Prognostic factors for survival of patients with ampullary carcinoma after local resection. Abstract

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1 UPPER GI ANZJSurg.com Prognostic factors for survival of patients with ampullary carcinoma after local resection Xiangqian Zhao, Jiahong Dong, Xiaoqiang Huang, Wenzhi Zhang and Kai Jiang Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China Key words ampullary cancer, local resection, pathology, prognosis. Correspondence Professor Jiahong Dong, Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Beijing , China. X. Zhao MD; J. Dong MD, PhD; X. Huang MD; W. Zhang MD; K. Jiang MD. Accepted for publication 3 March doi: /ans Abstract Background: Local resection (LR) is a potentially effective alternative to pancreaticoduodenectomy for treatment of ampullary cancer, but the prognostic factors remain undefined. The purpose of this study was to identify the prognostic factors for ampullary cancer patients who had undergone LR. Methods: We retrospectively reviewed the clinical, pathological data and surgical approach of 34 ampullary cancer patients who had undergone LR during at People s Liberation Army General Hospital. Prognostic factors for survival and recurrence were analysed. Results: The 1-, 3- and 5-year survival rates of the patients were 97.1, 69.5 and 53.7%, respectively. The gender, age, preoperative bilirubin levels, CA19-9 levels and preoperative biopsy did not correlate with the survival rates. The survival rates of patient with T1 and T2 tumours were superior to that of patients with T3 tumours (P = 0.000). Tumour size, surgical margin status and the extent of differentiation had no effect on survival rates (P = 0.464, P = and P = 0.121, respectively). The survival rate of patients who had extraduodenal LR (12 cases) was superior to that of patients who had transduodenal LR (22 cases) (P = 0.026). Tumour recurrence occurred in 14 (41.2%) patients. Tumour infiltration (P = 0.014) correlated with the recurrence. Conclusion: The degree of tumour infiltration is the pathological factor that most affects the survival of ampullary cancer patients who undergo LR. Extraduodenal LR is a promising surgical procedure, the efficacy of which is superior to that of transduodenal LR. The depth of tumour invasion correlated with the recurrence. Introduction Ampullary cancer is a rare cancer located in the duodenal papilla, the mucosa around the papilla, the mucosa within the ampulla, the pancreatic duct opening, or the mucosa between the common bile duct and the duodenal wall. Ampullary cancer has a better prognosis than pancreatic cancer or cholangiocarcinoma, 1 and surgical resection is associated with a satisfactory prognosis. The current surgical treatments for ampullary cancer are radical pancreatoduodenectomy (PD) and local resection (LR). Although PD is still the preferred surgical procedure, it has a high rate of surgical trauma, postoperative mortality and complications; 2 LR has a lower rate of these outcomes. Nikfarjam et al. 3 reported that the complication rate of PD was as high as 71%, whereas the complication rate of LR was 20%. Feng et al. 4 reported a complication rate of 34.8% and a mortality rate of 6.5% with PD compared with corresponding rates of 6.5 and 0% with LR. Transduodenal LR is the conventional surgical approach for ampullary cancer. Its main drawback is that the resection field is too small to permit complete resection of tumours at the distal end of the common bile duct, and extended resection is greatly limited. However, the extraduodenal LR that we recently reported can expose the entire common bile duct, permit estimation of the resection length of the common bile duct according to the site of tumours and offer a better chance for complete removal of the tumours. 5 In addition, the extraduodenal approach permits excision of lymph nodes behind the pancreas and duodenum concurrently, if necessary. However, predictive factors for survival of ampullary cancer patients after operation vary in different reports. These factors include preoperative jaundice status, 6 surgical margin status, 7 the presence or absence of lymph node metastases, 7 9 tumour size, 10 blood vessel invasion, 9 nerve invasion, 8 tumour differentiation 8 and the degree of tumour infiltration. 7,9 11 Additionally, the report about prognostic factors for LR is few. In view of this, we retrospectively ANZ J Surg 85 (2015) This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 568 Zhao et al. analysed the clinical, pathological data and surgical approach of ampullary cancer patients who had undergone LR at the Chinese People s Liberation Army General Hospital from February 1996 to February We assessed the efficacy of LR and explored the prognostic factors for long-term survival and recurrence after the operation. Methods Patients Between 1996 and 2009, LR was performed on 35 ampullary carcinoma patients at our hospital. Inclusion criteria All patients reviewed had histologically confirmed duodenal papilla or ampullary adenocarcinoma. Exclusion criteria Patients who had duodenal cancer, distal cholangiocarcinoma, pancreatic cancer, involvement of these cancers in the ampulla or duodenal papilla, and tumours of ambiguous origin. Surgical indications and contraindications LR was considered for patients who met one of the following conditions: (i) preoperative diagnosis of benign tumour or malignant transformation of benign tumour; negative biopsy of the base after local tumour resection; (ii) tumour diameter 3 cm; no infiltration outside the papilla of Vater; biopsy of the base after local tumour resection was negative; (iii) well-differentiated cancer; histological confirmation intraoperatively; negative biopsy of the base after local tumour resection; (iv) the patient was old or had poor general condition or other associated diseases that prevented PD but likely could tolerate LR; (v) patients who refused PD but his or her physical condition allowed LR. Patients with any of the following conditions were not considered suitable for LR: (i) poor general condition, high risk of operative complications, unable to tolerate laparotomy; (ii) the presence of metastases to parenchymal organs or lymph nodes; (iii) duodenal obstruction; (iv) ulcerated bleeding tumour; (v) tumour invasion into the pancreas; (vi) positive basilar biopsy after LR; (vii) tumour recurrence after LR. Surgery Before 2000, LR was performed via the transduodenal approach; after 2000, the patients were randomized to be operated via either the transduodenal or the extraduodenal approach. The transduodenal LR method has been described. 12 For extraduodenal LR, a Kocher manoeuvre was performed to mobilize the duodenum. The head of the pancreas was turned over, the postero-superior pancreaticoduodenal artery was cut off, the second part of the duodenum was turned to the medial side, and the attachments of the pancreas and duodenum were freed. A probe was placed into the common bile duct via the cystic duct opening or the common bile duct opening in order to identify the distal end of the common bile duct. The common bile duct was opened 2.5 cm prior to the site entering the duodenum to find the tumour. A further circumferential incision along the duodenal papilla was made to locate the main pancreatic duct at the connection between the duodenum and pancreas. The pancreatic duct was severed, the lower part of the common bile duct and the papilla were excised. The pancreatic and common bile ducts were anastomosed to the duodenum. 5 Pathology and follow-up The general data (including surgical approach, gender, age, preoperative bilirubin levels, CA19-9 levels and preoperative biopsy) of all 35 patients were reviewed. The gross specimens, the original pathology reports and the specimens were examined by two experienced pathologists who were blind to any prior knowledge regarding the clinical data. The histological type, diameter, degree of differentiation, depth of invasion, lymph node metastases, vascular invasion and surgical margin of the tumours were evaluated and recorded. Follow-up results were obtained for 34 of the 35 patients who had undergone LR, with a 97.1% follow-up rate. One patient was lost to follow-up. Follow-up visits were performed once every 3 months during the first year, re-examined once every 6 months during the second and third years, and re-examined once a year later. Items checked during the follow-up visits included routine laboratory tests, tumour markers, chest roentgenogram, abdominal ultrasound and computed tomography/magnetic resonance imaging. The follow-up deadline was 1 March 2011, and the follow-up duration ranged from 10 to 152 months, with a median duration of 36 months. Statistical analysis All data were presented as figures and percentages and analysed by non-parametric tests, using SPSS 16.0 statistical software (SPSS, Inc., Chicago, IL, USA). Survival of ampullary carcinoma patients was calculated using the Kaplan Meier method, log-rank test and Cox regression analysis. Logistic regression analysis was also performed to evaluate the prognostic parameters for recurrence. A value of P < 0.05 was considered statistically significant. Results Patient characteristics Patients clinical data are presented in Table 1. Of the 34 patients, 16 were men and 18 women, aged years. There were 22 CA19-9-negative patients and 12 CA19-9 positive. Preoperative jaundice was present in 22 patients. Twenty-two patients were operated via the transduodenal approach and 12 via the extraduodenal approach. Duodenoscopic biopsy of the papilla of Vater was performed before surgery in 22 patients. After LR, one patient received chemotherapy, another one received radiotherapy and the others received neither radiotherapy nor chemotherapy. There were 14 cases of recurrent cancer during the follow-up period, including local recurrence in nine patients, liver metastases in four and abdominal wall metastases in one. Post-operative complications occurred in six patients: four cases of pancreatic leakage, one case of gastrointestinal bleeding and one case of wound dehiscence.

3 Prognostic factors for survival 569 Table 1 Clinical and pathologic characteristics Age (years) Median (range) 62 (30 75) Gender (Male : Female) 16:18 (47.1%:52.9%) CA19-9 (U/L) Median (range) 34.3 (7 3160) Positive : Negative 12:22 TB (μmol/l) Median (range) 47.2 (9 757) Positive : Negative 22:12 Approach Transduodenal 22 Extraduodenal 12 Duodenoscopic biopsy Yes 22 No 12 Diameter (cm) Median (range) 2 ( ) 2 19 >2 15 Differentiation High 21 (61.8%) Moderate 9 (26.5%) Low 4 (11.8%) Infiltration T1 12 (35.3%) T2 17 (50.0%) T3 5 (14.7%) Margins Positive 3 (8.9%) Negative 31 (91.1%) Recurrence Yes 14 (41.2%) No 20 (58.8%) Results of pathology examinations Table 1 illustrates features of the 34 resected tumours. The tumour diameters ranged from 0.8 to 3.5 cm (median, 2.0 cm). There were 12 cases of T1, 17 cases of T2 and five cases of T3 stage tumours; T1 and T2 cases accounted for 85.3% of all cases. Twenty-one tumours (61.8%) were well differentiated, nine were moderately differentiated and four were poorly differentiated. Three resected cancers had positive surgical margins. Local lymph node dissection was performed in five patients who underwent extraduodenal LR; metastasis was found in one case. There was no adjacent vascular involvement case. Survival and recurrence analysis The impact of clinicopathological factors on patients survival rates are shown in Table 2. Seventeen patients died during the follow-up period. The 1-, 3-, and 5-year survival rates were 97.1, 69.5 and 53.7%, respectively. Survival rates did not differ among different gender or age groups (P = and P = 0.935, respectively). Survival rates were not statistically different between CA19-9- negative and CA19-9-positive patients, or between patients with different levels of CA19-9 (P = and P = 0.566, respectively). The survival rates of patients with or without preoperative jaundice, or of patients with different bilirubin levels, also were not significantly different (P = and P = 0.516, respectively). Preoperative biopsy had no impact on survival rates (P = 0.659). Most notably, extraduodenal LR led to a better survival rate than did the transduodenal LR approach (P = 0.026) (Table 2 and Fig. 1). Tumour size, surgical margin status and the extent of differentiation had no effect on survival rates (P = 0.464, P = and P = 0.121, respectively), but the depth of tumour invasion correlated with survival (P = 0.000) (Table 2 and Fig. 2). Because only five patients underwent regional lymph node dissection, we did not perform survival analysis regarding lymph nodes and tumour stages. Further analysis indicated that there was no significant difference between T1 and T2 groups (P = 0.169), but the survival rates of T1 and T2 groups were significantly superior to those of T3 group (P = and P = 0.000). Tumour recurrence occurred in 14 (41.2%) patients. Logistic regression analysis showed that tumour infiltration (P = 0.014) correlated with recurrence (Table 3). No significant differences were found between T1 and T2 patients in recurrence (P = 0.096). The recurrence was significantly higher in the T3 group than the T1 group (P = 0.016). Discussion Ampullary tumour is a relatively rare gastrointestinal tumour that appears in the duodenal papilla, the mucosa around papilla, and at the biliary and pancreatic duct openings. Tumours in this location early block the common bile duct and cause jaundice, which is easily detected. Most ampullary tumours are relatively small when they become symptomatic, so LR is an advisable choice for their treatment. Although LR has played an important role in ampullary cancer treatment, prognostic factors for LR are still not clearly defined. In this retrospective analysis of 34 ampullary cancer patients treated with LR, we found that the degree of tumour infiltration was the pathological factor that most affected post-operative survival. In addition, extraduodenal LR was superior to the conventional transduodenal LR approach. It has been reported that the 5-year survival rates of ampullary cancer patients who underwent PD were % 4,6,13,14 and the 5-year survival rates of LR patients were %; 4,15,16 the results suggested comparable efficacy of LR and PD. Consistent with these reports, the 5-year survival rate of our ampullary carcinoma patients who underwent LR was 53.7%. Therefore, LR is still a choice of ampullary carcinoma treatment if a patient s condition is suitable for the operation. The commonly used transduodenal LR 12 procedure for ampullary carcinoma suffers from the drawback that exposure of the common bile duct is difficult to attain and the resection range is restricted. Thus, if the tumour has infiltrated along the mucosa of bile duct and the pancreatic duct, complete resection of the tumour is difficult to achieve, and if the scope of the resection is extended, re-anastomosis of the ducts is also difficult. In 2000, Huang et al. reported the resection of ampullary tumours via an extraduodenal approach. 17 This approach permits exposure of the entire common bile duct, determination of resection length of the common bile duct according to the site of tumours, and resection of pancreaticoduodenal lymph nodes if necessary. Thus, this procedure can result in a nearly complete excision of the cancer. Our results indicate that among patients with similar clinical features, the survival rates of those who had received extraduodenal LR were superior to the rates of those who had received conventional LR. Surgical approach, therefore, is an important determinant of survival. Although extraduodenal LR can be performed in patients who are suitable for LR, this procedure is relatively complex and demanding even for experienced surgeons. It has been reported that TNM, pt, pn stage, tumour size and resection margin status affect patient survival. 4 In contrast, our data showed that the survival rates of patients were independent of the

4 570 Zhao et al. Table 2 Impact of clinicopathological factors on survival rates Outcome Cases 3-year survival 5-year survival P-value Gender Male (59.2%) 8 (40.6%) Female (77.8%) 12 (64.2%) Age (years) (66.2%) 10 (51.5%) > (73.1%) 10 (54.8%) CA19-9 (U/L) Positive 12 9 (72.9%) 6 (33.3%) Negative (67.9%) 14 (62.2%) (63.5%) 15 (58.6%) > (88.9%) 5 (37.0%) TB (μmol/l) Positive (61.7%) 11 (43.6%) Negative (83.3%) 9 (71.4%) (72.3%) 16 (56.3%) > (57.1%) 4 (42.9%) Approach Transduodenal (62.9%) 6 (38.1%) Extraduodenal 12 9 (82.5%) 6 (82.5%) Duodenoscopic biopsy Yes (76.3%) 14 (57.6%) No 12 8 (50%) 6 (37.5%) Diameter (cm) (57.9%) 11 (57.9%) > (84.8%) 9 (43.1%) Differentiation High (75.9%) 13 (57.8%) Moderate 9 6 (66.7%) 5 (55.6%) Low 4 1 (0%) 1 (0%) Infiltration T (90.0%) 9 (67.5%) T (76.5%) 11 (60.8%) T3 5 0 (0%) 0 (0%) Margins Positive 3 2 (50.0%) 2 (50.0%) Negative (66.7%) 18 (53.9%) Wilcoxon rank sum test and chi-square/fisher s exact test were used for data analysis. Fig. 1. The survival curves of extraduodenal and transduodenal groups. Fig. 2. Survival curves of patients with different degree of tumour infiltration. patients gender, age, preoperative bilirubin levels, CA19-9 levels and preoperative biopsy. We also found that tumour size, differentiation and surgical margin status had no relationship to survival rates, a result that differs from results previously reported. 7,8,10 Consistent with previous studies, 7,9 11 though, we found that the degree of tumour invasion and survival were closely correlated. Moreover, also consistent with previous reports, 4,10 we found that the 5-year survival rates of T1, T2 and T3 stage patients were 67.5, 60.8 and 0%, respectively, and there was no significant difference in survival rates between T1 and T2 patients. These findings indicate that the prognosis of ampullary cancer will be poor if the cancer has invaded into the pancreas. There are few studies in the literature that have focused on the recurrence of ampulla cancer after surgical resection. Lindell et al. 18 showed that 22% of patients after PD and 80% of patients after LR developed a recurrence. Feng et al. 4 reported that recurrence was diagnosed in 23.3% of patients after PD and 48.0% of patients after LR. The risk factors of recurrence include TNM stage, pt stage and

5 Prognostic factors for survival 571 Table 3 Clinical features and tumour histopathological characteristics of recurrent group and disease-free group patients Outcome Recurrent group Disease-free group P-value Age (years) median (range) 63 (30 75) 60 (36 73) Gender (male : female) 7:7 9: CA19-9 (U/L) median (range) 35.8 ( ) 28.5 (7 1750) TB (mol/l) median (range) 45.2 (10 757) 47.2 (9 218) Preoperative biopsy Yes No 6 6 Diameter (cm) median (range) 2 ( ) 2.0 ( ) (57.1%) 11 (55%) >2 6 (42.9%) 9 (45%) Differentiation Well 10 (71.4%) 11 (55%) Moderately 4 (28.6%) 5 (25%) Poorly 0 (0%) 4 (20%) Infiltration T1 2 (14.3%) 10 (50%) T2 8 (57.1%) 9 (45%) T3 4 (28.6%) 1 (5%) Margins Positive 1 (7.1%) 2 (10%) Negative 13 (92.9%) 18 (90%) pn stage; 4 tumour differentiation; 6 and lymph node ratio, lymphovascular. 19 In our study, tumour recurrence occurred in 14 (41.2%) patients. Logistic regression analysis showed that tumour infiltration (P = 0.014) was correlated with recurrence. No significant differences were found between T1 and T2 patients in recurrence (P = 0.096). The recurrence was significantly higher in the T3 group than the T1 group (P = 0.016). These findings indicated that pancreatic invasion increased risk of recurrence for ampulla cancer after LR. Because only five patients underwent local lymph node dissection, metastasis was found in one case. Therefore, we did not perform survival analysis in accordance with lymph nodes or metastasis staging. Because ampullary cancer is usually found at early stage, the tumours rarely affect the portal vein or superior mesenteric vein. In this study, no vascular invasion was observed in any patient, so we did not take blood vessel invasion into account for analysis of survival. In summary, we found that the degree of tumour infiltration is a pathological factor that affects the post-operative outcome of ampullary cancer patients who have undergone LR. Also, extraduodenal LR is associated with a higher survival rate than that associated with conventional LR. The depth of tumour invasion correlated with the recurrence of ampulla cancer after LR. However, because our study is a single-centre retrospective study, our conclusions need to be validated by additional, preferably prospective, studies. References 1. Hatzaras I, George N, Muscarella P, Melvin WS, Ellison EC, Bloomston M. Predictors of survival in periampullary cancers following pancreaticoduodenectomy. Ann. Surg. Oncol. 2010; 17: Balachandran P, Sikora SS, Kapoor S et al. Long-term survival and recurrence patterns in ampullary cancer. Pancreas 2006; 32: Nikfarjam M, Muralidharan V, McLean C, Christophi C. Local resection of ampullary adenocarcinomas of the duodenum. ANZ J. Surg. 2001; 71: Feng J, Zhou X, Mao W. Prognostic analysis of carcinoma of the ampulla of Vater: pancreaticoduodenectomy versus local resection. Hippokratia. 2012; 16: Zhao XQ, Huang XQ, Zhang WZ, Liu Z. Comparison between two types of local resection in the treatment of ampullary cancer. ANZ J. Surg. 2014; 84: Choi SB, Kim WB, Song TJ, Suh SO, Kim YC, Choi SY. Surgical outcomes and prognostic factors for ampulla of Vater cancer. Scand. J. Surg. 2011; 100: Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability. Virchows Arch. 2007; 451: Lee JH, Lee KG, Ha TK et al. Pattern analysis of lymph node metastasis and the prognostic importance of number of metastatic nodes in ampullary adenocarcinoma. Am. Surg. 2011; 77: Sakata E, Shirai Y, Yokoyama N, Wakai T, Sakata J, Hatakeyama K. Clinical significance of lymph node micrometastasis in ampullary carcinoma. World J. Surg. 2006; 30: Yoon YS, Kim SW, Park SJ et al. Clinicopathologic analysis of early ampullary cancers with a focus on the feasibility of ampullectomy. Ann. 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Improvement in the local resection of benign tumors in the distal bile duct. Chin. J. Surg. 2000; 38: 328 (in Chinese). 18. Lindell G, Borch K, Tingstedt B et al. Management of cancer of the ampulla of Vater: does local resection play a role? Dig. Surg. 2003; 20: Roland CL, Katz MH, Gonzalez GM, Enell EL, Ihse I. A high positive lymph node ratio is associated with distant recurrence after surgical resection of ampullary carcinoma. J. Gastrointest. Surg. 2012; 16: