193

Malignant tumors of the bile ducts remain a majormanagement challenge. They occur most commonlyin the proximal bile duct, at the hepatic duct conflu-ence (hilar cholangiocarcinoma), or in the distal com-mon bile duct near the papilla (distal cholangiocarci-noma) (Fig. 9–1). Resection offers the best chance oflong-term survival, but many patients present withadvanced disease that is not amenable to extirpation.The assessment and treatment of distal bile duct can-cers is similar to that of cancers of the head of thepancreas. This chapter focuses on managementissues specific to hilar cholangiocarcinoma.

EPIDEMIOLOGY

Cholangiocarcinoma is an uncommon disease. Theannual incidence in the United States is 1 to 2 per100,000, and it accounts for approximately 2 percentof all cancers.1 Men and women are affected innearly equal proportions. Although occasionallyseen in young patients, cholangiocarcinoma is pri-marily a disease of the elderly. The majority ofpatients are over 65 years of age, and the peak inci-dence occurs in the eighth decade of life.1 Untreated,hilar cholangiocarcinoma generally results in deathwithin 12 months, from liver failure or from compli-cations arising from biliary tract obstruction.

ETIOLOGY

Cholangiocarcinoma usually occurs sporadically,and most patients have no obvious risk factors. Whilethe etiology of cholangiocarcinoma is unknown,

9

Hilar CholangiocarcinomaPIERRE F. SALDINGER, MDWILLIAM R. JARNAGIN, MDLESLIE H. BLUMGART, MD, FACS, FRCS (ENG, EDIN, GLAS)

there are several conditions that are associated withan increased risk.

Primary Sclerosing Cholangitis

Perhaps the most common associated condition inWestern countries is primary sclerosing cholangitis(PSC), an autoimmune disease characterized by

Figure 9–1. Diagram illustrating the anatomy of the extrahepaticbiliary tree. (CD = cystic duct; GB = gallbladder; LHD = left hepaticduct; RHD = right hepatic duct.)

194 HEPATOBILIARY CANCER

inflammation of the periductal tissues, ultimatelyresulting in multifocal strictures of the intrahepaticand extrahepatic bile ducts.2,3 The natural history ofPSC is quite variable, and the true incidence ofcholangiocarcinoma is unknown. The reported inci-dence in PSC ranges from 8 to 40 percent.2,3 Unlikemost patients with sporadic cholangiocarcinoma ofthe extrahepatic biliary tree, patients with PSC are atrisk for multifocal disease that is often not amenableto resection.

Congenital Biliary Cystic Disease

The increased risk of cholangiocarcinoma in patientswith congenital biliary cystic disease (choledochalcysts, Caroli’s disease) is well described.4 Malignantdegeneration is uncommon in choledochal cysts thathave been completely excised early. However, theincidence of cancer increases substantially (approxi-mately 15 to 20%) in patients who are not treated untilafter the age of 20 years or in those previously treatedby cyst drainage.5,6 The reason for the high incidenceof cancer in patients with cystic diseases appears to berelated to an abnormal choledochopancreatic ductjunction that predisposes to reflux of pancreaticsecretions into the biliary tree, bacterial contamina-tion, and chronic inflammation.5–7 An increased inci-dence of cholangiocarcinoma has also been reportedin patients subjected to transduodenal sphinctero-plasty,8 and a similar mechanism may be responsible.

Hepatolithiasis and Biliary Parasites

Hepatolithiasis, also known as recurrent pyogeniccholangiohepatitis or Oriental cholangiohepatitis, isprevalent in Japan and parts of Southeast Asia.Obstruction of intrahepatic ducts leads to chronicrecurrent episodes of cholangitis and stricture forma-

tion.9–11 Approximately 10 percent of patients willdevelop cholangiocarcinoma.10 Biliary parasites(Clonorchis sinensis and Opisthorchis viverrini) arealso prevalent in parts of Asia and are similarly asso-ciated with an increased risk of cholangiocarcinoma.3

LOCATION

Although cholangiocarcinoma can arise anywherewithin the biliary tree, hilar cholangiocarcinoma ortumors involving the biliary confluence are the mostcommon (see Fig. 9–1). In most large series, the pro-portion of patients with tumors involving the hilusranges from 40 to 60 percent (Table 9–1).12–14 Tumorsof the distal bile duct are somewhat less common,accounting for 20 to 30 percent of all cholangiocarci-nomas and 5 to 10 percent of all periampullarytumors.13,15,16 Approximately 10 percent of cholangio-carcinomas arise within the intrahepatic biliarytree.17–19 These tumors usually present as an intrahep-atic mass, and although uncommon, jaundice mayresult from intrabiliary tumor extension (Fig. 9–2).

HISTOPATHOLOGY

The overwhelming majority of cholangiocarcinomasare adenocarcinomas, often well differentiated andmucin producing.1,20

There are three well-described macroscopic sub-types of cholangiocarcinoma: sclerosing, nodular,and papillary.20 Sclerosing tumors account for themajority of cases. Sclerosing tumors are very firmand cause an annular thickening of the bile duct,often with diffuse infiltration and fibrosis of theperiductal tissues (Fig. 9–3). Nodular tumors arecharacterized by a firm irregular nodule of tumorthat projects into the lumen of the duct. Features ofboth types are often seen, hence the frequently used

Table 9–1. INCIDENCE OF HILAR CHOLANGIOCARCINOMA IN SELECTED SERIES

Institution Years* Patients with Cholangiocarcinoma Patients with Hilar Cholangiocarcinoma

UCLA (1981)† 24 96 47 (49%)Mayo Clinic (1993)12 9 171 79 (46%)Johns Hopkins (1996)13 23 294 197 (67%)MSKCC (1998)14 6 225 90 (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;194:447–57.

Hilar Cholangiocarcinoma 195

descriptor “nodular-sclerosing.” The papillary vari-ant accounts for approximately 10 percent of allcholangiocarcinomas and is more common in thedistal bile duct.21 A polypoid mass that expandsrather than contracts the duct is a characteristic fea-ture (Fig. 9–4). Although papillary tumors may growto significant size and appear surgically unapproach-able (based on radiographic studies), they often arisefrom a well-defined stalk and histologically may beconfined to the superficial layers of the duct wall(Fig. 9–5). Recognition of papillary cholangiocarci-nomas is important since they are more oftenresectable and have a more favorable prognosis thanthe other types.3

Longitudinal spread along the duct wall andperiductal tissues is an important pathologic feature

of cholangiocarcinomas.20 There may be substantialextension of tumor beneath an intact epithelial lin-ing—as much as 2 cm proximally and 1 cm dis-tally.22 The full tumor extent may thus be underesti-mated by radiographic studies and may not be fullyappreciated by palpation at the time of resection.This feature underscores the importance of checkingall resection margins with frozen-section histologyat operation.

STAGING

According to the American Joint Commission onCancer (AJCC), the staging of extrahepatic cholan-giocarcinomas is based on the extent of the primarytumor (T stage), the extent of regional lymph node

Figure 9–2. Images from a patient with an intrahepatic cholangio-carcinoma and jaundice. A, Cross-sectional computed tomographyimage showing dilated left biliary tree (arrow) but no clearly definedmass. B, Cross-sectional magnetic resonance cholangiopancreatog-raphy (MRCP) image showing a heterogeneous mass in segment IV(arrow). Dilated bile ducts appear as white areas. C, Coronal MRCPreconstruction showing the tumor growing down the left hepatic ductand extending across the right hepatic duct and into the commonhepatic duct (arrow). The dilated bile ducts again appear as whiteareas. (Reproduced with permission from Jarnagin WR, Saldinger PF,Blumgart LH. Cancer of the bile ducts: the hepatic ducts and commonbile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and bil-iary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

A B

C

196 HEPATOBILIARY CANCER

involvement (N stage), and the presence of distantmetastases (M stage) (Table 9–2). An alternativestaging system proposed by Bismuth and Corletteclassifies cholangiocarcinomas on the basis of theirlocation with respect to the hilus and on the extent of

ductal involvement.23 The AJCC staging is basedlargely on pathologic criteria and has little clinicalapplicability. The majority of patients in our practicehave T3 (stage 4A) tumors based on invasion intothe liver, but this alone says very little about theirresectability. Moreover, this finding does not corre-late with survival, provided that complete resection

Figure 9–3. A, Endoscopic cholangiogram showing the typical irreg-ular biliary stricture characteristic of sclerosing adenocarcinomas(arrow). These tumors cause a circumferential thickening of the ductwall and periductal fibrosis, which ultimately obliterates the lumen.(Reproduced with permission from Jarnagin WR, Saldinger PF, Blum-gart LH. Cancer of the bile ducts: the hepatic ducts and common bileduct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliarytract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.) B, Coronalmagnetic resonance cholangiopancreatography reconstruction show-ing an infiltrating tumor involving the hepatic duct confluence (arrow).The right and left intrahepatic ducts, which appear white, are dilated.

A

B

Figure 9–4. A, Transhepatic cholangiogram showing a markedlydilated bile duct from the confluence of the right and left hepaticducts to the ampulla of Vater. Filling defects are apparent throughoutthe length of the duct (black arrows). A percutaneous biliary stent isin place (white arrow). B, Cross-sectional computed tomographyimage of the same patient. The stent (white arrowhead) is seenwithin the duct, adjacent to a large tumor mass (white arrow). Theunderlying portal vein (black arrow) is free, and there is no evidenceof lobar atrophy.

B

A

Hilar Cholangiocarcinoma 197

Figure 9–5. A, Excised bile duct from thepatient discussed in Fig. 9–4. The duct has beenopened longitudinally to reveal two separate poly-poid masses (arrows). B, View looking down theincised bile duct, with one of the tumors seen aris-ing from the mucosal surface. Most of the tumormass extends into the bile duct lumen. C, Pho-tomicrograph showing the malignant cells largelyconfined to the mucosa of the duct wall (arrow)(hematoxylin-eosin stain, low power view).

A

B

C

198 HEPATOBILIARY CANCER

can be achieved.14 In the AJCC system, patients withinvolvement of N1- and N2-lymph nodes are stagedsimilarly. This is inappropriate since patients withmetastatic disease to N2-level lymph nodes (celiac,periduodenal, or retroperitoneal) are not candidatesfor resection and should be considered to have M1disease. The Bismuth-Corlette system is more clini-cally relevant but is too simplified and, like theAJCC system, correlates poorly with resectabilityand survival.14 None of the current staging systemstakes into account local factors such as vascularinvasion or hepatic lobar atrophy, which are impor-tant determinants of resectability, which (in turn) isa major determinant of outcome. A more reliableand systematic method of selecting candidates forresection is clearly needed (see below).

DIAGNOSIS

Symptoms and Physical Examination

The early symptoms of hilar cholangiocarcinomaare nonspecific. Abdominal pain or discomfort,anorexia, weight loss, and pruritus are the mostcommon symptoms and are seen only in one-third ofpatients.3,11,13,24 Most of these tumors come to atten-tion because of jaundice or abnormal liver functiontests. Jaundice is not present initially in cases ofincomplete biliary obstruction (ie, right or left

hepatic duct) or segmental ductal obstruction.Patients with papillary tumors of the hilus may havea history of fluctuating jaundice, which may be theresult of loose tumor fragments intermittentlyobstructing the bile duct. In patients with cholangio-carcinoma and no previous biliary intervention,cholangitis is uncommon at initial presentationdespite a 30 percent incidence of bacterial contami-nation (bacterbilia).11,25

The physical findings are often nonspecific.Jaundice will usually be obvious. The gallbladder isusually decompressed and nonpalpable with hilarobstruction; thus, a palpable gallbladder suggests amore distal obstruction or an alternative diagnosis.Patients with long-standing biliary obstructionand/or portal vein involvement may have findingsconsistent with portal hypertension.

Alternative Diagnoses

The vast majority of patients with proximal biliaryobstruction and jaundice have cholangiocarcinoma.However, alternative diagnoses are possible and canbe expected in 10 to 15 percent of patients.26 Gall-bladder carcinoma, Mirizzi syndrome, and idiopathicbenign focal stenosis (“malignant masquerade”) arethe most common conditions that may be mistakenfor cholangiocarcinoma. Over a 28-month period atMemorial Sloan-Kettering Cancer Center, we evalu-ated 109 patients with obstruction involving the biliaryconfluence consistent with hilar cholangiocarcinoma.In 90 patients, this diagnosis was confirmed while19 patients were found to have other conditions (9with gallbladder cancer, 6 with malignant masquerade,3 with neuroendocrine tumor of the bile duct, and 1with Mirizzi syndrome).

Distinguishing gallbladder carcinoma from hilarcholangiocarcinoma can be difficult. A thickenedand irregular gallbladder with infiltration into seg-ment IV, selective involvement of the right portalpedicle, and obstruction of the common hepatic ductwith occlusion of the cystic duct on endoscopiccholangiography are all suggestive of gallbladdercarcinoma. Mirizzi syndrome is a benign conditionresulting from a large gallstone impacted in the neckof the gallbladder (Fig. 9–6).21,27 Benign focal stric-tures (malignant masquerade) can occur at the

Table 9–2. CURRENT AMERICAN JOINT COMMISSION

ON CANCER STAGING SYSTEM FOR CANCER OF

EXTRAHEPATIC BILE DUCTS

Stage Tumor Node Metastasis

0 Tis N0 M01 T1 N0 M02 T2 N0 M03 T1 or 2 N1 or 2 M04A T3 Any N M04B Any T Any N M1

Tis = carcinoma in situ; T1 = tumor invades subepithelial connective tissue orfibromuscular 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 nodeswithin the hepatoduodenal ligament (cystic duct, pericholedochal, and/orhilar lymph nodes); N2 = metastasis to peripancreatic, periduodenal, periportal, celiac, superior mesenteric, and/or posterior pancreaticoduodenallymph nodes.M0 = no distant metastasis; M1 = distant metastasis.

Hilar Cholangiocarcinoma 199

hepatic duct confluence but are uncommon (Fig.9–7).26,28,29 Relying on the results of percutaneousneedle biopsy or biliary brush cytology is dangeroussince they are often misleading and because one maymiss the opportunity to resect an early cancer.30,31 Itis often impossible to establish the diagnosisunequivocally before operation, and this is indeedunnecessary in nearly all cases since lesions at thebiliary confluence (including benign strictures) arebest assessed and treated at operation. We firmly

believe that in the absence of clear contraindications(see below), exploration is indicated in all patientswith suspicious hilar lesions.

TREATMENT

Preoperative Evaluation

Evaluation of patients with hilar cholangiocarci-noma is principally an assessment of resectability,

Figure 9–6. Endoscopic retrograde cholangiography (ERCP) and cross-sectional computed tomography (CT) scan images of a patient withMirizzi syndrome. Left, The ERCP shows a characteristic large gallstone (arrow) impacted in the neck of the gallbladder, causing obstructionof 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 theliver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

Figure 9–7. A, Endoscopic cholangiogram in a patient with a benign focal stricture of the common hepatic duct (white arrowhead). Thesmooth, 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 sur-rounding scar tissue (arrowhead) (hematoxylin-eosin stain, low power view).

A B

Figure 9–8. Left, Cross-sectional computed tomography image of a patient with cholangiocarcinoma involving the left hepatic duct. The leftlobe, 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 involv-ing the left hepatic duct. The left lobe is small, and the bile ducts (which appear black) are dilated and crowded. There is evidence of hypoper-fusion of the left lobe, which appears darker. There is also evidence of hypoperfusion of the right posterior sector, which also appears darkerand is clearly demarcated from the well-perfused right anterior sector (arrowheads) but does not as yet show evidence of atrophy. These radi-ographic features suggest that the tumor involves the left hepatic duct and the left portal vein and is beginning to involve the right portal pedi-cle. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: the hepatic ducts and common bileduct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: Churchill Livingstone; 2000.)

200 HEPATOBILIARY CANCER

since resection is the only effective therapy. First andforemost, the patient’s general health and fitness formajor surgery (possibly including partial hepatec-tomy) must be examined. The presence of signifi-cant comorbid conditions, chronic liver disease,and/or portal hypertension generally precludesresection. Patients with potentially resectable tumorsmay develop biliary tract sepsis, often after intuba-tion of the biliary tree. These patients require resus-citation and treatment of the infection before surgeryis undertaken.

The preoperative evaluation must address fourcritical determinants of resectability: (1) tumorextent within the biliary tree, (2) vascular invasion,(3) hepatic lobar atrophy, and (4) metastatic dis-ease.14 Tumors that extend into the second-order bil-iary radicles bilaterally are not amenable to resec-tion with clear margins, but this is often difficult todetermine before operation. Likewise, the presenceof metastatic disease (to distant sites or N2-levellymph nodes) is a contraindication to resection.Lobar atrophy is an often overlooked but importantfactor in assessing the resectability of these tumors32

(see below). Long-standing biliary obstruction maycause moderate atrophy whereas concomitant portalvenous compromise induces rapid and severe atro-phy of the involved segments. On cross-sectional

imaging, atrophy is characterized by a small andoften hypoperfused lobe, with crowding of thedilated intrahepatic ducts14 (Fig. 9–8).

Radiographic Studies

High-quality radiographic studies are critical inselecting patients for resection. In the past, computedtomography (CT), percutaneous transhepatic cholan-giography (PTC), and angiography were consideredthe standard investigations. Currently, we rely almostexclusively on magnetic resonance cholangiopancre-atography (MRCP), and duplex ultrasonography(US). These noninvasive studies provide the sameinformation regarding the extent of disease as theaforementioned studies but with less risk.

Magnetic resonance cholangiopancreatographyhas emerged as a powerful investigative tool, andwe prefer it to the more invasive endoscopic retro-grade cholangiography (ERCP) or PTC. Severalstudies have demonstrated the utility of MRCP inevaluating patients with biliary obstruction.33–35 Itmay identify the tumor and level of obstruction andmay also reveal obstructed and isolated ducts notseen by PTC. It also provides information regard-ing the patency of hilar vascular structures, thepresence of nodal or distant metastases, and lobar

Hilar Cholangiocarcinoma 201

atrophy (Figs. 9–9 and 9–10). Furthermore, unlikedirect cholangiography, MRCP does not requirebiliary intubation. Potential infectious complica-tions, which may increase operative morbidity, arethus avoided.

Duplex US is a valuable study in patients withhilar obstruction; in experienced hands, US rivals allother modalities for assessing extent of disease andvascular involvement36–38 (Fig. 9–11). In our prac-tice, MRCP and duplex US have become the pre-ferred investigations.

Patient Selection

Distinguishing resectable from irresectable tumorsdemands careful consideration of all available data.Bilateral tumor extension to second-order intrahep-atic biliary radicles and encasement or occlusion ofthe main portal vein clearly preclude resection. Onthe other hand, involvement of the right or leftbranch of the portal vein does not necessarily pre-clude resection. In this situation, complete resectionwill require ipsilateral partial hepatectomy, but thiswould not be possible if the contralateral lobe isatrophic or if the tumor extends to the contralateralsecond-order biliary radicles. The detailed criteria ofirresectability are outlined in Table 9–3.

Despite improvements in radiologic techniques,only 20 to 50 percent of patients submitted to explo-ration have tumors that can be resected.13,14,39 Wehave therefore proposed a preoperative staging sys-tem aimed at improving patient selection.14 Basedon the radiographic interpretation of local tumor

Figure 9–9. A, T1-weighted gadolinium-enhanced magnetic resonance image of a patient with hilar cholangiocarcinoma. In this image, thebile ducts appear black. A hilar tumor (T) is seen, apparently adherent to or encasing the right portal vein branch (PV) (white arrowhead). Thetumor 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 cholangiopancreatogra-phy image through the same area of the liver. Similar findings are shown in this image, in which the bile ducts appear white. The vascular find-ings seen on magnetic resonance imaging were confirmed on duplex ultrasonography. Biopsies of the main tumor and the intrahepatic metas-tases confirmed adenocarcinoma. (Reproduced with permission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer of the bile ducts: thehepatic ducts and common bile duct. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edinburgh [UK]: ChurchillLivingstone; 2000.)

A B

Figure 9–10. Cross-sectional magnetic resonance cholangiopan-creatography image from a patient with hilar cholangiocarcinomaextending into the left hepatic duct and with left lobe atrophy.The bileducts appear white. The left lobe is small, with dilated and crowdedducts (short arrow). The principal caudate lobe duct, seen joining theleft hepatic duct, is also dilated (long arrow). (Reproduced with per-mission from Jarnagin WR, Saldinger PF, Blumgart LH. Cancer ofthe bile ducts: the hepatic ducts and common bile duct. In: BlumgartLH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed. Edin-burgh [UK]: Churchill Livingstone; 2000.)

202 HEPATOBILIARY CANCER

Figure 9–11. A, Duplex ultrasonography ina patient with a hilar cholangiocarcinoma. Thetumor is clearly seen at the biliary confluencejust above the portal vein (arrow).The mass isclearly in contact with the portal vein, butthere is no clear invasion or venous narrow-ing. A transtumoral stent is also visible.(Reproduced with permission from JarnaginWR, Saldinger PF, Blumgart LH. Cancer ofthe bile ducts: the hepatic ducts and commonbile 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 bil-iary confluence shows a papillary cholangio-carcinoma (m) extending into both the rightanterior (a) and posterior (p) sectoral ductsand the origin of the left duct (l). The adjacentportal vein (v) is not involved and has normalflow. (Reproduced with permission from HannLE, Fong Y, Shriver CD, et al. Malignanthepatic hilar tumors: can ultrasonography beused as an alternative to angiography with CT arterial portagraphy for determination of resectability? J Ultrasound Med 1996;15:37–45.)

A

B

extent (T stage), this system analyzes resectabilityand considers the following factors: extent of biliaryductal involvement, portal venous involvement, andlobar atrophy (Table 9–4). Analyzing our patientdata by using the proposed system, we found that

resectability and the need for partial hepatectomyboth increased progressively with increasing T stagewhile 5-year survival was inversely related (Table9–5). By contrast, there was no correlation betweenthese variables and AJCC stage. The proposed stag-

Hilar Cholangiocarcinoma 203

ing system does not consider the status of the peri-hepatic lymph nodes. Enlarged reactive lymph nodesare common in these patients, particularly those whohave been subjected to biliary instrumentationbefore referral. Moreover, resection is not unreason-

Table 9–3. CRITERIA OF IRRESECTABILITY IN PATIENTS

WITH HILAR CHOLANGIOCARCINOMA

Patient FactorsMedically unfit for operationCirrhosis/portal hypertension

Local FactorsHepatic duct involvement up to secondary radicles bilaterallyEncasement or occlusion of the main portal vein proximal to

its bifurcationAtrophy of one lobe, with encasement of contralateral portal

vein branchAtrophy of one lobe, with contralateral involvement of

secondary biliary radiclesDistant Disease

Histologically proven metastases to N2 lymph nodesLiver, 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 presurgicalclinical staging system. Ann Surg 1998;228:386 by permission of the pub-lisher Lippincott Williams and Wilkins.

Table 9–4. PROPOSED PREOPERATIVE TUMOR STAGING OF HILAR CHOLANGIOCARCINOMA

Tumor Ipsilateral Lobar Ipsilateral Portal Main Portal Stage Biliary Involvement Atrophy Vein Involvement Vein Involvement

T1 Hilus and/or right or left hepatic duct No No NoT2 Hilus and/or right or left hepatic duct Yes No NoT3 Hilus and/or right or left hepatic duct Yes/No Yes NoT4 Secondary biliary radicles bilaterally Yes/No Yes/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. T2tumors are associated with ipsilateral lobar atrophy but not portal vein branch involvement. T3 tumors are characterized by ipsilateral portal venous branchinvolvement and may or may not be associated with lobar atrophy. T4 tumors are defined as irresectable, based on tumor extension to secondary biliary radiclesbilaterally 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 clinicalstaging system. Ann Surg 1998;228:387 by permission of the publisher Lippincott Williams and Wilkins.

able even in the setting of metastatic disease to N1-level nodes since these are routinely cleared with thetumor. By contrast, metastasis to N2-level nodeswould preclude resection, and biopsies should beperformed on suspicious nodes in these areas to con-firm the diagnosis.

Preoperative Biliary Decompression and Infection

In patients considered candidates for resection andwithout evidence of cholangitis, preoperative biliarydecompression is unnecessary and may be harmful.There is substantial evidence that preoperative bil-iary intubation does not improve outcome, and theobserved increase in perioperative complicationsoutweighs any potential benefit.25,40–44

Operation

The treatment goals in patients with hilar cholangio-carcinoma are resection with negative histologicmargins and the restoration of enterobiliary continu-

Table 9–5. RESECTABILITY, INCIDENCE OF PARTIAL HEPATECTOMY, AND 5-YEAR SURVIVAL, BY PROPOSED TUMOR STAGE

T Stage No. of Patients No. Resected No. Requiring Partial Hepatectomy* 5-Year Survival (%)†

1 40 19 (48%) 11 (58%) 202 7 3 (43%) 3 (100%) 293 32 8 (25%) 8 (100%) 164 8 0 0 0Total 87 30 (35%) 22 (73%) 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 clinicalstaging system. Ann Surg 1998;228:390 by permission of the publisher Lippincott Williams and Wilkins.

204 HEPATOBILIARY CANCER

ity. Hepatic transplantation is associated with a pro-hibitively high incidence of recurrence, which hasled many centers to abandon its routine use in thisdisease.45 All patients should be evaluated for possi-ble resection before any intervention. Ill-advisedattempts to place biliary stents, especially when notindicated, may result in complications that delayoperation, and stent-associated infection andinflammation may hinder further radiographic andoperative assessment.40,45,46If resection is clearly notfeasible, then transtumoral drainage or intrahepaticenterobiliary bypass offers satisfactory palliation(see below).

At operation, the objective should be the com-plete resection of the tumor, with negative histologicmargins. Partial hepatectomy is usually required toachieve this goal. Several recent series show a strongcorrelation between negative histologic margins andthe percentage of patients subjected to partial hepa-tectomy (Table 9–6).14,39,47–49 Additionally, tumorsthat extend into the left hepatic duct usually involvethe principal caudate lobe ducts and require en bloccaudate lobectomy (see Fig. 9–10).39,47–50

Operative Technique

The operation begins with a thorough exploration ofthe abdomen. Contrary to popular belief, metastaticdisease is common in patients with hilar cholangio-carcinoma.14,47,51 Performing staging laparoscopybefore proceeding to open exploration may helpidentify some patients with unresectable disease.

The details of resection are illustrated in Fig-ures 9–12 to 9–16. The duodenum and liver aremobilized, and the gallbladder is taken down. Thebridge of liver tissue that often connects segments

III and IV should be divided to expose the lefthepatic duct at the base of the umbilical fissure.Lowering the hilar plate will expose the biliaryconfluence. Palpation of the duct in this area willgive the surgeon a sense of the tumor extent. Thedistal bile duct is transected and elevated upwards,allowing inspection of the anterior wall of the por-tal vein for evidence of tumor invasion; a portionof the distal duct should be sent for frozen-sectionhistology. Once it has been determined that resec-tion is feasible and will leave behind a tumor-freeliver remnant with intact blood supply and biliarydrainage, the surgeon should then control anddivide the inflow blood supply to the lobe that is tobe removed. The contralateral hepatic duct abovethe tumor should be divided likewise, and a por-tion should be sent for frozen-section histology.The hepatic vein draining that portion of the liverto be excised should be exposed and divided extra-hepatically. The parenchymal transection shouldnow be pursued. Finally, enterobiliary reconstruc-tion is completed, using a 70-cm Roux-en-Y loopof jejunum.

Results

It must be stressed that with the approach outlinedabove, long-term survival can be achieved with an acceptable operative mortality.12–14,39,48,49,52–54

Patients resected with negative histologic marginssurvive significantly longer than those with micro-scopically positive margins (Table 9–7).14,39,52 Overthe past 20 years, there has been a steady increasein the use of hepatic resection in patients with hilarcholangiocarcinoma, resulting in an increase in theproportion of R0 resections (ie, resections with neg-

Table 9–6. CORRELATION BETWEEN PARTIAL HEPATECTOMY AND HISTOLOGIC MARGINS IN

PATIENTS WITH HILAR CHOLANGIOCARCINOMA: SUMMARY OF RECENT SERIES

Author Period of Study (yr) Resected (N) Partial Hepatectomy (%) Negative Margins (%)

Cameron (1990)47 15 39 20 15Hadjis (1990)39 8 27 60 56Nimura (1990)49 10 55 98 83Klempnauer (1997)48 25 147 79 79Burke (1998)14 6 30 73 83

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

Hilar Cholangiocarcinoma 205

Figure 9–14. The left hepatic duct is divided well beyond thetumor, and a portion is sent for frozen-section analysis. Further dis-section exposes the portal vein confluence, and the right branch isdivided. (Reproduced with permission from Blumgart LH, Fong Y,editors. Surgery of the liver and biliary tract. Edinburgh [UK]:Churchill Livingstone; 1997 [CD-ROM].)

Figure 9–15. The hepatic parenchyma is divided after extrahep-atic control of the right hepatic vein has been achieved. We crush theparenchyma with a Kelley clamp and control intrahepatic vesselsand ducts with clips and ties. The central venous pressure is closelymonitored 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 Liv-ingstone; 1997 [CD-ROM].)

Figure 9–12. Initial operative approach. The round ligament hasbeen divided and is held upwards, exposing the undersurface of theliver. The hilar plate at the base of segment IV has been lowered,exposing the tumor at the biliary confluence. The bridge of liver tissueattaching segments III and IV has been divided; this provides greaterexposure of the left hepatic duct. The gallbladder has been takendown, and the distal bile duct has been divided. (Reproduced with per-mission from Blumgart LH, Fong Y, editors. Surgery of the liver and bil-iary tract. Edinburgh [UK]: Churchill Livingstone; 1997 [CD-ROM].)

Figure 9–13. Upward traction on the divided bile duct and periduc-tal lymphatic tissues exposes the underlying portal vein. Developingthe plane between the tumor and the portal vein is the only way toassess vascular invasion. Provided that the vein is not involved, aplane between the tumor and the portal vein can easily be devel-oped. Once it has been determined that resection is feasible, theright 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 Liv-ingstone; 1997 [CD-ROM].)

206 HEPATOBILIARY CANCER

ative histologic margins). This is illustrated by thesenior author’s personal series of 269 patients accu-mulated over a 20-year interval (Table 9–8).14,39,53

Figure 9–16. Biliary reconstruction is performed, using interruptedabsorbable sutures to a Roux-en-Y loop of jejunum. The enteroen-terostomy is created at least 70 cm distal to the enterobiliary anas-tomosis. (Reproduced with permission from Blumgart LH, Fong Y,editors. Surgery of the liver and biliary tract. Edinburgh [UK]:Churchill Livingstone; 1997 [CD-ROM].)

Palliation

The majority of patients with cholangiocarcinomahave irresectable disease at presentation or at laparo-tomy. Palliative biliary decompression may beaccomplished surgically or by percutaneous transtu-moral biliary stenting. Adequate drainage of hilartumors is more difficult to achieve endoscopically,and this approach is associated with a higher failurerate and greater complications.55 Most patientsfound to have irresectable tumors at presentation aresubmitted for percutaneous drainage whereas thosefound to have irresectable disease at laparotomy maybe suitable for intrahepatic enterobiliary bypass.56

External biliary drainage catheters can often providerelief of jaundice or itching. When left in place forlong periods of time, however, these catheters can bea source of cholangitis and may require frequentchanging. In addition, tumor growth along the tubetract can occur, which can sometimes result in apainful mass in the subcutaneous tissues (Fig. 9–17).Self-expandable biliary endoprostheses, such asWallstents, are permanent internal devices that avoidmany of the problems and complications associatedwith external drainage catheters. These stents, whilean improvement, are prone to occlusion secondary

Table 9–7. INFLUENCE OF HISTOLOGIC MARGINS ON SURVIVAL AFTER RESECTION OF HILAR CHOLANGIOCARCINOMA

R0 R1 R0 R1 Operative Study Resections Resections Median Survival (mo) Median Survival (mo) Mortality (%) p

Hadjis 199039 12 15 43 25 7 .04Pichlmayr 1996* 91 27 26 13 10 .01Burke 199814 25 5 > 60 22 7 .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;19:83–8.Adapted from Burke E, et al. Hilar cholangiocarcinoma. Patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinicalstaging system. Ann Surg 1998;228:391 by permission of the publisher Lippincott Williams and Wilkins.

Table 9–8. EXPERIENCE WITH 269 HILAR CHOLANGIOCARCINOMA PATIENTS OVER 20 YEARS

Results 1977–1985 (Hadjis NS39) 1986–1990 (Baer HU53) 1991–1997 (Burke EC14)

Patients evaluated 131 48 90Patients resected 27 21 30 Negative margin 15 (56%) 14 (67%) 25 (83%)Hepatectomies performed 16 (60%) 9 (43%) 22 (73%)Operative mortality (%) 7.4 5 6Median survival (mo) 25 36 40 5-yr survival (%) 22 NR 56

NR = not reported.

Hilar Cholangiocarcinoma 207

measure for tumors of the esophagus, colon, stom-ach, bronchus, bladder, and brain. Although promis-ing as a means of providing biliary decompressionwithout stents or perhaps as a way of treating thosewith microscopically involved bile duct margins,photodynamic therapy clearly needs further scrutinybefore it is widely adopted.

Chemotherapy

Chemotherapy has not been shown to improve sur-vival in patients with unresectable disease, and itsuse in this setting is difficult to justify outside thecontext of a clinical trial.

to growth of tumor into the interstices (Fig. 9–18).Once this occurs, patients usually require permanentexternal biliary catheters passed through the previ-ously placed metallic stent.

It cannot be overemphasized that patients withunresectable hilar cholangiocarcinoma have a lim-ited life expectancy, and palliative procedures asso-ciated with significant morbidity and/or frequent re-admissions to the hospital have a tremendousnegative impact on quality of life.

Palliative Radiation Therapy

Patients with irresectable locally advanced tumorsmay be candidates for palliative radiation therapy. Acombination of external beam radiation and intralu-minal iridium-192 delivered percutaneously is typi-cally used. Several authors have demonstrated thefeasibility of this approach although improved sur-vival compared with that achieved with biliarydecompression alone has not been documented in acontrolled study.47,57–59

Photodynamic Therapy

Ortner and colleagues reported their limited experi-ence with photodynamic therapy in patients withirresectable hilar cholangiocarcinoma.60 Thisapproach has been used successfully as a palliative

Figure 9–18. A, Photograph of a Wallstent removed at operation ina patient with hilar cholangiocarcinoma. Notice the ingrowth of tissueinto the stent wall. B, Computed tomography scan of a patient withrecurrent cancer after resection. A Wallstent had been previouslyplaced to relieve a biliary obstruction (black arrowhead); it subse-quently became occluded and caused biliary obstruction proximal tothe stent. The left hepatic duct (white arrowhead) is markedly dilatedas a result of the occluded stent within its lumen.

Figure 9–17. Computed tomography scan showing tumor growthalong a percutaneous tube tract (arrowhead), with a large subcuta-neous tumor mass.

A

B

208 HEPATOBILIARY CANCER

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