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EDITORIALS |
From the Surgical Unit, The University of Dublin, Trinity College Dublin, and The Adelaide Meath Hospital, Dublin, Ireland.
Correspondence: Address correspondence to: Kevin C. P. Conlon, MD, MBA, Professorial Surgical Unit, The University of Dublin, Trinity College Dublin, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland; Fax: 353-1-6083788; E-mail: lkeenan{at}tcd.ie
Carcinoma of the ampulla of Vater is an uncommon tumor accounting for approximately 0.2% of all gastrointestinal malignancies with an estimated incidence of less than 6 cases per million population per year.1 It has particular biological and clinical features that help differentiate it from other periampullary tumors such as ductal carcinoma of the pancreas. In specialized centers, where it can account for up 20% of all pancreaticoduodenectomies, patients with the disease are often combined for analytic, diagnostic, and therapeutic purposes with the more common and lethal ductal carcinoma of the pancreas under the "umbrella" of periampullary carcinoma.2
In this issue of the journal Todoroki et al., retrospectively reviewed 66 consecutive patients with ampullary carcinoma treated in their institution over a 25-year period.3 Of this group, 59 were considered to have resectable disease and subsequently had a pancreaticoduodenectomy for a resectability rate of 89%. An R0 resection was achieved in 55 patients. Their high resectability rate is in contrast to that observed with adenocarcinoma of the pancreas in which less than 25% of patients ultimately have their tumors resected, often with a positive surgical margin.1 The explanation for the greater resectability rate for ampullary adenocarcinoma, which is not clear-cut, is most likely multifactorial. In part, it can be explained by earlier presentation because of the anatomic location of the tumor, but it also may reflect a differing biological aggressiveness with regard to pancreatic cancer. It has been noted that ampullary carcinomas have two differing histopathologic morphologies, with most tumors exhibiting an intestinal morphology resembling primary adenocarcinomas of the colon and rectum, whereas a minority exhibit pancreaticobiliary features similar to adenocarcinoma of the pancreas or distal bile duct.1 Although ampullary and pancreatic carcinomas share many molecular features, recent work also suggests that ampullary carcinomas are less likely to show loss of tumor suppressor gene Dpc4 expression or K-ras oncogene mutations.4
Currently, surgical resection remains the treatment of choice. The authors should be congratulated because they report no perioperative deaths and a low major complication rate of 5.1%. Other contemporary series have reported similar mortality figures,1,5 emphasizing the point that for this disease, major extirpative surgery is safe when offered to appropriately selected patients. An actuarial 5-year survival after an R0 resection of 52.6% was noted. Again, this is similar to the overall 5-year survival range of 46% to 68% recently reported from major specialized centers in the United States1,5,6 and in contrast to survival figures of 10% to 25% for pancreatic cancer.1,6 The greater resectability rate alone does not explain the improved survival relative to pancreatic cancer. Whereas the patient groups are not directly comparable, Howe et al. 1 from Memorial Sloan-Kettering Cancer Center noted that the rates of positive lymph nodes were not significantly different between resected ampullary, distal bile duct, duodenal, or pancreatic cancers, ranging from 46% to 55%. They argued that undefined biologic factors might be important in prognosis, a suggestion that appears bolstered by recent work.4 Regarding the optimal surgical procedure, these authors did not address the issue of local resection for adenocarcinoma. Others, however, have noted significant issues with recurrence,1 suggesting that the role of local excision for ampullary adenocarcinoma is probably confined to the elderly and patients at high risk who are considered unsuitable for pancreaticoduodenectomy.
Following complete resection, the authors determined that TMN stage, microscopic lymphatic vessel, and venous invasion in the primary tumor were significant independent predictors of overall survival. A degree of caution should be exercised in relation to the authors’ contention that carcinoembryonic antigen (CEA) significantly influenced survival and with CA 19–9 predicted distant failure. In a retrospective review over a prolonged period such as this study, the best that can be said is that the elevated tumor marker was in the authors’ analysis associated with poor outcome. Whether this is truly significant is questionable and certainly remains to be confirmed. In addition to the finding of this current study, other contemporary series have also suggested that important prognostic variables include absence of nodal metastases, small primary size, well-differentiated tumors, absence of perineural invasion, T1/2 disease, and negative surgical resection margins.1,4,5
It was interesting to note that excellent local control was achieved following surgical resection. A standard pancreaticoduodenectomy and nodal clearance was performed in most patients, with an extended retroperitoneal lymphadenectomy performed only in selected cases. Nonetheless, no patient had evidence of locoregional recurrence alone, with all 24 patients with relapsing disease in the current study having distant disease. As would be expected, the liver was the predominant site of metastatic disease, followed by lymph nodes outside the surgical field, peritoneum, lung, and bone. This information is important and, although noted previously, has not been emphasized in the design of adjuvant trials. The significant failure rate (44%) at 30 months observed in the current study argues strongly for the use of adjuvant therapy following resection. Novel systemic therapies are required but the role and benefit of radiation therapy following an R0 resection is certainly debatable.
As mentioned, it could be argued that these impressive results presented by Todoroki et al. in conjunction with other recently published series support the hypothesis that periampullary tumors represent a spectrum of diseases, with intestinal-type tumors (duodenal and most ampullary) at the biologically more favorable end and pancreaticobiliary tumors at the other end. Thus, it could be argued that the inclusion of patients with ampullary cancers in adjuvant trials in which the predominant entity is pancreatic cancer is questionable. Even with sophisticated stratification and subset analyses, interpretation of results remains problematic. A more rational approach would be to develop a therapeutic strategy directed against ampullary carcinoma alone. Given the relatively small number of patients involved, such trials would need to be organized as a multi-institutional and, possibly, even a multinational effort, offering an opportunity for cooperative groups interested in gastrointestinal cancer to take a lead in this area.
Received for publication October 8, 2003. Accepted for publication October 17, 2003.
REFERENCES
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