Introduction
Carcinoma of the papilla of Vater (the so-called ampulla of Vater) is relatively uncommon and has been reported to have high resectability rates and favorable overall 5-year survival rates compared with distal cholangiocarcinoma and pancreatic cancer [
1‐
6]. Currently, pancreatoduodenectomy (PD) is considered the curative treatment of choice [
3‐
8]. Although the mortality rate for PD has decreased significantly over the last few decades to less than 5%, it still carries a high morbidity rate. For these reasons, many authors have investigated the possibility of less-invasive procedures for ampullary carcinoma [
3,
5‐
11], and the majority concluded that limited resection should be reserved only for patients with high operative risk or benign adenomas because of the increased likelihood of recurrence due to lymphatic or venous invasion, even for early ampullary carcinomas [
3,
5‐
11]. On the other hand, some investigators have suggested that endoscopic papillectomy (EP) or local resection is potentially curative for a selected population of patients [
12,
13]. To achieve the complete removal of an ampullary tumor by limited resection, 2 criteria—no lymph node metastasis and a definite tumor-free margin—must be satisfied. The most important consideration is whether these two criteria can be diagnosed before resection. Lymph node metastasis is one of the most significant predictors of poor prognosis for ampulla of Vater carcinoma [
2‐
6,
9,
14], and local resection cannot be associated with the dissection of lymph nodes. That is, no lymph node metastasis is an absolute requirement for limited resection of ampullary cancer. Furthermore, a free surgical margin means that the tumor must be located at the area of the ampulla of Vater within the extent of local resection in the absence of mucosal tumor infiltration into the pancreatic duct, although the presence of tumor extension into the common bile duct does not hinder the limited surgery because of the possibility of complete excision of the extrahepatic portion of the common bile duct en bloc with the ampulla of Vater [
15].
In the present study, therefore, our purpose was to clarify the clinico-pathological factors that correlate with lymph node metastasis and local extension, including invasion of the duodenum and tumor infiltration of the pancreatic duct, through a detailed histopathological evaluation of specimens retrieved by standardized radical resection and systematic lymph node dissection, or local resection with curative intent. The findings from this analysis could lead to indications for limited resection of early ampulla of Vater carcinoma.
Patients and methods
A retrospective cohort study was performed for all consecutive Japanese patients at Keio University Hospital, Tokyo, Japan who underwent resection for ampulla of Vater tumors, including adenoma and adenocarcinoma, with curative intent from May 1986 through December 2010. The hospital charts, surgery records, and pathology reports were analyzed. Patients who had tumors without distant organ metastases and/or major vessel invasion by preoperative radiological studies were considered surgical candidates. Whipple resection or pylorus-preserving pancreatoduodenectomy (PPPD) with concurrent lymph node dissection at the anterior and posterior aspect of the pancreatic head, the hepatoduodenal ligament, and the right border of the superior mesenteric artery was the principal procedure. At our institution, transduodenal papillectomy (TDP) and endoscopic papillectomy (since 2000), if applicable, have been the alternative options for benign tumors of the ampulla of Vater, diagnosed as tubular adenoma by endoscopic biopsy without evidence of local extension to the common bile duct or the main pancreatic duct [
16,
17]. In some cases, the final histopathological evaluation of the specimens resected by TDP or EP revealed adenocarcinoma. In addition, complete resection of the extrahepatic portion of the common bile duct and the ampulla of Vater (CRBA) was performed in a high-risk patient with an early stage of ampullary carcinoma extending into the common bile duct without involvement of the pancreatic duct [
15]. Two pathologists independently examined all cases to distinguish ampulla of Vater carcinoma from tumors of the pancreas, the distal common bile duct, or the duodenum by microscopic evaluation of the lesion according to the Classification of Biliary Tract Carcinoma by the Japanese Society of Biliary Surgery [
18]. Positive tumor invasion to the duodenum (≥Du1) was defined as invasion beyond the sphincter of Oddi. Negative invasion to the duodenum (Du0) was defined as invasion limited to the duodenal mucosa or sphincter of Oddi. Likewise, positive invasion of the pancreas was defined as invasion of the pancreas beyond the sphincter of Oddi or the duodenal wall. The gross appearance of the tumor on the mucosa of the duodenum was categorized as a macroscopic type according to the main macroscopic findings, [
18] and was allocated to one of 3 types: an exposed protruded type, a non-exposed protruded type, both of which are without ulceration, and an ulcerative type, including both mixed types of predominant protruded and ulcerative types according to the Classification of Biliary Tract Carcinoma by the Japanese Society of Biliary Surgery. Endoscopic ultrasonography (EUS) was performed with mechanical radial endoscopes at a frequency of 5 or 7.5 MHz (GF-UM 2000; Olympus Optical Co., Ltd, Tokyo, Japan) to define the extent of local involvement, especially invasion of the duodenal wall and pancreas, before endoscopic retrograde cholangiopancreatography (ERCP) with intraductal ultrasonography (IDUS) and biliary drainage. After ERCP and before biliary drainage, transpapillary IDUS was performed with an IDUS probe at a frequency of 20 MHz (UM-G20-29R; Olympus), mainly to evaluate tumor extension into the bile duct and pancreatic duct. Tumor infiltration into the bile duct was examined by inserting an IDUS probe into the pancreatic duct. By contrast, tumor infiltration into the pancreatic duct was examined by inserting an IDUS probe into the bile duct.
Statistical analyses
The data are presented as percentages, median (range) and mean ± standard error. The chi-squared test or Fisher’s exact probability test were used when appropriate to determine the correlations between the clinico-pathological variables and lymph node metastases and between the macroscopic type and histopathological differentiation or duodenal invasion. Multivariate analyses by logistic regression model were performed to identify independent risk factors of nodal spread. Statistical significance was defined as p < 0.05. All statistical analyses were performed with SPSS statistical software (SPSS Inc., Chicago, IL, USA).
Discussion
This is the first study to propose indications for limited resection of early ampulla of Vater carcinoma based on preoperative information and to provide detailed histopathological criteria to confirm complete resection. We must predict a successful local resection of ampullary carcinoma with preoperative information, that is, endoscopic findings of macroscopic type, pathological findings of endoscopic forceps biopsy, depth of duodenal invasion by EUS, and extent of tumor infiltration into the pancreatic duct by IDUS or ERCP. In early ampulla of Vater carcinomas (deepest invasion limited to the sphincter of Oddi), a strictly selected subset of tumors fulfilling the following conditions: an exposed protruding macroscopic type, adenoma or papillary/well-differentiated adenocarcinoma by preoperative endoscopic biopsy, negative duodenal invasion (Du0) with EUS, no tumor infiltration into the pancreatic duct with IDUS, and pancreatic duct diameter of 3 mm or less at ERCP were not associated with lymph node metastasis and were resectable with tumor-free margins achieved by local resection, suggesting potential cure. Determining whether or not tumor invasion is limited to mucosa before resection is very important, because patients with tumor invasion limited to the sphincter of Oddi may have nodal involvement. There have been some reports that patients with tumor invasion limited to the sphincter of Oddi did have nodal involvement [
5,
9,
28,
29]. However, with regard to the extent of tumor invasion of the duodenum, it is impossible to completely discriminate between mucosa and the sphincter of Oddi even using EUS and IDUS preoperatively [
20,
23,
25]. We need to elucidate the characteristics of the subset of patients with tumor invasion limited to the sphincter of Oddi who do not have nodal involvement. Furthermore, since we could not preoperatively diagnose lympho-vascular invasion and perineural invasion of ampullary tumors, which were significant risk factors for lymph node metastases, we tried to narrow down the characteristics of Du0 ampullary tumors without nodal involvement using preoperative findings from the endoscopy, endoscopic biopsy, and combined findings from examinations such as EUS, IDUS, and ERCP. The most important concept is that local resection could be accomplished after the resected specimens were confirmed pathologically to be not moderately/poorly differentiated adenocarcinoma and to show negative invasion of the lympho-vasculature, perineural, duodenum, and pancreas as well as to have negative surgical margins. In our series, 11 patients who met our limited resection criteria were identified. All patients actually underwent limited resection of the tumor in our institution, and 4 of these patients had well-differentiated adenocarcinoma. During a median (range) follow-up of 49 (14–161) months, none of the 11 patients experienced disease recurrence (5-year overall and disease-free survival, 100%). However, the duration of follow-up was not sufficient, because only five of the 11 patients were followed for more than 5 years. In addition, although our data satisfy the assumptions stated above, this study is a retrospective analysis, and the number of patients was small.
The diagnostic accuracy of EUS and T1 staging for ampulla of Vater carcinoma is reported to be 60–90 and 80–100%, respectively [
19‐
25]. In particular, whether EUS can correctly assess the depth of invasion within or beyond the sphincter of Oddi is still controversial [
20,
23,
25]. Our study also showed that it was impossible to identify 100% of duodenal invasion by preoperative EUS (our diagnostic accuracy rate was 82%). Therefore, we referred to other tumor findings, such as endoscopic findings and the pathology of the endoscopic biopsy to predict no lymph node metastases.
Likewise, a single IDUS examination for tumor infiltration into the pancreatic duct was limited in diagnostic accuracy [
20,
23]. Therefore, we needed to make a more precise diagnosis by combining several examinations. Our data indicated that the combination of IDUS with ERCP could make up for the diagnostic drawbacks of each for tumor infiltration into the pancreatic duct. Since this study was a retrospective study, we analyzed all patients with ampullary tumor from 1986 to 2010. EUS and IDUS were not performed during the early part of this period. However, 37 (72.5%) of 51 patients who were treated in our institution after January 2000 received comprehensive preoperative examinations that consisted of EUS, IDUS, and ERCP. Furthermore, 19 of 23 patients (82.6%) who underwent limited resection received comprehensive preoperative examinations. Therefore, we believe that these proposed clinical criteria may be realistic. The major reason for failure of comprehensive examinations was the inability to insert a catheter into the main pancreatic duct during ERCP. Determining the diameter of the pancreatic duct using magnetic resonance cholangiopancreatography may be an appropriate avenue for future investigation.
Two critical factors must be considered: the curability of the disease by limited resection and its technical feasibility. Regarding curability, the operative mortality rate of Whipple resection or PPPD is reported to be 1–5% in high-volume centers, and the overall 5-year survival rates for pT1 tumors ranged from 70 to 90% in recent studies [
3,
5,
6,
9]. Limited resection would be an acceptable alternative for early ampulla of Vater carcinoma if the risk of lymph node recurrence is estimated to be less than 1%. Meanwhile, there is currently no definition for “limited resection”. Advocated procedures include EP, TDP, segmental resection of the duodenum, resection of the head of the pancreas with segmental duodenectomy, pancreas-preserving biliary amputation with pancreatic diversion, and CRBA, and their indications have yet to be defined, which leaves the door open for “tailored” limited resection according to tumor size and location within the papilla of Vater and possibly the inferior bile duct [
12,
13,
15,
26,
27]. Our surgical strategy for ampullary tumors is as follows: EP is indicated for patients who fulfill the 5 requirements described above and have a tumor diameter 2 cm or less (that is, the diameter of a snare) without involvement of the bile duct; TDP is indicated for patients who fulfill the 5 requirements with tumor diameter more than 2 cm or with small tumor infiltration of the bile duct; CRBA is indicatied for patients who fulfill the 5 requirements with the tumor extending into the bile duct to a high degree; and PPPD is indicated for patients who have a tumor infiltrating into the pancreatic duct despite adenoma or adenocarcinoma. Naturally, after limited resection, precise pathological examination and close follow-up are inevitable. Obviously, the worst scenario is that those cases that should have been subjected to radical surgery undergo inappropriate follow-up after limited resection, directly affecting long-term survival. Taking the viewpoints of both curability and technical feasibility together, limited resection must allow thorough histopathological evaluation.
This study has certain limitations: the number of cases was small, the length of follow-up period was not satisfactory, and the analysis was retrospective. Accordingly, we should not rush to conclusions. More histopathological data is needed from patients, especially from those with tumor invasion limited to the sphincter of Oddi, before a multicenter, randomized trial that assigns patients to a limited resection arm and a PPPD arm is planned.
In conclusion, ampulla of Vater carcinomas meeting the following criteria may benefit from limited resection for potential cure: (1) an exposed protruding macroscopic type, (2) adenoma or papillary/well-differentiated adenocarcinoma detected by endoscopic biopsy preoperatively, (3) negative duodenal invasion with EUS, (4) no tumor infiltration into the pancreatic duct with IDUS, (5) a pancreatic duct diameter of 3 mm or less at ERCP. Furthermore, confirmation of no moderately/poorly differentiated adenocarcinoma and negative invasion of the lympho-vasculature, perineural, duodenum, and pancreas, as well as negative surgical margins by precise histopathological examination of resected specimens is very important to accomplish the limited procedure. Further improvements in diagnostic accuracy and accumulation of cases for justification of our proposed indications are warranted.