Comparison of the Sixth and the Seventh Editions of the UICC Classification for Perihilar Cholangiocarcinoma

Benjamin Juntermanns 2 3 Georgios Charalambos Sotiropoulos 2 3 Sonia Radunz 2 3 Henning Reis 1 2 Matthias Heuer 2 3 Hideo Andreas Baba 1 2 Ali Canbay 0 2 Martin Schuler 2 4 Guido Gerken 0 2 Andreas Paul 2 3 Gernot Maximilian Kaiser 2 3 0 Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen , Essen, Germany 1 Department of Pathology and Neuropathology, West German Cancer Center University Hospital Essen, University Duisburg-Essen , Essen, Germany 2 First Received: 22 October 2011; Published Online: 18 July 2012 3 Department of General, Visceral and Transplantation Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen , Essen, Germany 4 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen , Essen, Germany - Background. The seventh edition of the TNM classification separates extrahepatic bile duct tumors into perihilar and distal tumors and further changes the definition of the TNM classification. The impact of the seventh edition on stage-based prognostic prediction for patients with perihilar cholangiocarcinoma was evaluated. Methods. Between January 1998 and March 2010, 223 consecutive patients with perihilar cholangiocarcinoma underwent surgery at the West German Cancer Center. Median survival times were calculated for the 195 evaluable patients (excluding those with in-hospital mortality) after separate classification by both sixth and seventh editions. Results. Median overall survival was increased in patients classified using the seventh compared with the sixth edition (UICC I: 56.5 vs 23.75 months; II: 45.9 vs 31.6 months; III: 21.3 vs. 8.76 months; IV: 7.03 vs 5.93 months). The T category of the seventh edition did not alter median survival times of T1 (54.07 months) and T4 (7.83 months) cases, but median survival was prolonged for T2 patients (29.4 vs 31.6 months), and shortened for T3 patients (19.43 vs 11.8 months) staged using the seventh edition. According to Cox proportional hazards regression analysis, patient The Author(s) 2012. This article is published with open access at Springerlink.com survival was better predicted by the seventh edition UICC stage and pT categories (p = 0.0014 and p = 0.0396, respectively), than the corresponding sixth edition categories (p = 0.4376 and p = 0.0926, respectively). Conclusions. The UICC seventh edition TNM classification for perihilar cholangiocarcinoma improves separation of patients with intermediate stage tumors compared with the sixth edition. The prognostic value of the UICC staging system has been strengthened by the introduction of the seventh edition. With only 24 new cases per 100,000 people per year, the hilar cholangiocarcinoma is an uncommon malignant tumor, but is the fourth most common gastrointestinal malignancy.1,2 Surgical treatment of hilar cholangiocarcinoma comprises extrahepatic bile duct resection, hepatic resection, vascular resection, and lymph node dissection. This strategy is associated with up to 19 % patient mortality and perioperative morbidity from 14 to 76 %.3 These higher morbidity and mortality rates are observed as a result of the necessity of more extensive hepatic resection combined with resection of the extrahepatic bile duct.4,5 Recent studies report 5-year survival following complete surgical resection of the perihilar cholangiocarcinoma combined with major hepatic resections in the range of 2540 %.3,6 In addition to resection, liver transplantation may also offer a curative treatment option for selected patients suffering from hilar cholangiocarcinoma.79 The UICC TNM classification aims to reflect the outcome of patients with perihilar cholangiocarcinoma.3,1012 The sixth edition was published in 2002 and primarily relied on the presence of lymph node metastasis and the extent of vascular invasion, the latter requiring vascular resection and reconstruction in this tumor entity.13 The seventh edition, published in 2009, further separates extrahepatic cholangiocarcinoma into two groups by either perihilar (proximal) or distal localization of the tumor.14 Interestingly, T3 stage of the sixth edition included tumors infiltrating neighboring organs, such as the gall bladder, pancreas, or the liver parenchyma. A tumor infiltrating the duodenum was classified as T4. In contrast, perihilar cholangiocarcinoma infiltrating neighboring organs such as the duodenum, but not the hepatic parenchyma, is not clearly defined by the seventh edition. Cases with regional lymph node metastases have also been reclassified in the seventh edition. In particular, tumors spreading into celiac and superior mesenteric lymph nodes, which were staged as N1 by the sixth edition, are classified as M1 by the seventh UICC edition. These changes result in the reclassification of former UICC Stage IIB tumors (sixth edition) as UICC stage IVB tumors (seventh edition) if lymph node metastases were not regional. A staging system that more exactly separates patients suffering from hilar cholangiocarcinoma into prognostic groups is desirable to support patient stratification for treatment in light of future multimodal perioperative therapeutic strategies. Clinical staging of perihilar cholangiocarcinoma prior to surgery is challenging since computed tomography (CT) or magnetic resonance imaging frequently fails to define the full extent of the tumor. Dual-modality PET/CT imaging has been shown to detect metastases of hilar cholangiocarcinoma in lymph nodes and other distant locations with high specificity.15 In addition, expression of biomarkers such as vascular endothelial growth factor A and metallothionein has been shown to correlate with survival of patients suffering from extrahepatic cholangiocarcinoma.16,17 In a recent report, patients homozygous for the C allele of the GNB3 825C[T single nucleotide polymorphism exhibited a significantly prolonged survival compared with patients heterozygous for this polymorphism or lacking the C allele.18 However, the prognostic value of these markers will have to be prospectively confirmed before they can be applied to patient selection for adjuvant therapy regimens. Against this background, we compared the sixth and seventh editions of the UICC TNM classification for perihilar cholangiocarcinoma in 223 patients consecutively treated at our center over a 12-year period. The aim of this study was to investigate whether classification of perihilar cholangiocarcinoma according to the seventh TNM edition provides better differentiation between tumor stages and more accurately predicts patient survival. PATIENTS AND METHODS Between January 1998 and March 2010, 247 patients with the suspected diagnosis of hilar cholangiocarcinoma were surgically treated at our center. Routine histopathological workup was conducted for all resected tumors by the Department of Pathology and Neuropathology of the University Hos (...truncated)