Tumor-related factors and patient’s age infl uence survival after resection for ampullary adenocarcinoma

GIEDRIUS BARAUSKAS1, ANTANAS GULBINAS

1,3, DARIUS PRANYS2, ZILVINAS DAMBRAUSKAS

1,3, and JUOZAS PUNDZIUS1

1 Department of Surgery, Kaunas University of Medicine Hospital, LT 50009, Kaunas, Lithuania2 Department of Pathology, Kaunas University of Medicine, Kaunas, Lithuania3 Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania

Offprint requests to: G. BarauskasRedeived: September 12, 2006 / Accepted: October 1, 2007

AbstractBackground/Purpose. The majority of surgeons agree that ampullary adenocarcinoma should be removed by partial pan-creatoduodenectomy. Favoring extended resection, based on the uncertainty of the preoperative diagnosis and the higher probability of clear resection margins, we aimed to disclose the results of this surgical procedure in terms of postoperative morbidity and mortality, and to identify prognosticators of long-term survival.Methods. We documented, prospectively, 25 consecutive patients with adenocarcinoma of the papilla of Vater in whom pylorus-preserving pancreatoduodenectomy was performed. Clinical data, pathology reports, International Union Against Cancer (UICC) tumor stage, postoperative morbidity, mortal-ity, and long-term follow-up results were evaluated. The Kaplan-Meier method and log-rank test were applied for uni-variate analysis. The Cox proportional hazard model was used for multivariate analysis.Results. Postoperative mortality was 4%, overall morbidity was 32%, and pancreas-associated morbidity was 8%. Mean survival time was 53.8 months. Tumor size, N status, UICC stage, lymphatic invasion, blood vessel infi ltration, R0 resec-tion, and age of patient at the cutoff of 70 years were independent predictors of survival on univariate analysis. Multivariate analysis, however, disclosed no independent pre-dictors of prognosis.Conclusions. Pancreatoduodenectomy for ampullary carci-noma is reasonable in terms of postoperative morbidity and mortality. Tumor-related factors, R0 resection, and advanced age appeared as the main predictors of survival.

Key words Ampullary adenocarcinoma · Mortality · Pancre-atoduodenectomy · Surgery · Survival rate

Introduction

The anatomy of the ampulla of Vater is very complex. It consists of three different epithelia (bile duct, pancre-atic duct, and duodenum). Adenomas are considered as precancerous lesions and they usually occur in the fi fth to sixth decades of life. There is evidence supporting an adenoma-carcinoma sequence of neoplastic lesions in the ampulla of Vater.1–3 The frequency of malignant lesions in adenoma of the papilla is about 26%.4 In postmortem studies, carcinomas of the papilla of Vater have been reported in 0.2% of cases.5 Adenocarcinoma is the most common malignant tumor of the ampulla, but, in general, it is still rare. Hence, these tumors are diffi cult to study, and most reports concerning ampul-lary carcinoma are of retrospective design.

Through the increased use of endoscopy, ampullary tumors are being recognized more frequently. The dif-ferentiation of adenocarcinoma of the pancreas from ampullary tumors is also important, considering the better prognosis for long-term survival in the latter group. It is generally agreed that adenocarcinoma of the papilla of Vater should be removed by partial pancre-atoduodenectomy, and local resection should be reserved for pTis and pT1N0M0G1 or G2 tumors.4

As we are in favor of pancreatoduodenectomy for the management of ampullary cancers, because of the uncertainty of the preoperative diagnosis and the higher probability of clear resection margins, in the present study, our aim was to substantiate our approach, dis-closing the relative safety of this surgical procedure in terms of postoperative morbidity and mortality, and to determine prognosticators of long-term survival.

Patients and methods

Data from 25 consecutive patients with adenocar-cinoma of the papilla of Vater who were operated on

J Hepatobiliary Pancreat Surg (2008) 15:423–428DOI 10.1007/s00534-007-1313-7

424 G. Barauskas et al.: Ampullary cancer survival after surgery

at the Department of Surgery, Kaunas Medical University Hospital, between January 1, 1999 and May 2005 were documented prospectively and subsequently analyzed.

Surgical techniques

All 25 patients underwent major resection for malig-nant disease. Surgery was performed by two of the senior authors (G.B. and J.P.) Lymph-node dissection was performed in pursuance of extended lymphadenec-tomy, as in adenocarcinoma of the head of the pancreas.

Defi nition of surgical principles

Pylorus-preserving pancreatoduodenectomy (PPPD) was defi ned as a resection of the head of the pancreas, resection of the duodenum approximately 3 cm below the pylorus with subsequent duodenectomy, and resec-tion of the initial segment of the jejunum. Lymph-node dissection included the anterior and posterior lymph nodes of the pancreatic head, the supraduodenal lymph nodes, the common and proper hepatic artery nodes, the lymph nodes of the hepatoduodenal ligament, and the lymph nodes to the right of the superior mesenteric artery. Cholecystectomy was done with an en-bloc resection of the common bile duct; retroportal, retro-pancreatic fatty tissue dissection was done, as well as dissection of lymph-nodes from the interaortocaval space. Reconstruction followed, using the fi rst jejunal loop to create an end-to-side pancreaticojejunostomy and an end-to-side hepaticojejunostomy without internal stents or other intraluminal decompressing or draining devices, followed by sequential end-to-side duodenojejunostomy in front and above the transverse colon, using a one-layer running fi ne (4/0 or 5/0) resorb-able monofi lament suture. Thus, the latter anastomosis was located some distance from the pancreaticojejunos-tomy, with a fl ap of omentum interposed between the two.

Defi nitions of R0 and R1 resections were stated else-where.4 Stratifi cation of pancreas-related morbidity was described by our group earlier.6 In-hospital deaths and deaths within 30 days following the surgical procedure were registered, and postoperative mortality was estimated.

Statistical analysis

We used SPSS 12.0.1 (SPSS, Chicago, IL, USA) soft-ware in data processing. Values for results were reported as medians and as means ± SD. The Kaplan-Meier method and the log-rank test were applied for univari-ate survival analysis. Signifi cance was accepted at the

5% level. The Cox proportional hazard model was applied for multivariate analysis.

Results

Twenty-fi ve patients with a malignant tumor of the papilla of Vater underwent radical pancreatoduodenec-tomy. There were 9 male and 16 female patients (male-to-female ratio, 1 : 1.8). The mean age of the patients studied was 65.3 years: men, 63.7 (SD, 10.2) years, women, 64.7 (SD, 9,1) years. More than one-third of patients were older than 70 years of age (8 of 25; 32%). Median serum bilirubin in the cohort before surgery was 46 μmol/l (range, 5–190 μmol/l). Six of the 25 (24%) patients presented with serum bilirubin exceeding 100 μmol/l. In 4 of them, preoperative biliary drainage was established because of excessive serum bilirubin, elevated liver enzyme test results, and impaired cardiac function, requiring medical management prior to surgery. All these patients were older than 70 years of age.

Diagnostic tests performed were contrast-enhanced computed tomography (CT) scan and endoscopic retro-grade cholangiopancreatography (ERCP) with multiple biopsies prior to surgery.

All 25 patients underwent major resection–pylorus-preserving partial pancreatoduodenectomy (PPPD). Mean operating time was 323 min (SD, 57.4) with a median blood loss of 400 ml (quartile range, 200 ml). No blood transfusion was required in the patients undergo-ing pancreatoduodenectomy for ampullary carcinoma.

The median number of lymph nodes procured during lymph-node dissection was 23. Among the patients who underwent radical pancreatoduodenectomy none pre-sented with distant metastases at surgery.

Postoperative mortality after pancreatoduodenec-tomy was 4% (1 of 25). Overall morbidity was 32% (8 of 25), whereas major morbidity was encountered in 4 of the 25 (16%) patients. Pancreas-related morbidity was 8% (2 of 25), presenting as pancreatic fi stula in 1 patient and as peripancreatic abscess in the other. Relaparotomy was performed in 2 (8%) patients due to intraabdominal hemorrhage. We observed a low rate of delayed gastric emptying postoperatively (1 of 25 patients; 4%).

The fi nal pathology report stated that the diagnosis in all 25 patients was adenocarcinoma of the papilla of Vater. According to the pTNM stage (International Union Against Cancer [UICC], 5th edition), there was one patient with stage IV (UICC) tumor (4%), whereas patients with stage I-III were distributed equally. Dis-tribution according to cell differentiation revealed the predominance of low-grade tumors (16 of 25; 64%). In 36% of the patients (9 of 25), lymph nodes were involved

G. Barauskas et al.: Ampullary cancer survival after surgery 425

(pN1). In 24 patients, R0 resection was accomplished. In the only stage-IV patient, the partial pancreatoduo-denectomy was classifi ed as R1 resection (Table 1), and this was confi rmed by the postoperative pathology report showing malignant cell invasion into the retro-peritoneal tissues at the plane of resection.

The median follow-up of patients after surgery was 32.5 months, ranging from 4.4 to 67.8 months. Overall

1-, 3-, and 5-year actuarial survival rates were 85.2%, 75.2%, and 75.2%, respectively (Fig. 1), with a mean survival time of 53.8 months (95% confi dence interval [CI], 43.2–64.5.

The actuarial 5-year survival among the patients with stage I and II disease was 92%, and all the stage I patients remained alive during the follow up. Patients diagnosed with stage III and IV disease had an actuarial 5-year survival of 43.7%, and the difference in survival rates was signifi cant (P = 0.018; Fig. 2).

We tested long-term survival according to T (tumor) classifi cation, grouping T1 and T2 cases as group I, and T3 − T4 cases as group II. The rationale for the grouping was the presence (T3, 4) or absence (T1, 2) of pancre-atic tissue infi ltration by the tumor. Five-year survival in the T1, 2 patients was 92.3%, whereas the survival rate of 43.1% in the patients with more advanced disease (T3, 4) was signifi cantly lower (P = 0.01; Fig. 3).

Node (N)-negative patients were doing much better in terms of long-term survival when compared to their counterparts with N-positive disease (P = 0.009; Fig. 4).

Patients who had ampullary tumors with high or mod-erate cell differentiation (G1 and G2) survived better than the patients with poor cell differentiation (G3), though a signifi cant difference was not achieved (P = 0.26; Fig. 5).

Univariate analysis revealed that the presence of lym-phatic invasion and blood vessel infi ltration by malig-nant cells signifi cantly worsened survival rates (P = 0.007 and P = 0.002, respectively), whereas another tumor-related factor–neural invasion–had no signifi cant infl uence on the overall survival rates (Table 2). The only patient with malignant cell invasion into retroperi-

Table 1. Histopathological fi ndings in patients undergoing resection for carcinoma of papilla of Vater

Total n = 25 (%)

Resection status R0 24 (96) R1 1 (4)Tumor characteristicsT (TNM classifi cation) T1 4 (16) T2 13 (52) T3 7 (28) T4 1 (4)Positive lymph nodes (N+) 9 (36)Grading G1 2 (8) G2 14 (56) G3 9 (36)Tumor invasivenessNeural invasion 3 (12)Blood vessel infi ltration 4 (16)Lymphatic invasion 9 (36)Tumor stage (UICC 5th edition) I 8 (32) II 8 (32) III 8 (32) IV 1 (4)

Fig. 1. Actuarial 5-year survival was 75% after pancreatoduo-denectomy for ampullary adenocarcinoma

Fig. 2. Long-term survival in the patients with stage I–II tumors and those with stage III–IV tumors was signifi cantly different (P = 0.018)

426 G. Barauskas et al.: Ampullary cancer survival after surgery

Discussion

Ampullary cancer has the best resectability rate and the best prognosis among periampullary cancers. This can be explained by its earlier presentation because of the anatomic location of the tumor, and in part, by the difference in biological aggressiveness compared with pancreatic adenocarcinoma. Carcinoma of the ampulla exhibits differences in macroscopic growth pattern, showing a lower frequency of local infi ltration and of vascular or neural invasion when compared to pancre-

Fig. 3. Long-term survival according to T (tumor) classifi ca-tion, grouping T1 and T2 cases as one group, and T3-T4 as another group. The log-rank test showed a signifi cant differ-ence between the groups (P = 0.01)

Fig. 4. When the patients were grouped according to N (node) value as N-positive (N1) and N-negative (N0), the groups showed a signifi cant difference in survival (P = 0.009)

Fig. 5. Patients who had ampullary tumors with high or mod-erate cell differentiation (G1 and G2) survived better than patients with poor cell differentiation (G3); however, a signifi -cant difference was not achieved (P = 0.26)

toneal tissues (R1 resection) survived for 190 days, whereas the 5-year actuarial survival of patients with radical resection (R0) was 78.9%.

Patient-related factors, such as the patient’s sex, the presence of preoperative bilirubinemia, operating time, and blood loss, as well as other factors related to the surgical procedure, did not infl uence long-term survival. However, the age of the patient at the cutoff of 70 years was a signifi cant predictor of the survival. The results of the univariate analysis are presented in Table 2.

Multivariate analysis, using the Cox propor-tional hazard model, revealed no independent predic-tors of survival after curative resection for ampullary adenocarcinoma.

Table 2. Potential risk factors affecting survival after resec-tion in patients with carcinoma of the papilla of Vater (uni-variate analysis)

Variables Subcategories P value

Sex M vs F 0.88Age (years) <70 vs >70 0.018*Bilirubin (μmol/l) <100 vs >100 0.538Operating time (h) <6 vs >6 0.455Blood loss (l) <1 vs >1 1.000Curative resection Yes vs no 0.032*Tumor stage (UICC) I + II vs III + IV 0.018*T (TNM classifi cation) T1-2 vs T3 + 4 0.010*Lymph nodes N0 vs N1 0.009*Tumor differentiation G1-2 vs G3-4 0.263Neural invasion Yes vs no 0.600Blood vessel infi ltration

Yes vs no 0.002*

Lymphatic invasion Yes vs no 0.007*Complications Yes vs no 0.159Pancreas-related complications

Yes vs no 0.366

Re-operation Yes vs no 0.322

* Signifi cant difference

G. Barauskas et al.: Ampullary cancer survival after surgery 427

atic adenocarcinoma.7 The more extensive use of endo-scopic retrograde cholangiopancreatography (ERCP) in recent years has also contributed to the earlier and more precise diagnosis of this particular tumor. Though magnetic resonance cholangiopancreatography (MRCP) may take over the diagnostic role of ERCP, the direct visualization of the papilla and the possibility of obtain-ing multiple biopsy specimens under direct visual control remains unsurpassed.

Pancreatoduodenectomy is the procedure of choice in cancer of the papilla of Vater, though it still has a mortality of 2% to 5%, and substantial morbidity, of 30%–40%. Our data in the present study showed similar results, with overall morbidity of 32%; however, the incidence of the most feared pancreas-associated morbidity, pancreatic fi stula, in our series was lower than the reported average.8 The reasons for delayed gastric emptying after pancreatoduodenectomy are still debated, and a few hypotheses have been proposed.9–12 Whatever the trigger, we attribute the quite low rate of delayed gastric emptying in our series to the pattern of reconstruction of the gastrointestinal tract. Our pre-sumption was recently supported in a prospective ran-domized controlled trial.13

The uncertainty of gaining a reliable preoperative diagnosis and the unknown extent of malignancy have prompted physicians to consider all ampullary epithelial neoplasms as potentially malignant and to treat them with radical pancreatoduodenectomy,14,15 stressing the key importance of adequate lymph node dissection.16

We favor this approach on the basis that local recurrence of the tumor is much rarer after pancreato-duodenectomy than after the local excision of even a small ampullary lesion,17,18 and as the overall morbidity (32%) and mortality (4%) rates at our department are reasonable, and remain similar to those reported elsewhere.4,19

The published data show 1-year survival after pancre-atoduodenectomy for cancer of the papilla of Vater to be around 80%, 3-year survival around 60%–70%, and 5-year survival around 50%.20,21 Moreover, in a recently published series with R0 resection in T1 patients, the 5-year survival was 100%.22 It is obvious that R0 resec-tion is mandatory to achieve adequate long-term results, as was shown by our results.

The differences of survival in patients grouped on the basis of lymph-node status and infi ltration of pancreatic tissue are indicative of the prognosis of disease. It has been shown that in an “early” ampullary cancer, invad-ing the mucosa or muscle of the sphincter of Oddi, no lymph node metastases were observed, whereas inva-sion into the submucosa of the duodenum and deeper layers resulted in a 63% incidence of regional lymph node involvement.23 The number of positive nodes in the superior mesenteric artery lymph node group also

increased with increasing T stage, suggesting the exten-sion of the lymphatic spread from the posterior pancre-aticoduodenal to the superior mesenteric nodes.24

Beger and co-workers4 have reported a 60% inci-dence of lymph-node metastasis in patients with T3 and T4 carcinoma of the papilla of Vater, whereas an inci-dence of only 22% was observed in patients with T1-T2 disease. Our data revealed positive lymph nodes in 62.5% of patients with T3-T4 carcinoma of the papilla of Vater, whereas metastatic lymph nodes were present in 7.7% of the patients with T1-T2 carcinoma. It has been suggested, on this basis, that the pancreatic inva-sion of an ampullary tumor (T3-4) indirectly indicates the status of regional lymph nodes. Therefore D2 dis-section of lymph nodes is applied at our department when pancreatoduodenectomy is performed for ampul-lary tumors. However, there is still not enough evidence confi rming that more extensive lymph-node dissection translates directly into prolonged survival for patients with periampullary carcinoma.25

Patient age at the cutoff of 70 years emerged as a potential risk factor affecting survival in our series. There are not many reports analyzing the long-term results in the elderly. Bathe et al.26 retrospectively ana-lyzed a group of patients with various periampullary tumors who were aged more than 65 years at the time of surgery. The 5-year survival appeared to be 25%, not much different from that in younger populations. Similar data have been reported by Kojima et al.27 and others.28,29 It might be speculated that inferior long-term survival in elderly patients depends on a shorter overall life expectancy. This idea is supported by demographic data showing that life expectancy at birth in Lithuania was 65.3 years for men and 76.1 years for women in 2004, these fi gures being similar in the majority of other coun-tries through central and eastern Europe.

During the past few decades copious data have been collected on the prognostic factors infl uencing long-term and disease-free survival in patients with ampul-lary cancer. Multivariate analyses have most consistently shown that involvement of the lymphatic vessels or nodes, T category, TNM stage, tumor grade, and free resection margins were independent prognostic factors.4,14,22,23 The absence of independent predictors of survival after pancreatoduodenectomy in our patients in the Cox proportional hazard model may be attributed to the small sample size.

Conclusions

Analysis of our data has revealed that pancreatoduode-nectomy for ampullary carcinoma is safe in terms of postoperative morbidity and mortality, and reasonable in terms of long-term survival. Tumor-related factors,

428 G. Barauskas et al.: Ampullary cancer survival after surgery

R0 resection, and advanced age appeared to be the main predictors of survival.

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