of all available data. Bilateral tumor extension to second-order intrahepatic biliary radicles and encasement or occlusion of the main portal vein clearly preclude resection. On the other hand, involvement of the right or left branch of the portal vein does not necessarily preclude resection. In this situation, complete resection will require ipsilateral partial hepatectomy, but this would not be possible if the contralateral lobe is atrophic or if the tumor extends to the contralateral second-order biliary radicles. The detailed criteria of irresectability are outlined in Table 93.

Figure 910. Cross-sectional magnetic resonance cholangiopancreatography image from a patient with hilar cholangiocarcinoma extending into the left hepatic duct and with left lobe atrophy. The bile ducts appear white. The left lobe is small, with dilated and crowded ducts (short arrow). The principal caudate lobe duct, seen joining the left hepatic duct, is also dilated (long arrow). (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

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extent (T stage), this system analyzes resectability and considers the following factors: extent of biliary ductal involvement, portal venous involvement, and lobar atrophy (Table 94). Analyzing our patient data by using the proposed system, we found that

resectability and the need for partial hepatectomy both increased progressively with increasing T stage while 5-year survival was inversely related (Table 95). By contrast, there was no correlation between these variables and AJCC stage. The proposed stag-

Figure 911. A, Duplex ultrasonography in a patient with a hilar cholangiocarcinoma. The tumor is clearly seen at the biliary confluence just above the portal vein (arrow). The mass is clearly in contact with the portal vein, but there is no clear invasion or venous narrowing. A transtumoral stent is also visible. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.) B, Traverse color Doppler sonogram of the biliary confluence shows a papillary cholangiocarcinoma (m) extending into both the right anterior (a) and posterior (p) sectoral ducts and the origin of the left duct (l). The adjacent portal vein (v) is not involved and has normal flow. (Reproduced with permission from Hann LE, Fong Y, Shriver CD, et al. Malignant hepatic hilar tumors: can ultrasonography be used as an alternative to angiography with CT arterial portagraphy for determination of resectability? J Ultrasound Med 1996;15: 3745.)

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Table 93. CRITERIA OF IRRESECTABILITY IN PATIENTS WITH HILAR CHOLANGIOCARCINOMA Patient Factors Medically unfit for operation Cirrhosis/portal hypertension Local Factors Hepatic duct involvement up to secondary radicles bilaterally Encasement or occlusion of the main portal vein proximal to its bifurcation Atrophy of one lobe, with encasement of contralateral portal vein branch Atrophy of one lobe, with contralateral involvement of secondary biliary radicles Distant Disease Histologically proven metastases to N2 lymph nodes Liver, lung, or peritoneal metastases
Reprinted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998;228:386 by permission of the publisher Lippincott Williams and Wilkins.

able even in the setting of metastatic disease to N1level nodes since these are routinely cleared with the tumor. By contrast, metastasis to N2-level nodes would preclude resection, and biopsies should be performed on suspicious nodes in these areas to confirm the diagnosis.
Preoperative Biliary Decompression and Infection

In patients considered candidates for resection and without evidence of cholangitis, preoperative biliary decompression is unnecessary and may be harmful. There is substantial evidence that preoperative biliary intubation does not improve outcome, and the observed increase in perioperative complications outweighs any potential benefit.25,4044 Operation The treatment goals in patients with hilar cholangiocarcinoma are resection with negative histologic margins and the restoration of enterobiliary continu-

ing system does not consider the status of the perihepatic lymph nodes. Enlarged reactive lymph nodes are common in these patients, particularly those who have been subjected to biliary instrumentation before referral. Moreover, resection is not unreason-

Table 94. PROPOSED PREOPERATIVE TUMOR STAGING OF HILAR CHOLANGIOCARCINOMA Tumor Stage T1 T2 T3 T4 Biliary Involvement Hilus and/or right or left hepatic duct Hilus and/or right or left hepatic duct Hilus and/or right or left hepatic duct Secondary biliary radicles bilaterally Ipsilateral Lobar Atrophy No Yes Yes/No Yes/No Ipsilateral Portal Vein Involvement No No Yes Yes/No Main Portal Vein Involvement No No No Yes

T1 tumors are confined to the hilus with or without involvement of the right or left hepatic duct and are not associated with atrophy or portal vein involvement. T2 tumors are associated with ipsilateral lobar atrophy but not portal vein branch involvement. T3 tumors are characterized by ipsilateral portal venous branch involvement and may or may not be associated with lobar atrophy. T4 tumors are defined as irresectable, based on tumor extension to secondary biliary radicles bilaterally or encasement/occlusion of the main portal vein. Adapted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998;228:387 by permission of the publisher Lippincott Williams and Wilkins.

Table 95. RESECTABILITY, INCIDENCE OF PARTIAL HEPATECTOMY, AND 5-YEAR SURVIVAL, BY PROPOSED TUMOR STAGE T Stage 1 2 3 4 Total No. of Patients 40 7 32 8 87 No. Resected 19 3 8 0 30 (48%) (43%) (25%) (35%) No. Requiring Partial Hepatectomy* 11 3 8 0 22 (58%) (100%) (100%) (73%) 5-Year Survival (%) 20 29 16 0 17 (57)

T = tumor. *The percentage requiring partial hepatectomy is the percentage of those resected within a particular stage grouping. 5-year survival is recorded as a percentage of all patients seen, irrespective of therapy. The 5-year survival of all resected patients. Adapted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998;228:390 by permission of the publisher Lippincott Williams and Wilkins.

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ity. Hepatic transplantation is associated with a prohibitively high incidence of recurrence, which has led many centers to abandon its routine use in this disease.45 All patients should be evaluated for possible resection before any intervention. Ill-advised attempts to place biliary stents, especially when not indicated, may result in complications that delay operation, and stent-associated infection and inflammation may hinder further radiographic and operative assessment.40,45,46If resection is clearly not feasible, then transtumoral drainage or intrahepatic enterobiliary bypass offers satisfactory palliation (see below). At operation, the objective should be the complete resection of the tumor, with negative histologic margins. Partial hepatectomy is usually required to achieve this goal. Several recent series show a strong correlation between negative histologic margins and the percentage of patients subjected to partial hepatectomy (Table 96).14,39,4749 Additionally, tumors that extend into the left hepatic duct usually involve the principal caudate lobe ducts and require en bloc caudate lobectomy (see Fig. 910).39,4750
Operative Technique

III and IV should be divided to expose the left hepatic duct at the base of the umbilical fissure. Lowering the hilar plate will expose the biliary confluence. Palpation of the duct in this area will give the surgeon a sense of the tumor extent. The distal bile duct is transected and elevated upwards, allowing inspection of the anterior wall of the portal vein for evidence of tumor invasion; a portion of the distal duct should be sent for frozen-section histology. Once it has been determined that resection is feasible and will leave behind a tumor-free liver remnant with intact blood supply and biliary drainage, the surgeon should then control and divide the inflow blood supply to the lobe that is to be removed. The contralateral hepatic duct above the tumor should be divided likewise, and a portion should be sent for frozen-section histology. The hepatic vein draining that portion of the liver to be excised should be exposed and divided extrahepatically. The parenchymal transection should now be pursued. Finally, enterobiliary reconstruction is completed, using a 70-cm Roux-en-Y loop of jejunum.
Results

The operation begins with a thorough exploration of the abdomen. Contrary to popular belief, metastatic disease is common in patients with hilar cholangiocarcinoma.14,47,51 Performing staging laparoscopy before proceeding to open exploration may help identify some patients with unresectable disease. The details of resection are illustrated in Figures 912 to 916. The duodenum and liver are mobilized, and the gallbladder is taken down. The bridge of liver tissue that often connects segments

It must be stressed that with the approach outlined above, long-term survival can be achieved with an acceptable operative mortality.1214,39,48,49,5254 Patients resected with negative histologic margins survive significantly longer than those with microscopically positive margins (Table 97).14,39,52 Over the past 20 years, there has been a steady increase in the use of hepatic resection in patients with hilar cholangiocarcinoma, resulting in an increase in the proportion of R0 resections (ie, resections with neg-

Table 96. CORRELATION BETWEEN PARTIAL HEPATECTOMY AND HISTOLOGIC MARGINS IN PATIENTS WITH HILAR CHOLANGIOCARCINOMA: SUMMARY OF RECENT SERIES Author Cameron (1990)47 Hadjis (1990)39 Nimura (1990)49 Klempnauer (1997)48 Burke (1998)14 Period of Study (yr) 15 8 10 25 6 Resected (N) 39 27 55 147 30 Partial Hepatectomy (%) 20 60 98 79 73 Negative Margins (%) 15 56 83 79 83

Adapted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998;228:390 by permission of the publisher Lippincott Williams and Wilkins.

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Figure 912. Initial operative approach. The round ligament has been divided and is held upwards, exposing the undersurface of the liver. The hilar plate at the base of segment IV has been lowered, exposing the tumor at the biliary confluence. The bridge of liver tissue attaching segments III and IV has been divided; this provides greater exposure of the left hepatic duct. The gallbladder has been taken down, and the distal bile duct has been divided. (Reproduced with permission from Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

Figure 914. The left hepatic duct is divided well beyond the tumor, and a portion is sent for frozen-section analysis. Further dissection exposes the portal vein confluence, and the right branch is divided. (Reproduced with permission from Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

Figure 913. Upward traction on the divided bile duct and periductal lymphatic tissues exposes the underlying portal vein. Developing the plane between the tumor and the portal vein is the only way to assess vascular invasion. Provided that the vein is not involved, a plane between the tumor and the portal vein can easily be developed. Once it has been determined that resection is feasible, the right hepatic artery is divided and retracted upwards with the tumor. The left hepatic artery is retracted laterally, away from the tumor. (Reproduced with permission from Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

Figure 915. The hepatic parenchyma is divided after extrahepatic control of the right hepatic vein has been achieved. We crush the parenchyma with a Kelley clamp and control intrahepatic vessels and ducts with clips and ties. The central venous pressure is closely monitored and kept under 5 mm Hg until the liver has been divided. (Reproduced with permission from Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

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Palliation The majority of patients with cholangiocarcinoma have irresectable disease at presentation or at laparotomy. Palliative biliary decompression may be accomplished surgically or by percutaneous transtumoral biliary stenting. Adequate drainage of hilar tumors is more difficult to achieve endoscopically, and this approach is associated with a higher failure rate and greater complications.55 Most patients found to have irresectable tumors at presentation are submitted for percutaneous drainage whereas those found to have irresectable disease at laparotomy may be suitable for intrahepatic enterobiliary bypass.56 External biliary drainage catheters can often provide relief of jaundice or itching. When left in place for long periods of time, however, these catheters can be a source of cholangitis and may require frequent changing. In addition, tumor growth along the tube tract can occur, which can sometimes result in a painful mass in the subcutaneous tissues (Fig. 917). Self-expandable biliary endoprostheses, such as Wallstents, are permanent internal devices that avoid many of the problems and complications associated with external drainage catheters. These stents, while an improvement, are prone to occlusion secondary

Figure 916. Biliary reconstruction is performed, using interrupted absorbable sutures to a Roux-en-Y loop of jejunum. The enteroenterostomy is created at least 70 cm distal to the enterobiliary anastomosis. (Reproduced with permission from Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

ative histologic margins). This is illustrated by the senior authors personal series of 269 patients accumulated over a 20-year interval (Table 98).14,39,53

Table 97. INFLUENCE OF HISTOLOGIC MARGINS ON SURVIVAL AFTER RESECTION OF HILAR CHOLANGIOCARCINOMA Study Hadjis 199039 Pichlmayr 1996* Burke 199814 R0 Resections 12 91 25 R1 Resections 15 27 5 R0 Median Survival (mo) 43 26 > 60 R1 Median Survival (mo) 25 13 22 Operative Mortality (%) 7 10 7 p .04 .01 .01

R0 = resection with negative histologic margin; R1 = resection with positive histologic margin; p = probability. *Pichlmayr R, Lamesch P, Weimann A, et al. Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:838. Adapted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998;228:391 by permission of the publisher Lippincott Williams and Wilkins.

Table 98. EXPERIENCE WITH 269 HILAR CHOLANGIOCARCINOMA PATIENTS OVER 20 YEARS Results Patients evaluated Patients resected Negative margin Hepatectomies performed Operative mortality (%) Median survival (mo) 5-yr survival (%)
NR = not reported.

19771985 (Hadjis NS39) 131 27 15 (56%) 16 (60%) 7.4 25 22

19861990 (Baer HU53) 48 21 14 (67%) 9 (43%) 5 36 NR

19911997 (Burke EC14) 90 30 25 (83%) 22 (73%) 6 40 56

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measure for tumors of the esophagus, colon, stomach, bronchus, bladder, and brain. Although promising as a means of providing biliary decompression without stents or perhaps as a way of treating those with microscopically involved bile duct margins, photodynamic therapy clearly needs further scrutiny before it is widely adopted.
Chemotherapy

Chemotherapy has not been shown to improve survival in patients with unresectable disease, and its use in this setting is difficult to justify outside the context of a clinical trial.
Figure 917. Computed tomography scan showing tumor growth along a percutaneous tube tract (arrowhead), with a large subcutaneous tumor mass.

to growth of tumor into the interstices (Fig. 918). Once this occurs, patients usually require permanent external biliary catheters passed through the previously placed metallic stent. It cannot be overemphasized that patients with unresectable hilar cholangiocarcinoma have a limited life expectancy, and palliative procedures associated with significant morbidity and/or frequent readmissions to the hospital have a tremendous negative impact on quality of life.
Palliative Radiation Therapy

Patients with irresectable locally advanced tumors may be candidates for palliative radiation therapy. A combination of external beam radiation and intraluminal iridium-192 delivered percutaneously is typically used. Several authors have demonstrated the feasibility of this approach although improved survival compared with that achieved with biliary decompression alone has not been documented in a controlled study.47,5759
B

Photodynamic Therapy

Ortner and colleagues reported their limited experience with photodynamic therapy in patients with irresectable hilar cholangiocarcinoma.60 This approach has been used successfully as a palliative

Figure 918. A, Photograph of a Wallstent removed at operation in a patient with hilar cholangiocarcinoma. Notice the ingrowth of tissue into the stent wall. B, Computed tomography scan of a patient with recurrent cancer after resection. A Wallstent had been previously placed to relieve a biliary obstruction (black arrowhead); it subsequently became occluded and caused biliary obstruction proximal to the stent. The left hepatic duct (white arrowhead) is markedly dilated as a result of the occluded stent within its lumen.

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