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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2003.07.512 on November 17, 2003

Annals of Surgical Oncology 10:1176-1183 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Patterns and Predictors of Failure after Curative Resections of Carcinoma of the Ampulla of Vater

Takeshi Todoroki, MD, PhD, Naoto Koike, MD, PhD, Yukio Morishita, MD, PhD, Toru Kawamoto, MD, PhD, Nobuhiro Ohkohchi, MD, PhD, Junichi Shoda, MD, PhD, Yoshiharu Fukuda, MD and Hideto Takahashi, PhD

From the Departments of Surgery (TT, NK, TK, NO), Pathology (YM), and Internal Medicine (JS), Institute of Clinical Medicine, and Department of Epidemiology and Biostatistics (HT), Institute of Community of Medicine, University of Tsukuba, Tsukuba-Shi; and Department of Surgery (YF), Hitachi Mito General Hospital, Hitachi, Japan.

Correspondence: Address correspondence and reprint requests to: Takeshi Todoroki, MD, PhD, Associate Professor, Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-Shi, 305–8575 Japan; Fax: 81-29-853-3042; E-mail: todorov{at}md.tsukuba.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Curative resection does not always equate with long-term survival. The aim was to identify patterns and predictors of failure and independent factors of prognosis after curative resection.

Methods: Sixty-six patients with ampullary carcinoma who underwent surgical intervention were reviewed. Fifty-nine patients underwent pancreaticoduodenectomy. Cox regression analysis, log-rank test, Fisher exact test, or {chi}2 test was used.

Results: No patient died as a result of surgery; major complications occurred in three, and the 5-year survival rate after curative resection (n = 55) was 52.6%. Significant survival predictors were preoperative serum carcinoembryonic antigen level; gross tumor appearance; tumor, node, and tumor node metastasis stage; and microscopic lymphatic vessel and venous invasion in the primary tumor. Multivariate analysis demonstrated that lymphatic vessel invasion, tumor, and tumor node metastasis stage were significant independent prognostic factors. No patient experienced locoregional failure alone; all 24 relapsed patients had distant failure, and six of them had both. The liver was the most frequent metastatic organ, followed by nodes, peritoneum, lung, and bone. The carcinoembryonic antigen and carbohydrate antigen levels and lymphatic vessel and venous invasion were significant predictors of distant failure, and the mean time to relapse was 13 (range, 0.7–33) months.

Conclusions: Curative resection is associated with significant survival; however, effective systemic adjuvant therapy is needed to prevent distant failure for patients with elevated carcinoembryonic antigen and carbohydrate antigen levels or positive lymphatic vessel or venous invasion. A 3-year follow-up period would be necessary to document relapses.

Key Words: Ampullary carcinoma • Carcinoma of the papilla of Vater • Curative resection • Patterns of failure • Predictors of metastasis • Prognostic factors


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent advances in diagnostic techniques as well as operative and perioperative management have increased the curative (R0) resection rate to 80% to 90% and the operative death rate to <5%.1–6 R0 resection—complete surgical resection of tumor at the microscopic level—offers the only chance of cure; nevertheless, more than half of the patients die of relapses of disease after R0 resection. This suggests the necessity of adjuvant therapy for preventing relapse after R0 resection. To practice multidisciplinary treatment approaches appropriately, clarifying survival factors and assaying data on the actual patterns and predictors of relapse after R0 resections is critically necessary. However, the small number of patients who have undergone R0 resection for ampullary carcinoma has limited such information.

The current study was conducted to review the treatment results in 66 consecutive patients with ampullary carcinoma. The prognostic factors that impact long-term survival after R0 resections were analyzed in an attempt to identify patients who are at risk for relapse. The characteristics of relapse were analyzed in detail, and the correlation of clinicopathologic factors with relapse was evaluated to provide a basis for developing beneficial adjuvant therapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Characteristics
From January 1, 1977, to June 30, 2003, 66 patients with a confirmed pathologic diagnosis of carcinoma of the ampulla of Vater (excluding patients with cancers of the pancreas, duodenum, or distal bile duct) presented to our hospital. They included 59 patients who underwent radical resections by pancreaticoduodenectomy and 7 patients who did not because of distant organ metastasis (3), poor medical condition (3), or refusal (1). The tumors were classified by the tumor node metastasis (TNM) classification criteria.7 The mean age of all 66 patients was 63.8 (range, 40–82) years; 34 were female and 32 were male. The median follow-up time was 30.5 (range, 1.2–1178) months.

Of 66 patients, 49 had jaundice (>20.5 µmol/L) on admission, and their preoperative maximum serum total bilirubin level ranged from 7 to 400 µmol/L (mean and standard deviations: 169 ± 101 µmol/L). Percutaneous transhepatic cholangiodrainage (PTCD) was performed in 45 patients, not only to relieve jaundice but also to confirm the location and/or type of the biliary tract stenosis. Thirty-seven resections were performed after the alleviation of jaundice. As tumor markers, the preoperative serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19–9) levels were measured in 63 and 62 patients, respectively. The cut-off levels for the corresponding markers were 5.0 ng/mL and 37 units/dL, respectively. All patients were available for follow-up, and ultrasonography or computed tomography or both were used to detect relapses at various times during the 3- to 6-month interval. The levels of these serum markers were measured at 1- to 3-month intervals after treatment. Autopsies were performed on three patients, and salvage surgery was performed on six patients who developed distant metastasis.

Resection Procedures
Pancreaticoduodenectomy was performed for 59 patients, including 47 patients who underwent a Whipple procedure, 2 who underwent pylorus-preserving pancreaticoduodenectomy, and 10 who underwent pancreatic head resection with the second portion of the duodenum.8 The latter two procedures were done after preoperative imaging diagnosis with endoscopic ultrasonography of T1 or T2 disease or because of poor medical condition (n = 1).

The regional lymph nodes were used for TNM classification criteria,7 including the nodes within the hepatoduodenal ligament, peripancreatic area, and periportal area. Those in the celiac region and on the right side of the superior mesenteric artery were dissected regardless of the stage of disease. However, the lymph nodes on the right side of the aorta, above and below the bifurcation of the left renal vein, were dissected only when those nodes were visibly swollen.

Statistical Analysis
Survival curves were estimated by the Kaplan-Meier method, and statistical differences among groups were detected by log-rank test. Univariate and multivariate analyses with the Cox proportional hazard model were performed to determine the prognostic factors for survival. For the multivariate Cox regression, a stepwise procedure was used. The Akaike Information Criterion (AIC)9 index was applied to find the most preferable model among competing models. The Fisher exact or {chi}2 test was carried out to examine the correlation between the rate of metastasis and clinicopathologic factors. P values <.05 were considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histopathology and Tumor Node Metastasis (TNM) Stage Group
Among 66 patients with ampullary carcinoma, adenocarcinomas were the most frequently noted (63 patients; 95.5%), followed by adenosquamous carcinomas (2 patients; 3%) and squamous cell carcinoma (1 patient; 1.5%).

Fifty-six of 59 patients who underwent resection had adenocarcinoma, 2 had adenosquamous carcinoma, and 1 had squamous cell carcinoma (SCC). The histological grade (G) was classified according to TNM criteria;7 34 patients had well-differentiated (G1) tumors, 14 had moderately differentiated (G2) tumors, and 11 had poorly differentiated (G3) tumors. The frequency of metastasis to the regional lymph nodes increased significantly (P = .0392); advance of the primary tumor occurred in 11% of T1 (1 of 9), 35% of T2 (7 of 19), 55% of T3 (16 of 29), and 100% of T4 (2 of 2) tumors. Four of the 59 patients who underwent resection had M1 lesions, because multiple liver metastases coexisted with the primary lesion for three patients and node metastases were beyond N1 for the remaining patient. Three patients with M1 lesions had T3 tumors and the remaining one had a T4 tumor; the incidence of M1 lesions was significantly (P = .0362) correlated to the extent of the primary tumor (Table 1). In 55 R0 resections, 8 involved stage I, 25 involved stage II, 21 involved stage III, and 1 involved stage IV disease.


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  		TABLE 1. TNM group of 59 patients who underwent resection
 
Operative Mortality, Morbidity, and Survival
No patients died in the hospital during the perioperative period, although major complications occurred in five patients after resection (8.5%; 5 of 59), and three of them occurred after R0 resection (5.5%; 3 of 55). These complications consisted of intra-abdominal abscess (n = 1), leakage from hepaticojejunostomy (n = 1) or duodenal anastomosis (n = 1), intestinal obstruction (n = 1), and threatened rupture of pseudoaneurysm of hepatic artery (n = 1); all of these complications were treated with surgical intervention.

Of the seven unresected patients, six died within 28 months after biliary drainage or the start of treatment, and the remaining one (with stage I disease), who was in poor medical condition, was free of cancer for 35 months after radiotherapy, following placement of an expandable metallic stent at the end of the biliary tract. Four patients with stage IV lesions who had far-advanced disease died of cancer within 11 months after PTCD, with or without an internal metallic expandable stent. One with stage III lesions refused pancreaticoduodenectomy and died of disease 27 months after insertion of an internal metallic expandable stent. One patient with stage I disease died of progressed liver cirrhosis 9.2 months after complete disappearance of the primary tumor following proton beam therapy.

In the 55 cases of R0 resection, there was no residual macroscopic tumor after resection and no cancer cell invasion on the surgical margins, and lymph node metastasis was restricted to the scope of the dissection. In two patients, resections were classified as R1 despite complete gross removal of the cancerous lesions. In one of these patients, microscopic involvements were discovered after operation, not only in the surgical margin but also in the enucleated tissues of a small peritoneal nodule and in two small liver nodules. In the other patient, surgical margins were negative, but a small node removed from among several small hard nodes on the mesenterium was positive. In another two patients, resections were classified as R2 because macroscopic residual tumor was evident as multiple liver metastases.

On June 30, 2003, 29 of the 55 patients were alive and well after R0 resection. The overall 5-year survival rate (±SE) following R0 resection was 52.6% (±7.4). Nineteen of the 55 R0 resection patients have lived more than 5 years (range, 5.2 to 14.9), but 2 died of liver cirrhosis or infirmity 6.3 and 7.9 years later, respectively, with no evidence of relapse. Stages of these long-term survivors were: I in 4, II in 10, and III in 5 patients. The 5-year survival rate decreased significantly (P < .0001) with higher-staged lesions: 100%; 58.1% (±10.9); 30.8% (±10.4); and 0%. The median survival with stage III was 33.2 (±2.8) months (Fig. 1).



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  		FIG. 1. Survival curves after curative (R0) resection of ampullary carcinoma in relation to TNM stage.

 
Predictors of Survival
The extent of residual tumor (R) was a significant survival predictor (R0 vs. R1 + R2, P < .0001). Four patients who underwent noncurative R1 (n = 2) or R2 (n = 2) resection have survived <22 months after surgery. Univariate analysis revealed that the preoperative serum CEA level, gross tumor appearance, tumor and node categories, TNM stage group, and microscopic lymphatic vessel and venous invasion of the primary tumor significantly influenced survival after R0 resection (Table 2). However, age (P = .2320), gender (P = .3738), the presence of preoperative jaundice (as determined by comparing cases with bilirubin levels of <20.5 µmol/L versus 20.5 µmol/L or more) (P = .1833), preoperative serum CA19–9 level (P = .0889), histopathologic type (adenocarcinoma vs. nonadenocarcinoma; P = .1995), and histologic grade (P = .2937) did not have a significant influence on survival. Preoperative serum CEA and CA19–9 levels in patients who underwent PTCD were used for the analysis after relief of jaundice.


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  		TABLE 2. Significant survival predictors after R0 resection (n = 55) Cox univariate analysis
 
Independent factors influencing survival after R0 resection were analyzed by stepwise regression procedure in a Cox proportional hazard model. Seven significant survival predictors previously detected in univariate analysis were divided into groups A and B. Group A consisted of the preoperative serum CEA level, the gross tumor appearance, and the tumor, node, and TNM stage. These five variables are characterized by the possible preoperative estimations by means of serum test or image diagnosis and are important indicators for selecting treatment procedures. Group B is composed of lymphatic vessel and venous invasion in the primary tumor and characterized by impossibility of preoperative estimation. Therefore, we constructed models A and B separately in the multivariate regression analysis. In model A, variables of both groups A and B were used, but in model B variables of only group A were used. Stepwise regression demonstrated that in model A, lymphatic vessel invasion (hazard ratio, 10.25) was the only independent significant survival predictor after R0 resection, with the lowest AIC index (127.8) in comparison with the initial AIC index (142.3). In model B, tumor (hazard ratio, 2.53) and TNM stage (hazard ratio, 2.80) were significant independent survival predictors, with the lowest AIC index (129.6) in comparison with the initial AIC index (142.3) (Table 3).


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  		TABLE 3. Significant risk factors affecting survival after R0 resection (n = 55) Cox multivariate analysis
 
The Pattern and Predictors of Relapse after Curative Resection
Among 55 patients who underwent R0 resection, 29 are alive and well at 14.4 to 179 months, without evidence of relapse after R0 resection, except for 1 in whom liver metastasis developed. Relapse was indicated clinically in 24 patients, but biopsy revealed a liver metastasis derived from clear cell carcinoma in one patient and excluded from the analysis on relapse. Three patients died of other diseases. One died of advanced clear cell carcinoma of the urinary bladder with liver metastasis, another of liver cirrhosis, and the third of general infirmity (22, 76, and 95 months after R0 resection, respectively).

No patient had locoregional failure (LRF) alone; 18 patients had distant failure (DF) alone and 6 had both types of failure. The overall frequency of DF was 44% (24 of 54), excluding a patient with liver metastasis of clear cell carcinoma of the urinary bladder, and the overall frequency of LRF was 11% (6 of 54). The most frequent site of DF was the liver (16 of 24; 67%), and the second most common site was distant lymph nodes (13 of 24; 54%), followed by the peritoneum (5 of 24; 21%), the lungs (5 of 24), and bone (3 of 24; 13%). Mean time to clinical manifestations of relapse (MTR) after R0 resection was 13 (range, 0.7–33) months, regardless of the recurrence type. The MTR in patients who developed liver metastasis was 9.5 months, but it was significantly shorter (P = .0015) than 20 months in patients who developed metastasis in other sites.

The Fisher exact test revealed that the preoperative serum level of both CEA (P = .0234) and CA19–9 (P = .0451) correlated significantly with the development of DF after R0 resection. Regarding DF, the CEA level significantly influenced the development of liver (P = .0364) and distant node (P = .0155) metastasis, but not lung, bone, or peritoneal metastasis. Conversely, the preoperative serum CA19–9 level significantly correlated (P = .0260) with the development of lung metastasis but not with metastasis of other organs. Additionally, venous and lymphatic vessel invasion, pathologic factors of the primary tumor, were also significantly correlated with the development of DF, with P values of .0003 and .0008, respectively. The mode of DF was also correlated with these two pathologic factors. Both factors significantly correlated with hematogenous metastasis (venous invasion, P = .0005; lymphatic vessel invasion, P = .0121), including liver, lung, and bone metastasis, or lymphogenous metastasis (venous invasion, P = .0349; lymphatic vessel invasion, P = .0037), which includes metastasis of locoregional and distant nodes. However, neither venous invasion nor lymphatic vessel invasion influenced the development of peritoneal seeding. The correlation of pathologic factors of lymphatic vessel and venous invasion with individual metastatic sites was different in reference to the hematogenous or lymphogenous metastasis. That is, venous invasion significantly influenced only liver metastasis (P = .0026), and lymphatic vessel invasion correlated significantly only with distant node metastasis (P = .0037). There was no significant correlation of lymphatic vessel or venous invasion with the serum level of CEA and CA19–9 (Table 4).


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  		TABLE 4. Correlation of microscopic invasions of the primary tumor with the mode of distant metastasis (R0 resection; n = 54)a
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of our studies are interesting from a clinical point of view, since either CEA or CA19–9, preoperatively measurable serum tumor markers, influenced survival (Fig. 2) or acted as a predictor of distant metastasis after R0 resection, in different fashions. CEA significantly influenced survival but CA19–9 did not, and both markers were significant predictors of distant failure. Moreover, the former was a predictor of liver and distant node metastasis and the latter acted as a predictor of pulmonary metastasis. These results of our studies confirm the reports of Nakao et al.10 and Dorandeu et al.,11 which demonstrate a significant correlation between the immunohistochemical staining patterns of CA19–9 in the primary tumor and prognosis.



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  		FIG. 2. Survival curves after curative (R0) resection in relation to preoperative serum CEA level. The serum CEA level was not measured in three patients. CEA, carcinoembryonic antigen (cutoff level; 5.0 ng/mL).

 
With the lack of data supporting adjuvant therapy in the overall management of ampullary carcinoma, we evaluated the patterns of failure after R0 resections. There has been little in the literature regarding the site of relapse after R0 resection alone. Kopelson et al.12 reported that 43% (3 of 7) had LRF alone and 57% (4 of 7) developed DF with or without LRF following R0 resection. Willett et al.15 showed that the DF pattern was predominant after pancreaticoduodenectomy; their incidences were 13% (1 of 8) for LRF alone and 87.5% (7 of 8) for DF with or without LRF. Similarly, in our series, all failures (n = 24) involved the development of DF; 75% (18 of 24) involved DF alone, but none involved LRF alone. The most frequent site of DF was the liver, as was consistently shown in the reports of Kopelson et al.,12 Yamaguchi et al.,13 and Kayahara et al.14 The second most common location was distant lymph nodes, followed by the lung, peritoneum, and bone.

Our data and those of others clearly suggest the necessity of adjuvant systemic therapy, even with R0 resections, in order to prevent DF and improve long-term outcomes. Nevertheless, only one trial of radiotherapy with chemotherapy (5-fluorouracil) has been carried out exclusively for patients with ampullary carcinoma,15 although several trials of chemotherapy16,17 or chemoradiotherapy18,19 in conjunction with radical resections have been conducted involving patients with periampullary carcinoma (including carcinomas of the lower bile duct, ampulla, and duodenum). Those adjuvant therapies showed some success; however, their precise value has not yet been proven because of the small number of patients involved and the difficulty in sampling only ampullary carcinoma.

Of 24 patients whose treatment failed, 6 presented with both DF and metastases to regional lymph nodes as LRF, including nodes in the hepatoduodenal ligament, and around the superior mesenteric artery and lateral aortic node. However, no T1 or T2 tumor had metastasis on the nodes beyond regional ones, as defined by TNM classification criteria. Therefore, complete dissection of the regional lymph nodes, including the lateral aortic nodes, is not inevitable for cure, except for cases of T3 or T4 disease.7

Because the preoperative serum CEA and CA19–9 levels and lymphatic vessel and venous invasion in the primary tumor significantly correlated with the development of DF after R0 resection, they should serve as important predictors of DF after R0 resection, especially in the liver, lung, bone, or distant nodes (Table 4), or as indicators for adjuvant therapy with R0 resections. Given that the average time between R0 resection and clinical manifestations of metastasis was 13 (range, 0.7–33) months, careful follow-up should continue for about 3 years after R0 resection, and some kind of postoperative adjuvant therapy during the follow-up time might be beneficial.

Recent multivariate analysis demonstrated that histological grade and local invasiveness,20 age, jaundice, lymphatic vessel invasion,21 venous invasion,,13 tumor size,22 surgical margin,23 gross tumor appearance and histological grade,24 blood transfusion,4 N stage,3 surgical margin and N stage,2 or N stage and hematocrit25 were independent significant predictors of survival, although this has not been observed consistently in all studies. Our multivariate analysis of patients who underwent R0 resections uniquely demonstrated that the independent survival predictors were lymphatic vessel invasion, tumor stage, and TNM group.

Regarding ulceration of the primary tumor, our data confirmed the conclusion of others14,24,26 that it is a significant survival predictor.

In conclusion, pancreaticoduodenectomy with regional lymph node dissection is a safe R0 resection procedure for ampullary carcinoma, with a minimal LRF rate. However, R0 resection alone is not always sufficient as a curative treatment modality because of the high DF rate. Therefore, an effective adjuvant systemic therapy should be developed to complement R0 resections. Preoperative serum CEA and CA19–9 levels and lymphatic vessel and venous invasion in the primary tumor may be useful predictors of DF, including the liver, lung, bone, and distant nodes, after R0 resection. A follow-up period of at least 3 years is necessary, even after curative resection, to detect relapses. The tumor category, TNM stage, and lymphatic vessel invasion in the primary tumor were significant independent predictors of long-term survival after R0 resections.


   FOOTNOTES
 
Microscopic lymphatic vessel/venous invasion and tumor node metastasis stage are independent prognostic factors after curative resection of ampullary carcinoma. All 24 relapsed patients had distant failure; preoperative carcinoembryonic antigen and carbohydrate antigen levels and lymphatic vessel or venous invasion are significant predictors of distant failure.

Received for publication July 18, 2001. Accepted for publication August 13, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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H.-P. Hsu, T.-M. Yang, Y.-H. Hsieh, Y.-S. Shan, and P.-W. Lin
Predictors for Patterns of Failure after Pancreaticoduodenectomy in Ampullary Cancer
Ann. Surg. Oncol., January 1, 2007; 14(1): 50 - 60.
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 Arch SurgHome page
K. M. Brown, A. J. Tompkins, S. Yong, G. V. Aranha, and M. Shoup
Pancreaticoduodenectomy Is Curative in the Majority of Patients With Node-Negative Ampullary Cancer
Arch Surg, June 1, 2005; 140(6): 529 - 533.
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D. Santini, B. Vincenzi, G. Tonini, S. Scarpa, F. Vasaturo, C. Malacrino, F. Vecchio, D. Borzomati, S. Valeri, R. Coppola, et al.
Cyclooxygenase-2 Overexpression Is Associated with a Poor Outcome in Resected Ampullary Cancer Patients
Clin. Cancer Res., May 15, 2005; 11(10): 3784 - 3789.
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 Annals of Clinical & Laboratory ScienceHome page
L. Li, Q.-H. Chen, J. D. Sullivan, and F. U. Breuer
Signet-Ring Cell Carcinoma of the Ampulla of Vater
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 Ann. Surg. Oncol.Home page
K. C. P. Conlon
Carcinoma of the Ampulla of Vater: A Distinct Disease Entity?
Ann. Surg. Oncol., December 1, 2003; 10(10): 1136 - 1137.
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