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Long-term Survival after resection for perihilar cholangiocarcinoma: Impact of UICC staging and surgical procedure.

INTRODUCTION

Perihilar cholangiocarcinoma is a rare disease with unfavorable prognosis. A complete margin-free resection of the tumor is the only curative treatment for this condition (1). Palliative combination chemotherapy with gemcitabine and cisplatin is the standard treatment for advanced perihilar cholangiocarcinoma if the tumor cannot be resected (2). Extrahepatic bile duct resection, hepatic resection, vascular resection, and lymph node dissection comprise the surgical procedures for resectable disease. These operations are associated with up to 19% patient mortality and a perioperative morbidity ranging from 14% to 76% (3). The 5-year-survival rates for patients undergoing surgical resection for perihilar cholangiocarcinoma range from 10% to 30% depending on resection margins (4). Further, the UICC classification aims to reflect the outcome of patients with perihilar cholangiocarcinoma. For the first time, the seventh edition published in 2009 separates extrahepatic cholangiocarcinoma into two groups of either perihilar (proximal) or distal localization, and thus allows a more specific pathological staging and prediction of survival for this tumor (5). Precise tumor staging, potential infiltration in adjacent structures, lymph node involvement, and the detection of metastases are important to decide if a curative tumor resection can be performed. Therefore, preoperative tumor staging might be improved by the use of dual modality positron emission tomographycomputed tomography (6).

The long-term survival of patients with this morbid disease is low and corresponding studies are scarce; the relevant prognostic factors remain uncertain. We and other authors have reported that caudate lobe resection in combination with extended liver resection is associated with prolonged disease-specific overall survival (7-11). Consistent with this observation, microscopic tumor infiltration of the caudate lobe can be found in many patients with perihilar cholangiocarcinoma (12). Currently, caudate lobe resection is highly recommended for tumors classified as Bismuth Type II and higher (13). A multivariate analysis identified R1 resection, lymph node metastases, T stage of three or higher, and perineural invasion as independent prognostic factors for poor overall survival (14). These histopathological findings and surgical approaches have been frequently discussed. Given this background, in the present follow-up study (9), we compared the histopathological parameters and surgical procedures between mid- and long-term surviving patients with perihilar cholangiocarcinoma who underwent surgery at the University Hospital of Essen, to identify potential prognostic factors and recommendations for surgery.

MATERIAL AND METHODS

Patients

This study was approved by the ethics committee of the medical faculty of the University Hospital of Essen, Germany. A total of 322 patients with perihilar cholangiocarcinoma were surgically treated at our center. Out of these patients, 76 had an overall survival of 2, 3, or >5 y. The remaining 246 were excluded from the study. A routine histopathological workup was conducted for all resected tumors or biopsies by the Institute of Pathology at the University Hospital of Essen. Of the 76 patients in the study population, 28 were females (36.8%) and 48 were males (63,2%) with a mean age of 59.0[+ or -]11.6 y. Patients were subdivided into the following three groups: group A, B and C corresponding to >2-3, >3-5, and >5 y of survival, respectively. The routine follow-up ended in 2017 to ensure that at least a 5-year-follow-up for every patient was possible. The histopathological characteristics according to the seventh UICC classification and surgical procedures between the groups were compared and correlated with patients' survival, respectively.

Statistical analysis

Data are displayed as mean[+ or -]standard deviation and percentage of total (%) unless stated otherwise. Categorical variables were analyzed using the [chi square] test and continuous variables using one-way ANOVA with the Bonferroni post-test. The overall survival was defined as the time from surgery to the tumor-specific death or date of last follow-up. Kaplan-Meier survival plots were generated and analyzed using the log-rank test. All parameters that revealed significance in the univariate Kaplan-Meier analysis were additionally analyzed using the multivariate cox proportional hazards regression survival analysis. A confidence interval of 95% was used and p value of <0.05 was considered statistically significant.

RESULTS

In the present study cohort of 76 patients with perihilar cholangiocarcinoma for >2 y, the >5-year-survival rate was 43.4% (>2-3 and >3-5-year-survival rate was 25.0% and 31.6%, respectively), with 14.5% of the patients surviving for >10 y after the surgery (Figure 1). After comparing the three survival groups, the following differences in histopathological features and surgical procedures were observed (Tables 1 and 2): in group A, patients significantly displayed more often a UICC stage IVb disease (i.e., non-regional lymph node positive tumors and/or distant metastasis; 26.3% vs. 8.3% and 3.0% for group B and C, respectively; p=0.0112), whereas UICC stage I (T1 tumors without positive lymph nodes or metastasis) was associated with group C (>5-year-survival; 15.2% vs. 0% in group A and B, p=0.0193; Table 1, Figure 2A). Group A was also associated with the highest rate of R2 resections (16.7%, p=0,0288) compared to groups B and C (4.5% and 0%, respectively; Table 1, Figure 2B). Perineural invasion had no significant impact on the overall survival. However, 29.0% patients surviving for >5 y displayed the lowest perineural infiltration prevalence (vs. 40% and 39.1% in group A and B, respectively; Table 1, Figure 2C). No significant differences were observed in tumor grading (G1-3) between the groups. Additional information is shown in Table 1.

Further, no significant differences in age or gender were observed among the three groups (Table 2). With regard to the Bismuth-Corlette classification, patients with stage IIIa surprisingly displayed a prolonged disease-specific overall survival (>5- vs. >3-5- vs. >2-3-year- survival rate, 30.3%, 8.3%, and 10.5%, respectively; p=0.0467; Table 2, Figure 2D).

Patients undergoing only exploratory laparotomy due to an unresectable disease displayed poor overall survival in this selected study cohort as expected (>2-3- vs. >3-5- vs. >5-year- survival rate, 36.8%, 12.5%, and 9.1%, respectively; p=0.0157; Table 2, Figure 2E). Regarding the different types of tumor resection (only bile duct resection or right/left hemihepatectomy; exploratory laparotomy due to unresectable disease excluded), no significant differences in survival were observed among the three groups. However, there was a tendency (p=0.1207) of right hemihepatectomy to be associated with prolonged survival (>5- vs. >3-5- vs. >2-3-year-survival rate, 39.4%, 20.8%, and 21.1%, respectively; Table 2). Interestingly, caudate lobectomy, which in some cases was independently performed of the above-listed surgical procedures, was frequently applied in groups B and C and associated with a very significant survival benefit (>5- vs. >3-5- vs. >2-3-year-survival rate, 48.5%, 25.0%, and 10.5%, respectively; p=0.0034; Table 2, Figure 2F).

Additionally, the Kaplan-Meier survival analyses revealed a significant association between the following clinicopathological parameters and improved overall survival rates (Figure 2A-F): UICC stages I-IVa [hazard ratio (HR), 0.3506; 95% confidence interval (CI), 0.0557-0.5659; p=0.0035; Figure 2A], R0 status (HR, 0.4908; 95% CI, 0.2058-0.8157; p=0.0111; Figure 2B), Bismuth-Corlette stage IIIb (HR, 0.5198; 95% CI, 0.3106-0.9899; p=0.0461; Figure 2D), tumor resection (HR, 0.3937; 95% CI, 0.1002-0.6059; p=0.0023; Figure 2E), and segment I resection (HR, 0.3612; 95% CI, 0.2375-0.6587; p=0.0004; Figure 2F). Kaplan-Meier survival analysis was also performed for perineural invasion, which did not show significant differences (HR of no perineural invasion, 0.8243; 95% CI, 0.4642-1.441; p=0.4862; Figure 2C).

Finally, in the present study cohort, multivariate cox proportional hazards regression survival analysis identified additional resection of liver segment I (i.e., caudate lobectomy) as the only independent prognostic parameter for prolonged overall survival (p=0.0013).

DISCUSSION

In the present follow-up study, we compared long- and mid-term survivors after surgery for patients with perihilar cholangiocarcinoma to identify the prognostic factors for prolonged disease-specific overall survival, including >5-year-survival. Our observations indicate that patients with metastatic perihilar cholangiocarcinoma and/or additional non-regional tumor cell positive lymph nodes (i.e., UICC IVb), R2 status, and (as expected) exploratory laparotomy only display dismal survival rates. Perineural tumor invasion did not differ significantly among the three survival groups, but the highest invasion rates were observed in the lower survival groups (groups A and B). Interestingly, Bismuth-Corlette stage IIIa and particularly caudate lobectomy were associated with improved overall survival. These findings are discussed in greater detail below.

Previous studies, similarly employing the seventh TNM classification, also demonstrated that patients with an UICC stage IVb disease have the poorest prognosis (5, 9, 15). Within the seventh UICC classification, tumor cell positive lymph nodes have been redefined regarding their tumor distance (i.e., non-regional lymph nodes in UICC stage IVb) emphasizing more on this prognostic parameter (15). Patients with such an advanced tumor stage unfortunately display overall survival rates <1 y despite systemic chemotherapy (2). The benefit of adjuvant chemotherapy following curative resection of hilar cholangiocellular carcinoma remains inconclusive. Studies are currently going on to evaluate the efficacy of gemcitabine, 5-FU, and cisplatin (13). There is a tendency of a potential benefit regarding radiotherapy or radiochemotherapy in patients with resection margin positive tumors or even with unresectable tumors (16-18).

Histopathological parameters, such as perineural invasion, could help identify patients that might benefit from adjuvant chemotherapies. As perineural invasion is frequently discussed as a prognostic marker for patient survival (14), we also assessed this parameter in the present study. The highest rates of perineural invasion (up to 40.0%) were observed in those groups with impaired survival. Conversely, <29.0% of the long-term survivors (>5 y) displayed perineural invasion. These findings are in line with a study of Tabata and coworkers who reported an association of perineural infiltration with higher T and UICC tumor stages, respectively (19). However, this parameter did not reach statistical significance in the present study, and thus should be investigated in larger patient cohorts.

Regarding the R status, R1/2 resections were associated with poor survival (Figure 2B). This finding is in line with previous studies reporting that a low R status is required to improve patient survival, particularly when radiotherapy has been used (13, 18). Histopathological grading in the present study had no impact on survival, which is in contrast to data from Vern-Gross and coworkers, who reported that moderately (G2) and poorly differentiated tumors (G3) negatively influence the patient outcome (20). However, in this study, 1491 patients were included within a 30-year-period, probably explaining the statistical difference in tumor grading. Interestingly, patients with Bismuth-Corlette stage IIIa also displayed improved survival rates in the present study. One explanation might be that complete tumor resection is more likely to be achieved with right hemihepatectomy. Consistently, patients who underwent this surgical procedure also displayed prolonged survival rates (although this parameter barely missed significance).

Regarding surgical procedures, the present data strongly suggest that caudate lobe resection is associated with improved long-term survival, which is in line with a pilot study of the present and previous reports (8-11). As previously mentioned, tumor infiltration into the caudate lobe is a common phenomenon in perihilar cholangiocarcinoma (12). Thus, it seems that caudate lobectomy should be performed whenever feasible to achieve long-term survival in patients suffering from this morbid disease.

In conclusion, patients with perihilar cholangiocarcinoma should undergo complete/extended tumor resection with additional caudate lobe resection (if possible) to achieve long-term survival. Perineural infiltration seems to have a negative impact on disease-specific overall survival. However, this prognostic parameter needs to be evaluated in larger study cohorts.

Ethics Committee Approval: This study was conducted in accordance with the Helsinki Declaration of 1975 and approved by the Ethics Committee of the University Hospital of Essen, Germany (License Number: 14-6101-BO).

Informed Consent: Written informed consent was obtained from the patients who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - B.J.; Design - G.M.K.; Supervision - A.P. and C.D.F.; Materials - H.R.; Data Collection and/or Processing - S.K., H.R. and S.G.; Analysis and/or Interpretation - G.M.K., C.D.F.; Literature Review - B.J.; Writing Manuscript - B.J., C.D.F.; Critical Review - G.M.K., A.C.

Acknowledgements: The superb secretarial assistance of J. Hunke is gratefully acknowledged.

Conflict of Interest: The authors have no conflicts of interest to declare.

Financial Disclosure: The authors declared that this study was supported by the grant IFORES (D/107-114400 to CDF).

REFERENCES

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(7.) Fingas CD, Katsounas A, Kahraman A, et al. Prognostic assessment of three single-nucleotide polymorphisms (GNB3 825C>T, BCL2-938C>A, MCL1-386C>G) in extrahepatic cholangiocarcinoma. Cancer Invest 2010; 28: 472-8. [CrossRef]

(8.) Gazzaniga GM, Filauro M, Bagarolo C, Mori L. Surgery for hilar cholangiocarcinoma: an Italian experience. J Hepatobiliary Pancreat Surg 2000; 7: 122-7. [CrossRef]

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(10.) Malago M, Frilling A, Li J, Lang H, Broelsch CE. Cholangiocellular carcinoma--the role of caudate lobe resection and mesohepatectomy. HPB (Oxford) 2008; 10: 179-82. [CrossRef]

(11.) Wahab MA, Fathy O, Sultan AM. Hilar cholangiocarcinoma fifteen-year experience with 243 patients at a single Egyptian center. Journal of Solid Tumors 2011; 3: 112-9.

(12.) Mizumoto R, Kawarada Y, Suzuki H. Surgical treatment of hilar carcinoma of the bile duct. Surg Gynecol Obstet 1986; 162: 153-8.

(13.) Serrablo A, Tejedor L. Outcome of surgical resection in Klatskin tumors. World J Gastrointest Oncol 2013; 5: 147-58. [CrossRef]

(14.) Nuzzo G, Giuliante F, Ardito F, et al. Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients. Arch Surg 2012; 147: 26-34. [CrossRef]

(15.) Sobin LH, Wittekind C. International union against cancer (UICC) TNM classification of malignant tumours. 7 New York: Wiley 2009.

(16.) Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012; 30: 1934-40. [CrossRef]

(17.) Kaiser GM, Paul A, Sgourakis G, et al. Novel prognostic scoring system after surgery for Klatskin tumor. Am Surg 2013; 79: 90-5.

(18.) Todoroki T, Kawamoto T, Koike N, et al. Radical resection of hilar bile duct carcinoma and predictors of survival. Br J Surg 2000; 87: 306-13. [CrossRef]

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(20.) Vern-Gross TZ, Shivnani AT, Chen K, et al. Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys 2011; 81: 189-98. [CrossRef]

Benjamin Juntermanns (1) [iD], Gernot Maximillian Kaiser (1,2) [iD], Henning Reis (3) [iD], Silvia Gries (1) [iD], Stefan Kasper (4) [iD], Andreas Paul (1) [iD], Ali Canbay (5) [iD], Christian Dominik Fingas (1) [iD]

(1) Department of General, Visceral and Transplantation Surgery, University Duisburg-Essen, University Hospital Essen, Essen, Germany

(2) Department of General and Visceral Surgery, St. Bernhard-Hospital Kamp-Lintfort, Kamp-Lintfort, Germany

(3) Institute of Pathology, 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

(5) Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Cite this article as: Juntermanns B, Kaiser GM, Reis H, et al. Long-term Survival after resection for perihilar cholangiocarcinoma: Impact of UICC staging and a surgical procedure. Turk J Gastroenterol 2019; 30(5): 454-60.

Corresponding Author: Gernot M. Kaiser; gernot.kaiser@st-bernhard-hospital.de

Received: May 3, 2018 Accepted: September 24, 2018 Available online date: February 14, 2019

DOI: 10.5152/tjg.2019.18275
Table 1. UICC tumor stages and histopathological differences among the
survival groups

                                      Group A
                         Overall (%)  (>2-3 year survival)
                         N=76 (100%)  N=19 (25.0%)

UICC 0 (Tis)              2 (2.6%)     1 (5.3%)
UICC I                    5 (6.6%)     0 (0%)
UICC II                  35 (46.1%)    6 (31.6%)
UICC IIIa                 9 (11.8%)    3 (15.8%)
UICC IIIb                14 (18.4%)    2 (10.5%)
UICC IVa                  3 (3.9%)     2 (10.5%)
UICC IVb                  8 (10.5%)    5 (26.3%)
G1                        6 (8.5%)     0 (0%)
G2                       54 (76.1%)   14 (87.5%)
G3                       11 (15.5%)    2 (12.5%)
R0                       44 (68.8%)    6 (50.0%)
R1                       16 (25.4%)    4 (33.3%)
R2                        3 (4.8%)     2 (16.7%)
Perineural (*) invasion  24 (34.8%)    6 (40.0%)

                         Group B               Group C
                         (>3-5 year survival)  (>5 year survival)
                         N=24 (31.6%)          N=33 (43.4%)

UICC 0 (Tis)              1 (4.2%)              0 (0%)
UICC I                    0 (0%)                5 (15.2%)
UICC II                  12 (50.0%)            17 (51.5%)
UICC IIIa                 2 (8.3%)              4 (12.1%)
UICC IIIb                 6 (25.0%)             6 (18.2%)
UICC IVa                  1 (4.2%)              0 (0%)
UICC IVb                  2 (8.3%)              1 (3.0%)
G1                        4 (16.7%)             2 (6.5%)
G2                       15 (62.5%)            25 (80.6%)
G3                        5 (20.8%)             4 (12.9%)
R0                       15 (68.2%)            23 (79.3%)
R1                        6 (27.3%)             6 (20.7%)
R2                        1 (4.5%)              0 (0%)
Perineural (*) invasion   9 (39.1%)             9 (29.0%)

                           p

UICC 0 (Tis)             0.2240
UICC I                   0.0193
UICC II                  0.1939
UICC IIIa                0.7721
UICC IIIb                0.6021
UICC IVa                 0.0622
UICC IVb                 0.0112
G1                       0.6369
G2                       0.7413
G3                       0.9915
R0                       0.0641
R1                       0.3776
R2                       0.0288
Perineural (*) invasion  0.4075

UICC: International Union Against Cancer; Tis: tumor in situ; N: nodus;
G: grading; R: residual tumor classification; %: percentage related to
groups

Table 2. Patient demographics, Bismuth-Corlette classification, and@2
surgical procedure

                                                Group A
                           Overall (%)          (>2-3 year survival)
                           N=76 (100%)          N=19 (25.0%)

Age, y                     59.03 [+ or -]11.63  58.68[+ or -]15.22
Female                     28 (36.8%)            5 (26.3%)
Male                       48 (63.2%)           14 (73.7%)
Bismuth I                   4 (5.3%)             1 (5.3%)
Bismuth II                  3 (3.9%)             0 (0%)
Bismuth IIIa               14 (18.4%)            2 (10.5%)
Bismuth IIIb               11 (14.5%)            3 (15.8%)
Bismuth IV                 44 (57.9%)           13 (68.4%)
Exploratory laparotomy     13 (17.1%)            7 (36.8%)
Bile duct resection alone  18 (23.7%)            5 (26.3%)
Right hemihepatectomy      22 (28.9%)            4 (21.1%)
Left hemihepatectomy       23 (30.3%)            3 (15.8%)
Caudate lobectomy          24 (31.6%)            2 (10.5%)

                           Group B               Group C
                           (>3-5 year survival)  (>5 year survival)
                           N=24 (31.6%)          N=33 (43.4%)

Age, y                     58.88[+ or -]10.08    59.33[+ or -]15.66
Female                      8 (33.3%)            15 (45.5%)
Male                       16 (66.7%)            18 (54.5%)
Bismuth I                   3 (12.5%)             0 (0%)
Bismuth II                  2 (8.3%)              1 (3.0%)
Bismuth IIIa                2 (8.3%)             10 (30.3%)
Bismuth IIIb                1 (4.2%)              7 (21.2%)
Bismuth IV                 16 (66.7%)            15 (45.5%)
Exploratory laparotomy      3 (12.5%)             3 (9.1%)
Bile duct resection alone   7 (29.2%)             6 (18.2%)
Right hemihepatectomy       5 (20.8%)            13 (39.4%)
Left hemihepatectomy        9 (37.5%)            11 (33.3%)
Caudate lobectomy           6 (25.0%)            16 (48.5%)

                             p

Age, y                     0.9790
Female                     0.1533
Male
Bismuth I                  0.2685
Bismuth II                 0.7438
Bismuth IIIa               0.0467
Bismuth IIIb               0.4249
Bismuth IV                 0.0786
Exploratory laparotomy     0.0157
Bile duct resection alone  0.4384
Right hemihepatectomy      0.1207
Left hemihepatectomy       0.2439
Caudate lobectomy          0.0034

%: percentage related to groups
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Title Annotation:ORIGINAL ARTICLE
Author:Juntermanns, Benjamin; Kaiser, Gernot Maximillian; Reis, Henning; Gries, Silvia; Kasper, Stefan; Pau
Publication:The Turkish Journal of Gastroenterology
Geographic Code:4EUGE
Date:Mar 1, 2019
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