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10.1245/s10434-006-9260-0
Annals of Surgical Oncology 14:1212-1219 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Distal Bile Duct Carcinoma: Prognostic Factors After Curative Surgery. A Series of 112 Cases

Qingbao Cheng, Xiangji Luo, Baihe Zhang, Xiaoqing Jiang, Bin Yi and Mengchao Wu

Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Road 225, Shanghai 200438, China

Correspondence: Address correspondence and reprint requests to: Baihe Zhang, E-mail: zhbh2005{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The identification of independent prognostic indicators in distal bile duct carcinomas (DBDCs) has been limited by the small number of tumors and a lack of molecular prognostic markers. Markers assessed in combination may perform better than those considered individually. We conducted this study to identify prognostic predictors of patients with DBDC with special focus on combination of expression of p53 protein and clinicopathological predictors.

Methods: Between December 1996 and 2002, 112 consecutive patients undergoing pancreaticoduodenectomy in the Eastern Hepatobiliary Surgery Hospital for distal bile duct carcinomas were identified in a prospectively collected database. The survival of patients was comparable with respect to patient characteristics, clinicopathological factors and degree of p53 protein expression followed by a univariate and multivariate analysis.

Results: Actual 1, 3, and 5-year survival rates were 85.7, 50.9, and 25.0%, respectively. By Cox proportional hazards survival analysis, the most powerful predictors of survival rate were p53 expression [relative risk (RR) 5.2, 95% CI 4.8–5.6], pancreatic invasion (RR 5.6, 95% CI 4.3–6.9), lymph nodes metastasis (RR 3.9, 95% CI 3.3–4.5), and operative time (RR 1.8, 95% CI 1.5–2.1).

Conclusions: Overexpression of p53 in DBDC is strongly associated with significantly reduced survival, independently of clinicopathological prognostic factors. The resection margin status provides little independent prognostic information. Longer operative time may have unfavorable effect on prognosis of patients with DBDC.

Key Words: Cholangiocarcinoma • Prognosis • p53 • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Distal bile duct carcinoma (DBDC) is rare, representing 5–14% of periampullary cancers1–6 and 13–23% of extrahepatic malignancies.7–10 DBDCs have one of the worst prognoses among various cancers; many patients succumb to their disease, with a resectability rate of 13–91% and a 5-year survival rate of 10–54%.1,11–18 Because of its rarity, reports about treatments for DBDC were sparse. Moreover, the literature regarding clinicopathological prognostic factors associated with DBDC is conflicting.15,19–22 The implications of these results are, however, subject to discussion as the series were either non-randomized, or included only a few patients, or reported cancer of the other periampullary carcinomas together.

Advances in our understanding of the molecular biology of DBDC have fuelled the search for novel molecular prognostic predictors; moreover, evidence is strong that p53-dependent pathways influence the cytotoxic effects of conventional chemotherapy and radiotherapy.23–26 Applied to clinical practice, these putative markers could be used to identify groups of patients with differing relative risks of recurrence and improve patient stratification for adjuvant treatment. In several tumor types, such as in breast, lung, colon, and gastric cancers, p53 mutations are associated with a poor prognosis.27–30 Herein, we conducted this study to identify prognostic predictors of DBDC, in order to determine the potential utility of combination of expression of p53 protein, a molecular marker, and clinicopathological markers in guiding treatment of patients with DBDC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients were treated at the Eastern Hepatobiliary Surgery Hospital for DBDC from December 1996 to 2002, and only those undergoing pancreaticoduodenectomy (PD) were considered suitable for our study. The rationale for not including patients who had undergone palliative surgery in this cohort was to acquire histological and immunohistochemical data to analyze. The Second Military Medical University (SMMU) institutional review board approved this study. Informed consent was obtained from each subject’s guardian. Data were collected from a prospective database, which included 1,532 patients with cholangiocarcinoma and started in 1996. These data included patient demographics, operative data, morbidity, mortality, follow-up, pathologic, and immunohistochemical data. Adenocarcinoma of bile duct origin was confirmed histopathologically in each patient. DBDCs were defined as malignant neoplasms arising from the distal portion of the bile duct, located between the superior border of the pancreas and the amplla. Pancreatic head, ampullary, and other adenocarcinomas were excluded from this study. Histological examination was performed emphasizing the following parameters: determination of epithelium of origin of the carcinoma, lymph node metastasis, differentiation grade, pancreatic invasion, duodenal invasion, microscopic lymphatic involvement, microscopic vascular involvement, microscopic perineural invasion, and resection margin involvement. Immunohistochemistry for p53 protein was performed using a standard avidin–biotin peroxidase method with p53 mAb clone DO-7 (1:20 dilution, Dako Ltd, Ely, UK). Pathologic and immunohistologic data were confirmed by the review of all slides by one pathologist, who was unaware of outcomes or clinical features. Resection was considered as curative in intent if all gross cancer was excised. The operation was classified according to the R classification.31 Lymph nodes were considered positive if any lymph node in the resected specimen contained adenocarcinoma.

Treatment Protocol
Preoperatively, diagnostic workup was performed. Patients were usually referred after at least partial radiographic evaluation had been completed. Preoperative imaging studies included abdominal contrast enhanced computed tomographic scan (CT), magnetic resonance cholangiopancreatography (MRCP), or endoscopic retrograde cholangiopancreatography (ERCP).

The bias at our institution was towards performing a standard PD with an attempt at regional lymph node dissection. The overall incidence of postoperative complications was evaluated. Any events prolonging or complicating patient recovery were classified as operative morbidity including hepatic failure, hemorrhage, biliary fistula, wound infection, intraabdominal abscess, cholangitis, pneumonia, etc. Operative mortality was defined as death within 90 days of surgery or during hospitalization of the index operation. Regular medical checks at 3-month intervals were made to detect recurrent tumors in the liver, lung, and para-aortic lymph nodes using computed tomography, ultrasonography, or magnetic resonance imaging. The determination of tumor markers was as an auxiliary examination.

Before operation no patient was given chemotherapy or radiotherapy, and perioperative adjuvant therapy was not performed. Postoperatively, patients with histologically positive metastatic lymph nodes were offered adjuvant radiotherapy or chemotherapy for postoperative treatment. All patients who had a satisfactory recovery from the operation by postoperative day 60 were encouraged to accept adjuvant therapy. External beam radiotherapy was given to patients choosing postresection radiotherapy.

Statistical Analyses
Follow-up was obtained through office records as well as direct patient contact. Follow-up was complete to death or to 31 May 2006. Survival was calculated from the date of resection until the date of death from this disease cause or censored at the latest follow-up. Comparisons of qualitative parameters were achieved by Student’s t test. Univariate analysis of possible prognostic factors related to patient demographics, preoperative laboratory values, tumor characteristics, degree of p53 protein expression, and adjuvant treatment was performed using Kaplan–Meier survival curves, the log-rank significance test for comparison of survival between groups. Significance was accepted at the 5% level. Potential predictors of survival were evaluated in multivariable Cox proportional hazards models. Beginning with a pool of statistically significant predictors identified in the univariate analyses, variables were selected using stepwise regression. All analyses were carried out using SAS Statistical Software version 8.2.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the Entire Cohort
In the 6-year period of this study, 131 patients with DBDC were admitted to our department. Of these patients, the tumor could be resected in 116 patients with a resectability rate of 88.5%. Excluding four patients who died postoperatively (hospital mortality 3.4%), altogether, 112 patients with complete follow-up were enrolled. The median age of this patient cohort was 55.5 years (range 27–74 years). Seventy-eight patients (69.6%) were male, for a male-to-female ratio of 2.3. Jaundice [100 patients (89.3%)] was the most common indicator, followed by itching [43 patients (38.4%)], epigastric or right subcostal pain [40 patients (35.7%)], and weight loss [37 patients (33.0%)]. Laboratory tests showed cholestatic jaundice with a mean bilirubin of 7.8 mg/dl (range 0.3–39.1 mg/dl). If the total serum bilirubin level was over 10 mg/dl, we considered that the patients were severely jaundiced. The American Joint Committee on Cancer (AJCC) Staging Manual (sixth edition) was used for tumor staging. Thirteen patients had stage I disease, 24 patients had stage II disease, 62 patients had stage III patients, and 13 patients had stage IV disease. All patients had a WHO performance below two. After treatment, patients were followed at intervals of 3 months the first 2 years and every 6 months thereafter.

Diagnostic and Therapeutic Procedures
All patients had cholangiographic findings consistent with malignancy. Ninety-five patients (84.8%) underwent computed tomography; six patients (6.3%) had their scan results interpreted as normal. MRCP was used in 31 patients (27.7%), and results were interpreted as negative for tumor in one patient (3.2%). Ultrasonography was used in all patients, and results were interpreted as normal in ten patients (8.9%). Preoperative biliary decompression was performed in 70 patients (62.5%), including endoscopic procedure in 69 patients, and percutaneous transhepatic procedure in 1 patient.

All patients in current study underwent PD by one of the nine hepatopancreatobiliary surgeons. Nine patients (8%) had extended lymphadenectomies of the paraortic, paracaval, and retropancreatic nodes. All patients had pancreatic reconstruction with a pancreaticojejunostomy. The mean ± SD operative time was 5.7 ± 1.1 h. The mean ± SD hemorrhage was 570 ± 243 ml, and 49 patients required intra-operative RBC transfusions, with a mean ± SD transfusion requirement of 412 ± 126 ml. Median ICU stay was 2 (range 0–7) days, median hospital stay was 14 (range 9–91) days. The difference of operative time between TNM stage I/II and III/IV tumors was not significant (P = 0.38). Patients with operative time more than 5 h received significantly more blood transfusions (P = 0.03), but the difference of estimated blood loss was not significant (P = 0.22).

The pathologic data could be obtained from Table 1Go. Because of the limited amount of tissue available for analysis, the number of molecular bio-markers studied for each patient varied. And data of Mdm-2, bcl-2, and p21 were incomplete for this cohort, so only degree of p53 expression was analyzed in the current study. Of 112 assessable tumors, 74 showed little or no expression of p53, whereas 38 showed overexpression, with dense p53 immunoreactivity in more than 30% of cells.


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  		TABLE 1. Prognostic factors for survival by univariate analysis
 
Complications and Death
Postoperative pancreatic fistula definition was according to an international study group definition. 32 Medical records and specific charts were continuously scrutinized for any complications. Postoperative morbidity occurred in 21 patients (18.8%). Five patients had multiple complications. Table 2Go shows the overall operative morbidity in detail. Three patients (2.7%) with intraabdominal bleeding required reoperation.


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  		TABLE 2. Complications for 112 patients analyzed
 
Adjuvant Therapy
Five patients chose radiotherapy and six patients chose chemotherapy. The mean dose administered with external beam radiotherapy was 50 ± 6 Gy. This dose was given in three fractions per day of 1 Gy each, and was continued 5 days per week for a total of 17 days. Acute complications attributable to the external beam irradiation and chemotherapy were nausea and vomiting. As adjuvant chemotherapy, fluorouracil (500 mg/days) was infused continuously and systemically for 14 days.

Survival and Prognostic Factors
Survival information was available for the entire cohort, with a mean follow-up of 27 ± 14 months and a median follow-up time of 31 months (ranged from 1 to 110 months) for all patients. Sixty-five patients had died of disease, 19 were alive with recurrence, and 28 were alive and cancer free. Recurrent malignancy developed in 84 patients at a median of 27 (range 5–71) months involving the liver in 50 and locoregional recurrence in 13. Globally, there were no major differences in quality of life in any groups. The median survival for this series was 35.5 months (range 1–100). Overall, 1, 3, and 5-year survival rates for our entire patient cohort were 85.7, 50.9, and 25.0%, respectively. The mean ± SD survival was 44.1 ± 2.7 months (Fig. 1Go).


Figure 1
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  		FIG. 1. Actuarial survival of all patients. Circle represents censored.

 
In univariate analysis, data for 17 variables were analyzed and 7 were found to have prognostic value. Table 1Go gives their degree of significance and the 1, 3, and 5-year survival rate in each sub-group. A strong inverse association between the level of expression of p53 and overall survival was observed (P < 0.01). Negative p53 expression increased median survival from 14 to 48.5 months (Fig. 2Go). Negative lymph node results increased median survival rate from 13 to 46 months. Longer operative time was associated with significant shorter survival (P < 0.01) (Fig. 3Go). If a negative microscopic margin was obtained after resection, survival was significantly prolonged (P = 0.01) in univariate analysis, but this did not retain independence on multivariate analysis. A stepwise regression model was used to further correlate significant univariate factors to survival. The detail results of multivariate analysis are presented in Table 3Go.


Figure 2
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  		FIG. 2. Actuarial survival of patients stratified by p53 expression. Circle represents censored.

 

Figure 3
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  		FIG. 3. Actuarial survival of patients stratified by operative time. Circle represents censored.

 

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  		TABLE 3. Prognostic factors for survival by Cox proportional hazards model
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
For the overall study, there were three main finding. Firstly, overexpression of p53 in DBDCs is strongly associated with a significant shorter survival time, independently of clinicopathological prognostic factors. Secondly, the resection margin status demonstrates little prognostic value. Finally, longer operative time may have unfavorable effect on prognosis. Additionally, this series confirmed the prognostic power of lymph node metastases and pancreatic invasion, as has been reported by others.

The use of molecular prognostic markers, which complement traditional clinicopathological markers, is not yet widespread in DBDC. Current practice for DBDC is to base therapeutic decisions and prognostic advice on clinicopathological data; however, within conventional groups many genetic and molecular tumor subtypes exist. p53 is known to play a central role in sensing and signaling for growth arrest and apoptosis in cell with DNA damage.33 To our knowledge few previous studies has investigated combining markers in such a large, representative cohort of patients with DBDC. Our results indicated that patient stratification by degree of expression of p53 protein provides clinicopathological markers-independent prognostic information. The rate of survival at 3 was 33.8% in the group of 74 patients whose tumors had low levels of expression of p53 and 7.9% in the group of 38 patients whose tumors had overexpression of p53 (P < 0.01). Similarly, Rijken et al.34 demonstrated patients in low p53 category survived significantly longer than those in high p53 category, and p53 expression was an independent prognostic marker for DBDC. In contrast, Ajiki et al.35 failed to confirm this finding; they found that overexpression of p53 was not predictive of a worse outcome for ampullary cancers. The implications of these results are, however, subject to discussion as the series were included only a few patients (<50 cases). Whatever the underlying biological mechanism, in this study we have found that the negative nuclear p53 expression in DBDC defines a population of patients with a good prognosis, indicating a clinically more indolent phenotype and a subset of patients for whom less aggressive adjuvant treatment is indicated.

In our study, 88.5% of patients were able to undergo attempted curative tumor resection, and 77.1% of them achieved R0 resection. The margin status was present demonstrated no independent impact on prognosis. This finding is similar to that of other series on resections for extrahepatic bile duct carcinoma, which found that only those variables that correlate to the inability to remove all macroscopic disease adversely affected survival.36,37 Pichlmayr et al.38 also found that incomplete resection imparted a survival advantage, albeit less than a complete resection, and could lead to survival times greater than 5 years. This observation may be related to the indolent growth pattern of these tumors.39

It is a long-held belief that prolonged surgery carries a higher than expected complication rate. Interestingly, our results suggested that longer operative time was associated with adverse prognosis. We adopted cut off points of 4, 5, and 6 h in univariate analysis for this cohort (data not shown for 4 and 6 h), and found that only 5 h as a cut off point reached statistical significance. No similar results were found in the literature. This is probably explained by a more immune depression that occurs with time as a result of trauma, blood loss, and shock. However, the adverse survival ascribed to operative time had multiple other risk factors, such as more complicated operation, extended lymphadenectomy, experience of surgeons, and blood transfusion. The association between operative time and survival rate must be validated in future.

The presence of lymph-node metastasis in DBDCs portends a poor long-term prognosis.1,12,19,40 Patients with negative lymph nodes in this series acquired 33 months longer median survival than patients with positive lymph nodes. Kayahara et al.41 have demonstrated significantly higher 5-year survival rates in patients without lymph node metastasis (P = 0.02). Fong et al.1 have demonstrated that the 5-year survival rate for radically resected, node-negative tumors was 54%. Yoshida et al.19 conducted a retrospective study and found that patients with up to two positive lymph nodes had a more favorable prognosis than that of other patients and recommended pancreaticoduodenectomy with extended lymphadenectomy and adjuvant chemotherapy for the treatment of patients with DBDC. However, extended lymphadenectomy did not have significant influence on survival in current cohort. This may be classified as the small number of patients and longer operative time resulted by extended lymphadenectomy. Similarly, Yeo et al.42 found that a survival benefit was not derived from the addition of extended lymphadenectomy. DBDC usually demonstrates a tendency of perineural infiltration.6 Perineural infiltration did not show statistical influence on survival, but pancreatic invasion was confirmed to have independent prognostic value in this series.

Liver metastasis remains problematic in current study. Recurrent cancer was identified in 75% of our patients; 59.5% were in the liver. Anatomically, the venous blood of the tumor is drained to the portal vein in DBDCs, which may be one of the reasons hepatic metastasis is frequent. Further, when lymph vessels are blocked by tumor, it might be easier for cancer cells to enter the portal blood flow.40 We were unable to find a statistically significant survival gain in patients who received adjuvant therapy. However, because the number of patients was small, this result might be without statistical meaning. Nevertheless, we believe that some subset of patients with overexpression of p53 or positive lymph nodes have a better chance of cure if adjuvant therapy is combined with surgical resection.43

In conclusion, the findings in this series of 112 DBDCs treated by PD showed that 4 factors were independently correlated with survival rate. Among these factors, degree of expression of p53 protein may provide additional criteria for assessing prognosis in DBDC. The resection margin status demonstrates little prognostic value. Additionally, longer operative time may have unfavorable effect on prognosis. As our knowledge regarding molecular biomarkers for DBDC increases, prognostic indices will be developed, that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. All these factors can also be evaluated postoperatively, to determine whether adjuvant therapy is indicated. To improve outcome in DBDC, large randomized controlled trials are warranted. Quality of life and cost-benefit aspects should also be incorporated as an objective of these studies.


   ACKNOWLEDGMENTS
 
The authors thank Hongzhi Li and Lichen Sun for their invaluable help with the referring of medical records. We also gratefully acknowledge the excellent assistance of Jian Lu for help with the statistical works.


   FOOTNOTES
 
Qingbao Cheng and Xiangji Luo contributed equally to this work.

Received for publication August 20, 2006. Accepted for publication October 4, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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