Surgery for extrahepatic cholangiocarcinoma: predictors of survival

HPB, 2008; 10: 190
195

REVIEW ARTICLE

Surgery for extrahepatic cholangiocarcinoma: predictors of survival

J. J. KLOEK1, F. J. TEN KATE2, O. R. C. BUSCH1, D. J. GOUMA1 & T. M. VAN GULIK1 1

Department of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands and 2Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands

Abstract The incidence of extrahepatic cholangiocarcinoma is increasing worldwide and is often in an advanced stage at diagnosis and difficult to treat. The TNM (tumor node metastasis) cancer staging system predicts survival on the basis of tumor histopathology and the presence of distant metastases. However, numerous prognostic factors have been described that are not included in the TNM system. This review focuses on the prognostic significance of clinical, surgical, and histopathological factors as reported in the literature. Overall, the most important independent prognostic factors for long-term survival are negative surgical margins, lymph node status, and differentiation grade of the tumor. Further improvement of staging systems and identification of prognostic factors are crucial if we are to better select patients for surgical and adjuvant therapy and, hence, increase the rate of curative resections.

Key Words: Cholangiocarcinoma, lymph nodes, prognostic factors, resection margin, survival

Introduction Cholangiocarcinoma (CCA) can be classified into intrahepatic and extrahepatic CCA, the latter including distal and hilar cholangiocarcinoma (HCCA), depending on its location within the biliary tree [1]. Surgical treatment, consisting of hilar resection with extended hepatectomy, pancreatoduodenectomy (PD), or sometimes local bile duct resection, is the only curative treatment option [2
6]. Despite comprehensive preoperative staging to select patients for potentially curative resection, many patients present with recurrences within 2 years after tumor resection. Overall, 5-year survival rates of 20% to 35% have been reported after resection [6
15]. There is no single staging system for all CCA, reflecting the different patho-biology of intrahepatic and extrahepatic tumors [16]. For staging of intrahepatic CCA, the proposed TNM (tumor node metastasis) system has been shown to correlate with survival after hepatic resection [17]. To stage extrahepatic CCA, accounting for approximately two-thirds of all CCA, a different pTNM system is used [18,19]. Several modifications and alternatives have been implemented with the objective of improving the prognostic and therapeutic predictions for each cancer

stage. However, to improve the currently available staging systems, additional clinical and histopathologic factors have been suggested [20]. The current study reviews the major clinical-pathological factors, operative techniques, and adjuvant treatment strategies that influence survival of resectable extrahepatic CCA. Future directions towards improving staging systems are proposed. Methods A review of the English-language literature (January 1995 through September 2007) concerning resectable CCA was performed (intrahepatic, gallbladder, and periampullary adenocarcinoma were excluded) focusing on the prognostic power of clinical, surgical, and histopathological factors in relation to resectable extrahepatic CCA. Results Clinical prognostic factors (summarized in Table I) Age and sex. In case of comparable therapy, age was found not to be of any prognostic significance in several studies [8,21,22]. However, two studies

Correspondence: T. M. van Gulik, Academic Medical Center, Department of Surgery, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands. Tel: 31 20 56 65572. Fax: 31 20 69 76621. E-mail: [email protected]

(Received 5 February 2008; accepted 14 February 2008) ISSN 1365-182X print/ISSN 1477-2574 online # 2008 Taylor & Francis DOI: 10.1080/13651820801992575

Surgery for extrahepatic cholangiocarcinoma

191

Table I. Clinical and surgical prognostic factors in extrahepatic CCA. Clinical/surgical factor Age Sex Level of jaundice Hepatolithiasis Tumor location Bismuth
Corlette staging Chemoradiation therapy Type of operation Portal vein resection Surgical complications

Prognostic impact

Favouring survival benefit

References

Minor Considerable Considerable None Dubious Dubious Considerable Considerable Considerable Considerable

Younger age Female Low initial plasma bilirubin level

[9,12] [8,9,23] [2,24,25]

Distal lesion Type I, II lesion (Neo)adjuvant therapy Concomitant PHx Portal vein resected No blood transfusion

[27] [25,34,35] [9,10,39
41] [3,67] [3,7,14,32,45] [23,33]

Prognostic impact on clinical and surgical factors is scored as none (no evidence), dubious (conflicting evidence), minor (evidence from univariate analysis), considerable (evidence from uni- and multivariate analysis) and strong (evidence from several multivariate analyses). PHxPartial hepatectomy.

showed a worse long-term outcome for older patients [9,12]. Three studies reported a survival benefit in multivariate analyses for female compared to male patients with extrahepatic CCA [8,9,23].

Symptoms at initial presentation. The majority of patients with extrahepatic CCA present with jaundice. Three studies describe a long-term favorable prognostic effect of low initial plasma bilirubin level in univariate analysis [24,25] as well as in multivariate analysis [2]. Weight loss is usually a reflection of advanced disease. However, none of the studies found this clinical sign to be a prognostic factor.

Co-morbidity. It has been suggested that the presence of hepatolithiasis hinders diagnosis of underlying CCA preoperatively and precipitates biliary sepsis, which affects resectability. Hepatolithiasis per se, however, did not influence long-term survival [26].

Tumor location. Extrahepatic CCAs are subclassified mostly according to their location within the biliary tree. It has been suggested that CCAs in the distal or middle part have better prognosis because these give rise to total obstruction and therefore are detected earlier, whereas proximal tumors tend to commence with partial biliary obstruction consequently resulting in fewer complaints and late jaundice. However, in one study there was only a survival benefit for patients with distal lesions at univariate analysis [27], and in the other two studies no difference in survival was found in respect of tumor location [11,28].

Bismuth
Corlette staging system. Hilar lesions can be classified according to location and segmental infiltration into the biliary tree, as suggested by the Bismuth
Corlette system [29]. In several studies, this staging system had no predictive value for survival [7,21,22,30
33]. In two studies at univariate analysis

[34,35] and in another at multivariate analysis [25] a favorable outcome for stages I and II was observed.

Chemoradiation therapy. The main goal of adjuvant chemoradion therapy is improvement of local control and consequently survival. In a retrospective analysis, improved survival was observed for patients with adjuvant radiation therapy [36]; however, this was not confirmed in other studies [37,38]. In one study, patients referred after neoadjuvant chemotherapy had an unexpected survival benefit [9]. Furthermore, a significant improvement in survival was demonstrated after adjuvant chemotherapy in both univariate analysis [39,40] and multivariate analysis [10,41]. Surgical prognostic factors (summarized in Table I) Type of operation. HCCA requires resection of the hepatic duct confluence, usually with extended liver resection. Distal and middle CCAs do not involve the hepatic duct confluence. In such cases, PD or occasionally local bile duct resection can be performed to attain cure. As mentioned above, no studies have shown a prognostic difference of distal and proximal tumors. The extent of surgical resection in proximal (hilar) tumors, however, has been crucial in the past two decades.

Caudate lobe resection. Because of frequent anterior and posterior infiltration of the tumor in the hepatic hilum, liver resection is advocated in combination with resection of segment 4 (Sg 4) and complete excision of the caudate lobe (Sg 1). Japanese surgeons, in particular, demonstrated survival benefit of a more aggressive approach [42
44]. In one series, multivariate analysis was performed in patients who had had an R0 resection to determine whether additional significant variables might emerge. This analysis identified concomitant liver resection as the only predictor of survival after resection with negative margins [3].

192

J. J. Kloek et al.

Portal vein resection. Portal vein invasion was previously considered a main cause of unresectability of HCCA. However, this view has been abandoned. Two studies found a survival benefit of portal vein resection in univariate analysis [3,32], and one in multivariate analysis [14]. In a multivariate analysis after R0 resection, additional resection of the portal vein was the only variable with a significant influence on patient survival [7,45]. However, microscopic invasion of the resected portal vein was found in only 12% of patients [7]. In another study, the microscopic invasion rate of the resected portal veins was 69% [6]. These authors did not find a survival benefit of portal vein resection.

Surgical complications. A prognostic relation between the amount of intraoperative blood loss (and consequently blood transfusions) and overall survival has been hypothesized. In patients resected for HCCA, two studies confirmed this hypothesis in multivariate analysis [23,33]. A study focusing on overall postoperative complications found a negative survival effect resulting from these complications, although this effect was not identified as an independent factor [9]. Pathologic prognostic factors (summarized in Table II) Pathologic staging systems. The 6th edition of the American Joint Committee on Cancer [19] (AJCC) and Union Internationale Contre le Cancer [18] (UICC) for adenocarcinoma of the extrahepatic biliary tract are TNM based. Compared to the 5th edition these systems now also focus on vascular invasion requiring vascular resection and reconstruction, as well as lymph node (LN) metastasis [20]. Obviously, stage groupings should represent strong independent prognostic factors, with a higher stage implying more advanced disease. Surprisingly, only five studies confirmed the TNM staging system as an independent prognostic factor [2,35,46
48]. In several studies, the staging system had no predictive

value for survival [3,8,21,32,33,49] and, in a few, only in univariate analysis [23,31,50].

Radicality. The incidence of a microscopically positive surgical resection margin in patients who have undergone a resection with curative intent can increase to 50%. The most consistent independent determinant for long-term survival after potentially curative resection of a biliary tumor is the surgical margin status of the resected bile duct [3,7
9,14,25,30
32,41, 45
49,51
57]. A study focusing particularly on radicality found a survival benefit for patients with residual carcinoma in situ in comparison to invasive carcinoma at the ductal resection margins [52].

Tumor invasion. Increased depth of tumor invasion is associated with the presence of lymphatic dissemination [13], vascular/perineural invasion, and is a known independent prognostic parameter [47,58,59].

Lymph nodes. The incidence of LN involvement in resected specimens has been reported to range from 30% to more than 50% [7,11,14,30,41,48,60
62]. In one study, already 55% of the T2 tumors had positive LN [62]. The presence of lymphatic dissemination is an important independent prognostic factor, as has been confirmed in many studies [6,8,10,12,14,21,25, 30
32,39,48,50,51,53,54,58,63].

Number of positive nodes (ratio). The chance of identifying involved LNs increases with the number of resected (pathologically identified) LNs and is influenced by the extent of dissection. A higher number of positive nodes indicates further progression of disease. Only two studies have reported a worse survival in patients with a higher number of positive LN metastases [41,58].

Table II. Pathological prognostic factors in extrahepatic CCA. Pathologic factor TNM staging systems Radicality Tumor invasion LN metastases No. of positive LN Location of positive LN Micrometastases in LN Extracapsular LN involvement Differentiation grade Vascular invasion Perineural invasion

Prognostic impact

Favouring survival benefit

References

Considerable Strong Considerable Strong Minor None Dubious None Strong Considerable Considerable

Early stage R0 resection Early stage Metastases absent (N0) Fewer positive nodes

[2,35,46
48] [3,7
9,14,25,30
32,41,45
49,51
57] [47,58,59] [6,8,10,12,14,21,25,30
32,39,48,50,51,53,54,58,63] [41,58]

Micrometastases absent

[65]

Good differentiation No invasion No invasion

[2,3,6
8,25,28,35,45,49,50,52,56] [12,49] [7,45,66]

Prognostic impact on clinical and surgical factors is scored as none (no evidence), dubious (conflicting evidence), minor (evidence from univariate analysis), considerable (evidence from uni- and multivariate analysis) and strong (evidence from several multivariate analyses). LN Lymph node.

Surgery for extrahepatic cholangiocarcinoma Location of positive LN. Although there is an individual preference of lymphatic spread of adenocarcinomas in the proximal, middle, and distal bile ducts [62], a pericholedochal node in the hepatoduodenal ligament is the most common site of metastasis [61]. Regional and para-aortic LNs are frequently involved in advanced CCA and extended lymphadenectomy has been suggested as providing a survival benefit in selected patients [13]. Survival was favorable in the presence of distant LN metastasis in selected patients [13,20,64]. Micrometastases in LN. In one study, LN micrometastases were detected in 24% of patients with pN0 disease, but this did not show any impact on survival [49]. In another study, LN micrometastasis in CCA had a negative effect on survival in univariate analysis [65]. Extracapsular LN involvement. So far, no reports have described the significance of extracapsular LN involvement in extrahepatic CCA. Differentiation grade. Microscopically, adenocarcinomas are graded as well differentiated, moderately differentiated, or poorly differentiated. Lack of differentiation increases the risk of lymphatic dissemination and therefore has a negative effect on survival. The grade of differentiation has been identified as an independent prognosticator in several studies [2,3, 6
8,25,28,35,45,49,50,52,56]. Vascular invasion. The impact of blood vessel invasion (microscopic venous invasion) has mainly been shown in univariate analysis [6,46,51,58,59]. Two studies reported vascular invasion as independent factor for worse survival [12,49]. Perineural invasion. Perineural invasion refers to growth of tumor along the nerve branches present within the biliary tract tissue. This mechanism of spread has shown prognostic significance in a few studies in univariate analysis [6,21] as well as in multivariate analysis [7,45,66]. Discussion Overall, the most important independent prognostic factors for long-term survival are negative surgical margins, LN status, and differentiation grade of the tumor. Therefore, all patients with a suspicious biliary obstruction should be considered for laparotomy and potential resection, as this provides the only chance for cure. Despite an aggressive surgical approach and advances in surgical techniques, the overall prognosis of patients undergoing potentially curative resection

193

for extrahepatic CCA is still poor, with high local failure rates and associated postoperative mortality. The adequacy of the current pTNM staging system has been questioned repeatedly, with several authors proposing a revision of the system [3,6,16,20,58]. Firstly of note, the current systems (the Bismuth
Corlette and the AJCC/UICC) are not satisfactory, because they fail to consider all of the relevant local, tumor-related variables that determine respectability, and they correlate poorly with survival. The Memorial Sloan
Kettering Cancer Center (MSKCC) devised a staging system for HCCA that encompasses a full radiological diagnosis and shows a correlation with increasing T stage and survival [3,67]. Secondly, in the current TNM staging system used for extrahepatic CCA, only a N0 and a N1 classification exist. Several studies propose including the number of positive LNs [41,58]. Thirdly, one study focusing on the differences between the 5th and 6th TNM staging systems concluded that cancer invasion of the portal bifurcation and regional LN metastasis should be weighed equally. The World Health Organization classification of extrahepatic CCA does not distinguish between distal and HCCA. According to the current literature, the prognostic significance of the location of an extrahepatic CCA is uncertain. Important independent factors predicting survival were the same for distal and proximal tumors. Therefore, there is a rationale for classifying all patients with extrahepatic tumors in one TNM staging system. However, the surgical procedure to obtain the most consistent independent prognosticator, i.e. a negative resection margin, is completely different between distal and HCCA. Several surgical prognostic factors were found to have an impact on patient survival specifically in patients with HCCA. One study showed a biological difference between distal and hilar tumors [28]. These findings favor a distinct staging system for distal and proximal CCA. Conclusions The simplicity of the TNM system, covering all extrahepatic CCA, is one of the reasons why it has continued to be applied. However, because biological diversity is high in patients with distal CCA or HCCA, many authors feel that additional factors can improve clinical staging. A challenge for the future is therefore to develop a new, dynamic staging system that includes the diverse variables which have been shown to impact on prognosis. Further improvement of staging systems and identification of prognostic factors is therefore crucial as means towards better selection of patients for appropriate surgical and adjuvant therapy and, hence, towards increasing the rate of curative resections.

194

J. J. Kloek et al.

References [1] Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology 2005;128:1655
67. [2] Su CH, Tsay SH, Wu CC, Shyr YM, King KL, Lee CH, et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg 1996;223:384
94. [3] Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507
17. [4] Gerhards MF, van Gulik TM, de Wit LT, Obertop H, Gouma DJ. Evaluation of morbidity and mortality after resection for hilar cholangiocarcinoma
a single center experience. Surgery 2000;127:395
404. [5] van Gulik TM, Gouma DJ. Changing perspectives in the assessment of resectability of hilar cholangiocarcinoma. Ann Surg Oncol 2007;14:1969
71. [6] Ebata T, Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 2003;238:720
7. [7] Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:808
18. [8] Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 1999;230:663
71. [9] Baton O, Azoulay D, Adam DV, Castaing D. Major hepatectomy for hilar cholangiocarcinoma type 3 and 4: prognostic factors and longterm outcomes. J Am Coll Surg 2007;204: 250
60. [10] Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ, et al. Improved survival in resected biliary malignancies. Surgery 2002;132:555
63. [11] Sakamoto Y, Kosuge T, Shimada K, Sano T, Ojima H, Yamamoto J, et al. Prognostic factors of surgical resection in middle and distal bile duct cancer: an analysis of 55 patients concerning the significance of ductal and radial margins. Surgery 2005;137:396
402. [12] Takao S, Shinchi H, Uchikura K, Kubo M, Aikou T. Liver metastases after curative resection in patients with distal bile duct cancer. Br J Surg 1999;86:327
31. [13] Kitagawa Y, Nagino M, Kamiya J, Uesaka K, Sano T, Yamamoto H, et al. Lymph node metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent regional and paraaortic node dissection. Ann Surg 2001; 233:385
92. [14] Miyazaki M, Ito H, Nakagawa K, Ambiru S, Shimizu H, Okaya T, et al. Parenchyma-preserving hepatectomy in the surgical treatment of hilar cholangiocarcinoma. J Am Coll Surg 1999;189:575
83. [15] Figueras J, Llado L, Valls C, Serrano T, Ramos E, Fabregat J, et al. Changing strategies in diagnosis and management of hilar cholangiocarcinoma. Liver Transpl 2000;6:786
94. [16] Lang H, Sotiropoulos GC, Fruhauf NR, Domland M, Paul A, Kind EM, et al. Extended hepatectomy for intrahepatic cholangiocellular carcinoma (ICC): when is it worthwhile? Single center experience with 27 resections in 50 patients over a 5-year period. Ann Surg 2005;241:134
43. [17] Okabayashi T, Yamamoto J, Kosuge T, Shimada K, Yamasaki S, Takayama T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374
83. [18] Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edn. New York: Wiley; 2002. [19] Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, et al. AJCC cancer staging manual, 6th edn. Berlin, Heidelberg, New York: Springer; 2002.

[20] Nishio H, Nagino M, Oda K, Ebata T, Arai T, Nimura Y. TNM classification for perihilar cholangiocarcinoma: comparison between 5th and 6th editions of the AJCC/UICC staging system. Langenbecks Arch Surg 2005;390:319
27. [21] Seyama Y, Kubota K, Sano K, Noie T, Takayama T, Kosuge T, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003;238:73
83. [22] Dinant S, Gerhards MF, Rauws EA, Busch OR, Gouma DJ, van Gulik TM. Improved outcome of resection of hilar cholangiocarcinoma (Klatskin tumor). Ann Surg Oncol 2006; 13:872
80. [23] Rea DJ, Munoz-Juarez M, Farnell MB, Donohue JH, Que FG, Crownhart B, et al. Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. Arch Surg 2004; 139:514
23. [24] Weber A, Landrock S, Schneider J, Stangl M, Neu B, Born P, et al. Long-term outcome and prognostic factors of patients with hilar cholangiocarcinoma. World J Gastroenterol 2007; 13:1422
6. [25] Todoroki T, Kawamoto T, Koike N, Takahashi H, Yoshida S, Kashiwagi H, et al. Radical resection of hilar bile duct carcinoma and predictors of survival. Br J Surg 2000;87: 306
13. [26] Chen MF, Jan YY, Hwang TL, Jeng LB, Yeh TS. Impact of concomitant hepatolithiasis on patients with peripheral cholangiocarcinoma. Dig Dis Sci 2000;45:312
16. [27] Alden ME, Waterman FM, Topham AK, Barbot DJ, Shapiro MJ, Mohiuddin M. Cholangiocarcinoma: clinical significance of tumor location along the extrahepatic bile duct. Radiology 1995;197:511
16. [28] Argani P, Shaukat A, Kaushal M, Wilentz RE, Su GH, Sohn TA, et al. Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts. Cancer 2001;91:1332
41. [29] Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 1975;140:170
8. [30] Kawasaki S, Imamura H, Kobayashi A, Noike T, Miwa S, Miyagawa S. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 2003;238:84
92. [31] Klempnauer J, Ridder GJ, Werner M, Weimann A, Pichlmayr R. What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer 1997;79:26
34. [32] Hasegawa S, Ikai I, Fujii H, Hatano E, Shimahara Y. Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications. World J Surg 2007;31:1256
63. [33] Liu CL, Fan ST, Lo CM, Tso WK, Lam CM, Wong J. Improved operative and survival outcomes of surgical treatment for hilar cholangiocarcinoma. Br J Surg 2006;93:1488
94. [34] Capussotti L, Muratore A, Polastri R, Ferrero A, Massucco P. Liver resection for hilar cholangiocarcinoma: in-hospital mortality and longterm survival. J Am Coll Surg 2002;195: 641
7. [35] Kondo S, Hirano S, Ambo Y, Tanaka E, Okushiba S, Morikawa T, et al. Forty consecutive resections of hilar cholangiocarcinoma with no postoperative mortality and no positive ductal margins: results of a prospective study. Ann Surg 2004;240:95
101. [36] Gerhards MF, van Gulik TM, Gonzalez GD, Rauws EA, Gouma DJ. Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma. World J Surg 2003;27:173
9. [37] Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995;221: 788
97.

Surgery for extrahepatic cholangiocarcinoma [38] Sagawa N, Kondo S, Morikawa T, Okushiba S, Katoh H. Effectiveness of radiation therapy after surgery for hilar cholangiocarcinoma. Surg Today 2005;35:548
52. [39] Hughes MA, Frassica DA, Yeo CJ, Riall TS, Lillemoe KD, Cameron JL, et al. Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys 2007;68:178
82. [40] Kelley ST, Bloomston M, Serafini F, Carey LC, Karl RC, Zervos E, et al. Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy. Am Surg 2004;70:743
8. [41] Yoshida T, Matsumoto T, Sasaki A, Morii Y, Aramaki M, Kitano S. Prognostic factors after pancreatoduodenectomy with extended lymphadenectomy for distal bile duct cancer. Arch Surg 2002;137:69
73. [42] Nimura Y, Kamiya J, Kondo S, Nagino M, Uesaka K, Oda K, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobil Pancreat Surg 2000;7:155
62. [43] Tsao JI, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg 2000;232:166
74. [44] Ogura Y, Kawarada Y. Surgical strategies for carcinoma of the hepatic duct confluence. Br J Surg 1998;85:20
4. [45] Neuhaus P, Jonas S, Settmacher U, Thelen A, Benckert C, Lopez-Hanninen E, et al. Surgical management of proximal bile duct cancer: extended right lobe resection increases resectability and radicality. Langenbecks Arch Surg 2003;388:194
200. [46] Pichlmayr R, Weimann A, Klempnauer J, Oldhafer KJ, Maschek H, Tusch G, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 1996;224:628
38. [47] Silva MA, Tekin K, Aytekin F, Bramhall SR, Buckels JA, Mirza DF. Surgery for hilar cholangiocarcinoma; a 10 year experience of a tertiary referral centre in the UK. Eur J Surg Oncol 2005;31:533
9. [48] Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, et al. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 1998;187:358
64. [49] Tojima Y, Nagino M, Ebata T, Uesaka K, Kamiya J, Nimura Y. Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with otherwise node-negative hilar cholangiocarcinoma. Ann Surg 2003; 237: 201
7. [50] Jang JY, Kim SW, Park DJ, Ahn YJ, Yoon YS, Choi MG, et al. Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. Ann Surg 2005;241:77
84. [51] Sasaki R, Takeda Y, Funato O, Nitta H, Kawamura H, Uesugi N, et al. Significance of ductal margin status in patients undergoing surgical resection for extrahepatic cholangiocarcinoma. World J Surg 2007. [52] Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of ductal resection margin status on long-term survival

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

195

in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 2005;103:1210
16. Kayahara M, Nagakawa T, Ohta T, Kitagawa H, Tajima H, Miwa K. Role of nodal involvement and the periductal softtissue margin in middle and distal bile duct cancer. Ann Surg 1999;229:76
83. Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF. Outcome of treatment for distal bile duct cancer. Br J Surg 1996;83:1712
15. Jan YY, Yeh CN, Yeh TS, Hwang TL, Chen MF. Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg 2005;29:894
8. Jarnagin WR, Bowne W, Klimstra DS, Ben-Porat L, Roggin K, Cymes K, et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg 2005;241:703
12. Blom D, Schwartz SI. Surgical treatment and outcomes in carcinoma of the extrahepatic bile ducts: the University of Rochester experience. Arch Surg 2001;136:209
15. Hong SM, Cho H, Lee OJ, Ro JY. The number of metastatic lymph nodes in extrahepatic bile duct carcinoma as a prognostic factor. Am J Surg Pathol 2005;29:1177
83. Hong SM, Kim MJ, Cho H, Pi DY, Jo D, Yu E, et al. Superficial vs deep pancreatic parenchymal invasion in the extrahepatic bile duct carcinomas: a significant prognostic factor. Mod Pathol 2005;18:969
75. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224:463
73. Yoshida T, Matsumoto T, Sasaki A, Morii Y, Shibata K, Ishio T, et al. Lymphatic spread differs according to tumor location in extrahepatic bile duct cancer. Hepatogastroenterology 2003;50:17
20. Kurosaki I, Tsukada K, Hatakeyama K, Muto T. The mode of lymphatic spread in carcinoma of the bile duct. Am J Surg 1996;172:239
43. Woo SM, Ryu JK, Lee SH, Yoo JW, Park JK, Kim YT, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 2007. Asakura H, Ohtsuka M, Ito H, Kimura F, Ambiru S, Shimizu H, et al. Long-term survival after extended surgical resection of intrahepatic cholangiocarcinoma with extensive lymph node metastasis. Hepatogastroenterology 2005;52:722
4. Taniguchi K, Tabata M, Iida T, Hori T, Yagi S, Uemoto S. Significance of lymph node micrometastasis in pN0 hilar bile duct carcinoma. Eur J Surg Oncol 2006;32:208
12. Tajima Y, Kuroki T, Fukuda K, Tsuneoka N, Furui J, Kanematsu T. An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg 2004;91:99
104. Chen RF, Li ZH, Zhou JJ, Wang J, Chen JS, Lin Q, et al. Preoperative evaluation with T-staging system for hilar cholangiocarcinoma. World J Gastroenterol 2007;13:5754
9.