Carcinoid of the ampulla of Vater
Dr Helmut Friess, Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Email: email@example.com
Abstract Endocrine neoplasms only rarely occur at the ampulla of Vater, comprising mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas). Only 105 cases are reported in the literature, most as single case reports. For many years, the neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract have been subsumed as ‘carcinoids’. Instead, in the latest World Health Organization (WHO) classification published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas). Patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis. Besides endoscopic retrograde cholangiopancreatography, endosonography, computed tomography or magnetic resonance imaging may complete the staging approach of this tumor. The Kausch–Whipple procedure or pylorus-preserving pancreaticoduodenectomy is considered the treatment of choice for ampullary, well-differentiated carcinoids >2.0 cm and for ampullary neuroendocrine carcinomas. However, it should be considered that long-term survival of patients with ampullary carcinoids is also reported after local tumor excision (5-year survival rate of 90%). The dilemma is that the differentiation of neuroendocrine tumors cannot be assessed intraoperatively in most cases. Therefore, considering that the 5-year survival rate in patients with neuroendocrine carcinomas of the ampulla of Vater is very low without radical resection, neuroendocrine tumors of the ampulla of Vater without definite histological differentiation should undergo extended surgery.
The incidence of carcinoids is 1.6–2.0 cases per 100 000 persons per year. Sixty percent of all carcinoid tumors within the gastrointestinal tract have their location in the appendix, followed by the small intestine, the rectum and the stomach. Only 0.05% involve the pancreas, making tumors of the ampulla of Vater very rare in comparison to carcinoid tumors involving the duodenum (2%).1–3 Only 105 cases have been reported in the literature, most as single case reports.4,5 In contrast to these clinical reports the incidence of carcinoids and endocrine cell micronests of the minor and major ampulla could be up to 10%.6 This discrepancy can be explained by the following facts: higher incidence is found in study groups with autopsy cases; specimens were more meticulously and carefully examined and smaller carcinoid tumors without clinical symptoms were detected (small carcinoids located in the minor papilla). Furthermore, different histological criteria of carcinoid may lead to lower or higher incidences.6 Thus, in case of surgery, carcinoid tumors of the ampulla of Vater have to be taken into account when tumors in this region appear. These tumors exhibit clinical, histological, and immunohistochemical characteristics, making them distinguishable from other duodenal or small intestinal carcinoid tumors.
For many years, the neoplasms of the disseminated neuroendocrine cell system of the GI tract have been subsumed as ‘carcinoids’. But because these tumors display a broad morphological and biological spectrum, this is no longer adequate.7 Instead, in the latest World Health Organization (WHO) classification, published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas).8 Whereas the latter two categories clearly represent malignant neoplasms, well-differentiated endocrine tumors may clinically either behave as benign or malignant: as a rule, non-angioinvasive tumors that do not exceed a size of 1 cm and show two or less mitoses per 10 high-power fields are considered benign, whereas the others harbor an increased risk of clinical malignancy.8
Endocrine neoplasms only rarely occur at the ampulla of Vater, consisting of mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas).9–12 Neuroendocrine tumors of the duodenum have to be considered as a differential diagnosis in tumors of the ampulla of Vater, and are differentiated into five types. Besides the low-differentiated neuroendocrine carcinomas, the duodenal gastrinomas (75%), the duodenal somatostatinomes, the non-functioning serotonin-, gastrin-, or calcitonin-producing tumors (highly differentiated) and the duodenal paraganglinomas belong to this category of tumor (Table 1).
Table 1. Neuroendocrine tumors of the duodenum
|Duodenal gastrinoma (approx. 75%)†||Sporadic (singular) or associated with MEN-1 (multiple)|
|Connected to Zollinger–Ellison syndrome|
|Usually not bigger than 1 cm|
|Very often lymph node metastasis (bigger than the primary tumor)|
|Duodenal somatostatinoma (approx. 15%)†||Often located at the ampulla of Vater|
|Potentially malignant if muscularis propria is infiltrated|
|Histologically characterized by glandular pattern with psammoma bodies|
|No somatostatin syndrome (diabetes mellitus, cholelithiasis, diarrhea)|
|Associated with neurofibromatosis type I (von Recklinghausen disease)|
|Non-functioning duodenal neuroendocrine tumors†||Mainly benign, highly differentiated|
|Serotonin-, gastrin-, or calcitonin-producing tumors without corresponding syndrome|
|Low-differentiated neuroendocrine carcinoma||Highly malignant disease|
|Gangliocystic paraganglioma||Located near the ampulla of Vater|
|Benign character, although infiltration of muscularis propria may appear and size often >2 cm|
Carcinoid tumors of the gastrointestinal tract are part of the amine precursor uptake and decarboxylation (APUD) system; they secrete diverse amines and polypeptide hormones that lead to the carcinoid syndrome.13–15 In contrast to patients with carcinoid tumors in the jejunum and ileum, patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Only 2 of 71 patients (2.8%) with papillary carcinoids reviewed in the literature had a history of flushing, diarrhea, and asthma.4 Furthermore, carcinoid tumors of non-ampullary duodenal and other small intestinal carcinoid tumors show immunohistochemical evidence of multiple hormone production that distinguish them from the ampulla of Vater.14,15 Up to 60% of patients with carcinoid tumor of the duodenum show evidence of gastrin production (only 5% with Zollinger–Ellison syndrome) and none of the ampullary carcinoids expressed gastrin.16 In most studies of the literature >50%17,18 of duodenal carcinoids produce somatostatin, only one series reported more expression of somatostatin in ampullary carcinoids (67%) than in duodenal carcinoids (30%).16 In contrast, none of the patients of the Makhlouf et al. study with duodenal carcinoids or ampullary carcinoids presented with a somatostatin syndrome (diarrhea, diabetes mellitus and cholecystolithiasis).16 Immunhistochemically, other hormonal markers such as chromogranin (92%), neuron-specific enolase, synaptophysin, and cytokeratin (all in 100% of the cases) have been studied in few cases, but the number of patients evaluated is too small to make these markers significantly reliable for diagnostic methods.16 Recent studies are suggesting that assessment of the proportion of proliferating cell nuclear antigen (PCNA) and Ki-67 may show an association between histologically aggressive neoplasias with frequent metastasis and Ki-67 or PCNA immunoreactivity.19–21 The results of these studies demonstrated that higher expression of PCNA and Ki-67 might reflect a more aggressive biologic behavior and metastatic potential in ampullary carcinoids than in duodenal carcinoids.19 In contrast, the labeling index was similar in ampullary carcinoids and duodenal carcinoids, suggesting that both tumors represent slow growing carcinomas. One reason for this mismatch could be anatomical variations; the ampulla of Vater is a strongly vascularized area where even small carcinomas are likely to disseminate.
In summary, the great variability in immunohistochemistry does not contribute to determining the clinical feature or the prognosis of the disease. Thus, the diagnostic pathway for carcinoid tumors of the ampulla of Vater is still a challenge. Corresponding to their location, carcinoid tumors of the ampulla of Vater cause jaundice in approximately two-thirds of patients.4 If jaundice or abdominal pain occur in patients with neurofibromatosis then the possibility of a carcinoid tumor should be considered.22,23 Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis.4 One explanation for this phenomenon could be that neurogenic and carcinoid tumors in patients with neurofibromatosis occur as a result of transformation of an endodermal–ectodermal complex. This complex is also present near the ampulla of Vater.24
In the literature the preoperative diagnosis of carcinoid tumor was correct in only 14% of the patients (10 of 71).4 The reason for this high failure rate is that only in rare cases carcinoid of the ampulla of Vater presents with an ulcerative lesion of the duodenal mucosa. Thus, the tumor is frequently submucosal and cannot be easily detected in the biopsy specimens. Nevertheless, duodenoscopy in combination with endoscopic retrograde cholangiopancreatography (ERCP) is the diagnostic method of choice, and often deeper biopsies are needed to identify carcinoid tumors. As well as ERCP, endosonography (EUS), computed tomography (CT) or magnetic resonance imaging (MRI) complete the staging approach of this tumor. Computed tomography usually fails to identify the small, primary carcinoid tumor, but can demonstrate the characteristic appearance of metastases in the liver or in the mesentery: rounded soft-tissue nodules surrounded by radiating soft-tissue strands.25 Small tumors seem to be best diagnosed by EUS (up to 100%),26,27 whereas this technique is to a very high degree dependent on the experience of the physician. Sensitivity of MRI to detect small ampullary tumors decreases to 33%,27 but uncertain tumor infiltration of blood vessels can be verified best by MRI (or EUS). The usefulness of positron emission tomography (PET) for the diagnosis of periampullary neoplasms could not be proved: despite high sensitivity and specificity in diagnosing these tumors, PET did not change clinical management in the majority of patients. In addition, PET failed to detect more than 10% of periampullary malignancies and did not provide the anatomical details of the tumors.28 Alternatively, somatostatin receptor scintigraphy is a sensitive diagnostic method to detect endocrine gastrointestinal tumors and their metastases. Sensitivity of this method is reported to be up to 86%.29 In the case of ampullary carcinoids the data are not so clear: density of somatostatin receptors is reported to be 88%;30 one clinical trial demonstrated a sensitivity of 100% for primary carcinoids and 95% for liver and lymph node metastases.31 In contrast, small tumors (≤1 cm) or liver metastases (<0.8 cm) cannot be verified by somatostatin receptor scintigraphy. This is one of the reasons why approximately 45% of metastatic ampullary carcinoids are still not identified preoperatively but intraoperatively.4 In the study by Krenning et al. only 54% of the lymph node metastases could have been identified preoperatively.30
The characteristics of all carcinoids of the ampulla of Vater published in the literature are summarized in Table 2.4,16,19,32–38 In a total of 105 patients the average age was 48.6 years, and the gender ratio of female to male was 2.8:1. Jaundice is the predominant symptom (53%) at time of admission to hospital, followed by pain (24.6%) and weight loss (3.7%). Another rare but specific symptom could be acute pancreatitis (6.0%).4 The reported tumor sizes are between 0.2 and 9.5 cm in diameter. Carcinoids of the ampulla of Vater are often associated with the von Recklinghausen disease (in 25.9% of all cases of the literature). In 58% of all reported patients with ampullary carcinomas the Whipple procedure was the favorite approach for therapy. In an average follow-up time for all patients in the literature of 25.3 months, 46.6% developed metastasis.
Table 2. Characteristics in up to 105 reported patients with carcinoids of the ampulla of Vater
|Mean age (years)||48.6 (105/105)|
|Sex male : female||1 : 2.8 (100/105)|
|Mean follow-up (months)||25.3 (61/105)|
|Clinical symptoms (%)|
| Jaundice||53.1 (81/105)|
| Pancreatitis||6.0 (81/105)|
| Pain||24.6 (81/105)|
| Weight loss||3.7 (81/105)|
|Von Recklinghausen disease (%)||25.9 (81/105)|
|Metastatic disease (%)||46.6 (60/105)|
|Kausch–Whipple operation (%)||58.0 (81/105)|
No definitive statement can be made regarding the optimal treatment of ampullary carcinoids given the small number of 105 cases in the literature. However, review of all published cases indicates that extent of resection does not significantly affect the prognosis. The classical Kausch–Whipple procedure or pylorus-preserving pancreaticoduodenectomy (PPPD) are considered to be the treatment of choice for ampullary carcinoids >2.0 cm. The mortality and morbidity rates are comparable between the two approaches,39 with rates lower than 5% and 15%, respectively. The discussion as to whether the classical or the pylorus-preserving version of the Kausch–Whipple operation should be preferred is still controversial. However, there is evidence that both procedures are equivalent in regard to oncological radicality, and that the pylorus-preserving operation has advantages in regard to operation time and blood loss.40–43
One reason favoring the Whipple procedure in comparison to local excision might be the aforementioned fact that many patients with ampullary carcinoids are operated on at advanced tumor stage, with lymph node metastasis that could not be diagnosed preoperatively.19 However, it should be considered that long-term survival of patients with ampullary carcinoids also was achieved after local excision.4,38 In cases with high cardiopulmonal comorbidity and especially in tumors <2 cm, local excision might be a good alternative approach demonstrated by retrospective review of the small number of reported cases. In contrast to this recommendation, some authors restrict ampullectomy to a limited number of selected patients, and the procedure has to be performed by experienced surgeons because operative morbidity can be significant and local recurrence high.44–46
Alternatively, in patients with very high comorbidity or age, conservative treatment or minimally invasive endoscopic papillotomy should be taken into consideration. This is because, following endoscopic papillotomy and recovery from jaundice, some patients had no progression of the disease for 1 year or more.34
Estimation of the prognosis in patients with ampullary carcinoids is difficult; only a few cases are reported in the literature and follow-up data are very often limited. In all published cases with carcinoids of the ampulla of Vater, the size of the tumor has no prognostic implication.4,16 Furthermore, in contrast to duodenal carcinoids a correlation between mitotic activity and metastatic potential could not be found.16 Most authors classify carcinoids of the ampulla of Vater as an almost benign disease. The prognosis is reported to be excellent, with an overall 5-year survival rate of 90%.4 This is likely to be related to the fact that in the Hatzitheoklitos et al. study the tumors subsumed as carcinoids predominantly were well-differentiated endocrine tumors.4 In only two reports with 12 patients and five patients, respectively, it was concluded that ampullary carcinoids are associated with a relatively poor prognosis.16,19 Like all studies with small study groups, these results are not representative for estimation of the prognosis of patients with ampullary carcinoids; in particular, in these two aforementioned studies most ampullary carcinoids had already metastasized into lymph nodes or liver and could not represent the average survival rate of this tumor entity. In addition, all studies in the past are lacking differentiation between well-differentiated and poor-differentiated endocrine carcinomas on the one hand, and well-differentiated neuroendocrine tumors with good prognosis on the other. By subsuming the different tumors under the term ‘carcinoid’, in these studies the prognosis of neuroendocrine tumors of the ampulla of Vater is depending on the percentage of neuroendocrine carcinomas.
Therefore, indications for limited resections such as ampullectomy are controversial and the threshold for conversion to pancreaticoduodenectomy should be low unless ampullectomy is performed with palliative intent. In centers for pancreatic surgery the classical or the pylorus-preserving Kausch–Whipple procedure can now be performed with the same low morbidity as an ampullectomy.
Since the new revision of the WHO classification published in 2000, carcinoids tumors are renamed as neuroendocrine tumors. Carcinoids of the ampulla of Vater comprise a broad spectrum of morphologically and biologically diverse tumors, such as various subtypes of well-differentiated endocrine tumors, well-differentiated endocrine carcinomas, and poorly differentiated endocrine carcinomas. Highly differentiated neuroendocrine tumors are considered to be benign if they do not infiltrate the muscularis (Table 1). Because the 5-year survival rate is higher than 90%, less radical approaches such as ampullectomy are preferred in highly differentiated tumors. Nevertheless, diagnostic approaches preoperatively might be misleading in many cases because endocrine neoplasms such as well- or poorly differentiated neuroendocrine carcinomas frequently do not involve the duodenal mucosa or have already metastasized into lymph nodes very early. Therefore, the tumor size serves as an important factor to predict the biological behavior of endocrine tumors, including the possibility of metastatic spread, and to plan the surgical strategy. Whereas the WHO classification of gastrointestinal endocrine tumors recommends a ‘critical size’ of 1 cm, some authors suggest local excision of ‘carcinoids’ <2 cm, if the histopathological diagnosis and the tumor stage cannot be evaluated preoperatively.38,47 Nevertheless, this rule may also be misleading, and some authors prefer to perform a partial pancreaticoduodenectomy (Kausch–Whipple) for radical resection in suspicious tumors of the ampulla of Vater regardless of their size. Because the Kausch–Whipple procedure can now be performed as safely as local excisions in ampullary tumors in specialized centers, the patients should not be put at risk for non-visualized metastatic lymphatic disease, which can be cured by an adequate oncological operation.
However, in patients with very high comorbidity or age and highly differentiated neuroendocrine tumors, conservative treatment, minimally invasive endoscopic papillotomy or local excision can be taken into consideration as demonstrated by cases with long-term survival after local excision.4,38
The goal of diagnostic approaches will be to detect primary neuroendocrine tumors earlier and to predict the tumor stage correctly, thereby supporting surgeons in planning the extension of the operation.
In conclusion, the old recommendations made under the impression to operate on ‘semi-malignant carcinoids’ should be reevaluated: local excisions or even conservative treatment for endocrine neoplasms of the ampulla of Vater, especially in young patients, should be avoided; pancreaticoduodenectomy can be safely performed in high-volume centers with a low morbidity rate and mortality rate.