Received Date: May 04th, 2016; Accepted Date: June 02nd, 2016
Context The neuroendocrine tumor of the ampulla of Vater represents a rare disease and, although the majority of them are indolent, this neoplasm has a relatively poor prognosis. A quarter of cases of ampullary neuroendocrine tumors have been detected in patients with neurofibromatosis type I (von Recklinghausen's disease). The biological behavior of ampullary neuroendocrine tumor shows no association to the dimension of the tumor and they are more aggressive than non-ampullary duodenal neuroendocrine tumor. The most frequent symptoms are jaundice (60%) and abdominal pain (40%), followed by weight loss (10%). The determination of histopathology is of utmost importance and involves specific immunohistochemical staining. In most ampullary neuroendocrine tumors, the expression of neuroendocrine markers as chromogranin A, neuron specific enolase and synaptophysin, either isolated or in combination is positive. The carcinoid syndrome is uncommon, unless hepatic metastases are present. Most neuroendocrine tumor of the duodenal ampulla is diagnosed incidentally in the duodenoscopy. Case report The authors describe three cases involving neuroendocrine tumor of the ampulla of Vater that were operated upon a single institution and report the etiopathogenic, clinical, diagnostic, therapeutic and prognostic characteristics of this rare neoplasm. Conclusions Neuroendocrine tumors of the ampulla of Vater without invasion and a diameter of <2 cm seem to have a better prognosis. Radical resection should be the standard approach in most patients due to the poor accuracy of preoperative and intraoperative assessments of lymph node involvement and the high incidence of lymph node metastases, even in tumors that are smaller than 2 cm.
Ampulla of Vater; Carcinoid Tumor; Carcinoma, Neuroendocrine; Gastrointestinal Neoplasms; NeuroendocrineTumors; Prognosis
NF1 neurofibromatosis type I; NSE neuron specificenolase
Neuroendocrine tumors (NETs) are slow-growing neoplasms that are derived from the enterochromaffin cells situated in the crypts of Lieberkühn, which belongs to the neuroendocrine system . Gastrointestinal NETs correspond to a group of well-differentiated neuroendocrine tumors originating from various neuroendocrine cells positioned in the gastrointestinal mucosa and submucosa . Consequently, there is diversity in their clinical presentation, incidence at specific anatomic sites, biological behavior, hormone production, morphologic characteristics and immunophenotype .
A NET of the ampulla of Vater is a rare and little isknown about its demographic, biologic behavior and clinical performance [2, 3, 4, 5]. Further, the detailed prognostic factors of this tumor have not until now beenestablished [6, 7].
These neoplasms correspond to 2% of the periampullary malignancies and less than 1% of gastrointestinal neuroendocrine tumors [1, 7, 8]. Less than 130 patients have been reported until 2013 in the majority as case reports [3, 9]. The most frequent age of patient involvement is between the 5th and 6th decades of life. Women are affected threetimes more often than men [4, 9].
The ultimate pre-operative diagnosis based on histology may be difficult since they present with a similar clinical picture to the adenocarcinomas of this region [9, 10, 11]. A quarter of cases of ampullary NETs have been detected in patients with neurofibromatosis type I (NF1) (von Recklinghausen's disease) .
The authors describe three cases of NET of the ampulla of Vater that were operated upon a single institution and report the etiopathogenic, clinical, diagnostic, therapeuticand prognostic characteristics of this unusual condition.
Male, white, fifty-eight-years-old; the patient complained of epigastric pain and weight loss. The duodenos copy revealed a tumor in the major papilla, and a biopsy showed a malignant undifferentiated small cell tumor (Figure 1). The patient underwent a Whipple procedure. A pathological exam of the resected neoplasm showed a tumor situated in the major ampullary region, with a 2.5 cm diameter that was considered as a well differentiated (Low Grade, G1) NET with mitotic index of1 mitose in 10 high-power fields (HPF). The lymph nodeswere not infiltrated and there was no angiolymphatic orperineural invasion. The TNM classification  of thetumor was stage I (T2N0M0). The immunohistochemical stained of the neoplasia showed a positive expression ofthe neuroendocrine markers neuron specific enolase (NSE) and chromogranin A. The patient progressed uneventfully and, after seven years following the operation, he is asymptomatic with a normal serum chromogranin A level.
Female, white, fifty-nine-years-old; the patient complained of weight loss of 10 kg without any apparent cause. The duodenoscopy revealed a submucosal tumor in the major papilla region and the endoscopic biopsies were inconclusive. The patient was submitted to a Whipple procedure. Pathological examination revealed a well differentiated (Low Grade, G1) carcinoma (Figure 2) in the region of the major duodenal ampulla, with a diameter of 3.5 cm and extensive areas of necrosis and hemorrhage, without lymph node metastases or angiolymphatic/ perineural infiltration. The mitotic index was 2 mitoses in 10 HPF. The TNM classification of the neoplasm was stage I (T2N0M0). The immunohistochemical study of the neoplasia showed chromogranin A antibody expression. Nine years after the operation, the patient has no abnormalities and his serum chromogranin A level isnormal.
In a forty-seven-years-old white male with jaundice, the duodenoscopy revealed a tumor with a diameter of 2.8 cm situated in the major duodenal papilla. Biopsies of the lesion showed a moderately differentiated (Intermediate Grade, G2) neuroendocrine carcinoma with mitotic index of 3 mitoses in 10 HPF. It was also observed the presence of nuclear atypia. Immunohistochemical study showed the expression of chromogranin A (Figure 3), NSE, synaptophysin, and anti-cytokeratin AE1/AE3 antibodies. The computed tomography (CT) revealed disseminated metastases in both hepatic lobes. The patient underwent laparotomy and a large mass in the hepatic hilum was found. Despite this mass, a hepaticojejunal Roux-en-Y anastomosis was performed. The TNM classification of the neoplasm was stage IV (TxNxM1). The immunohistochemical stained of hepatic metastases showed the same expression of the tumor situated in the major duodenal papilla, but they were nonfunctional. The patient received systemic chemotherapy and died withactive disease five years after the operation.
Figure 3: Photomicrograph of neuroendocrine tumor of the ampullaof Vater. A strong expression on the cytoplasmic membrane and in thecellular cytoplasm to the anti-chromogranin A antibody is represented by the brownish color, confirming the neuroendocrine nature of theneoplasm. (Immunohistochemistry, chromogranin A, 400x).
The World Health Organization (WHO) classification places neuroendocrine tumors into three main categories which emphasize the tumor grade: well-differentiated neuroendocrine tumors, further subdivided into tumors with benign and those with uncertain behavior; well differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior and poorly differentiated (high grade) neuroendocrine carcinomas, which are thelarge cell neuroendocrine and small cell carcinomas [13, 14]. Historically, well-differentiated neuroendocrine neoplasms have been referred to as carcinoid tumors, a term which may cause confusion because clinically a carcinoid tumor is a serotonin producing tumor associated with functional manifestations of carcinoid syndrome .
NETs are also categorized as their mitotic activity and the presence of necrosis [4, 14]. The well differentiated (Low Grade, G1) NET show less than 2 mitotic figures per 10 HPF and a lack of necrotic areas. Differently, the moderately differentiated (Intermediate Grade, G2) neuroendocrine carcinoma reveals 2-20 mitotic figures per 10 HPF or the presence of necrotic foci. In turn, the poorly differentiated (High Grade, G3) neuroendocrine carcinomas disclose more than 20 mitotic figures per 10HPF and the presence of necrotic foci .
The WHO categorizes neuroendocrine ampullary and duodenal neoplasms into an only one class, but studies [3, 4, 5] revealed that these neoplasms are actually different lesions. Unlike the non-ampullary duodenal NETs, the biological behavior of ampullary NETs shows no association to the dimension of the tumor and they are more aggressive than non-ampullary duodenal NETs. Moreover, ampullary NETs usually express somatostatin and are related with NF1, which is rare with duodenal NETs [4, 12, 14, 15].
NF1 patients are at increased risk of developing neoplasms in the gastrointestinal tract, including neuromas, gastrointestinal stromal tumors (GIST) and somatostatinrich ampullary carcinoids . Ampullary NETs are found in 30% of patients with NF1 and the presence of the NF1 is considered the only apparent risk factor for thedevelopment of the NET of the duodenal ampulla . One explanation for this risk is that, in patients with NF1, thetumors of a neural origin and NETs can occur as a result ofthe transformation of the endodermic-ectodermic complexnear the papilla, due to the mutation of the NF1 tumorsuppressor gene . None of the cases in this report hadalterations that were suggestive of NF-1.
In typical cases, NETs of the duodenal ampulla are composed of small islands of round cells and monomorphic nuclei that were surrounded by the cytoplasm with small edges. The pattern of trabecular or diffuse growth may be present. Mitoses are unusual and nuclear atypia may not be obvious [1, 4, 14], but both events were found in the third case of this series.
As a rule, NETs of the ampulla of Vater are not angioinvasive. They are <1 cm in diameter and show up to two mitoses per 10 HPF . Conversely, the spread of the neoplasm to the muscularis propria, with a diameter of >2 cm and the high degree of mitotic activity (3 or more mitoses per 10 HPF) are considered risk factors forthe onset of metastases [16, 17, 18], as occurred in case #3 of this report. Furthermore, the duodenal papilla is ahighly vascularized area, where even small tumors arelikely to spread, which contributes to the dissemination of metastases, regardless of the size of the primary NET [17, 18] as observed in case #3. Over half of the patients withan ampullary NET of <2 cm showed positive lymph nodedisease; the metastases were identified in 66% of tumorsthat were <1 cm, in 50% of tumors between 1 and 2 cm and in 46% of tumors that were >2 cm [19, 20]. Metastases usually occur in the lymph nodes and liver, as occurred in the case #3 within this series.
The determination of histopathology is of utmost importance and involves specific immunohisto chemical staining [4, 14, 16]. In most ampullary NETs, the expression of neuroendocrine markers as chromogranin A, NSE and synaptophysin, either isolated or in combination, is positive. The guidelines of The North American Neuroendocrine Tumor Society (NANETS) recommend the performing of chromogranin A and synaptophys in for the immunohistochemical study, and the obtaining of the mitotic rate or Ki67 expression as cell proliferation index . The cases of this series were characterized as neuroendocrine origin by the immunohistochemical positivity of chromogranin and /or synaptophysin and the mitotic rates were obtained in all of them. In case #3, a neuroendocrine carcinoma, cytokeratin, which is considered a carcinoma marker , had its expression positive in the immunohistochemical study. The tumor cells can also express somatostatin (58%-67%), insulin (25%), serotonin (17%) and cholecystokinin (17%) [1, 4, 14]. Ampullary NETs usually do not express gastrin, unlike the non-ampullary duodenal carcinoids, in which positive gastrin immunoreactivity is positive in more than half of the patients . The presence of the expression of cell proliferation markers PCNA and Ki-67 may reflect the more aggressive biological behavior and metastatic potential of an ampullary NETs [4, 11].
The most frequent symptoms of ampullary NETs are jaundice (60%) and abdominal pain (40%), followed by weight loss (10%), symptoms also observed in the cases of this series. Furthermore, upper gastrointestinal bleeding (3%) and acute pancreatitis (3 to 6%) may be observed [11, 22, 23]. The carcinoid syndrome is uncommon, unless hepatic metastases are present [11, 16, 22]. However, in case #3, despite the presence of hepatic metastases, the patient had no carcinoid syndrome probably because the primary tumor was nonfunctional. The NETs of the duodenal ampulla rarely cause functional syndrome associated with the over production of somatostatin, which can trigger diabetes mellitus, gallstones and steatorrhea; in this condition, the NET is named as somatostatinoma [11, 23, 24].
Most NETs of the duodenal ampulla is diagnosed incidentally in the duodenoscopy, as occurred with the case #2 of this report. The ampullary NETs often are covered by intact mucosa, which explains the high rate of false-negative or inconclusive biopsies [4, 11, 23]. Thus, the histological diagnosis with samples obtained by preoperativeendoscopic biopsies is performed in only 15% of patients [11, 22]. In this series, only the third case had a preoperative diagnosis that was made by endoscopic biopsy.
The abdominal CT, abdominal magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP) and duodenal endosonography (EUS) complete the assessment of a NET of the duodenal ampulla [11, 23, 25]. CT and MRI usually do not identify these small primary neoplasms in these cases because their sensitivity is only 33%. However, CT and MRI can reveal metastases in the liver or mesentery , as occurred in the third case in the present series. Magnetic resonance cholangiography associated with an angiography can simultaneously show the enhancement of a submucosal mass, as well the biliary and vascular structures . The possible involvement of the bile duct can be clarified by the ERCP and/or EUS. To detect smalltumors, the EUS can be extremely useful [11, 23].
A large variety of the ampullary NETs and their metastases can express a high density of somatostatin specific receptors. Octreotide, a somatostatin analogue, has a high affinity and a sensitivity of 86% [23, 26] in the detection of NETs with somatostatin receptors. This sensitivity is markedly reduced when the size of the tumoror metastases are < 1.0 cm in diameter [4, 11, 23].
The differential diagnosis of an ampullary NET should mainly be performed with non-ampullary NETs, a Brunner's gland hamartoma, heterotopic pancreatic and gastric tissues, adenoma, adenocarcinoma, gangliocytic paraganglioma, gastrointestinal stromal tumor (GIST), lymphoid hyperplasia and mesenchymal tumors, such as neurofibromas and schwannomas [8, 10, 11, 23].
A radical excision represented by the pancreaticoduodenectomy with lymphadenectomy is recommended, regardless of the tumor size, because the published date indicates that these tumors metastasize in half of the cases, regardless of the primary tumor’s size [8, 20, 26, 27]. The radical excision was adopted in two patients within this report, one with a well differentiated NET and other with a moderately differentiated neuroendocrine carcinoma. Both patients are alive seven and nine yearsafter the operation, respectively.
Less radical treatment as a reasonable alternative to a duodenopancreatic resection to reduce surgical morbidity and preserve organ function has the risk of producing an incomplete removal of the tumor because the preoperative evaluation is often inaccurate, especially regarding the lymph node involvement [16, 28]. Furthermore, the local resection of ampullary NETs is technically difficult and presents significant morbidity [28, 29]. Thus, it is reasonable that patients should not be placed at risk of failing to detect and resect their metastatic lymph node disease, thus avoiding their cure by the appropriate oncologic operation. However, it should be consideredthat the long-term survival of patients with an ampullary NETs was achieved with the local excision [19, 20, 23]. Consequently, the local excision may be considered forpatients with highly differentiated, slow-growth tumors witha diameter <2 cm, but who are at high surgical risk and whoare unable to tolerate a more extensive operation [22, 23].
An endoscopic ampullectomy may be a viable option in selected patients with mobile, superficial and well differentiated tumors that are confined to the mucosal layer without vascular or lymphatic invasion [22, 26, 28]. A laparoscopic transduodenal resection is suggested as a feasible procedure in select patients with an ampullary NET .
In metastatic tumors, the resection of the primary neoplasm and the administration of somatostatin analogs may become stable the disease and improve the patient's quality of life [22, 25]. Likewise, in patients with hepatic metastases and carcinoid syndrome, the surgical resection and/or cytoreductive techniques, such as radiofrequency ablation and/or chemoembolization of the hepatic metastases, may improve symptoms that are mediated by hormones produced by the tumor. Somatostatin analogs, such as octreotide or lanreotide, may provoke symptomatic and biochemical responses and decrease the enlargementof metastases via a cytostatic effect [23, 24].
The serum chromogranin A levels reflect the tumor load of the NETs and is a useful tumor marker for the monitoring of disease response to the treatment, progression and, particularly, to detect relapse [27, 28, 31].
The presence of distant metastases is the most important prognostic factor in determining survival. Other tumor aspects, such as nodal involvement, size and resection margins, appear to be of lesser significance in the long-term survival [4, 24]. Even ampullary NETs in advanced stages have more insidious progress than ampullary carcinoma. Concerning case #3, the patient with neuroendocrine carcinoma and multiple liver metastases who underwent palliative operation and chemotherapy survived 5 years after the operation. The overall fiveyear survival of patients with a resected ampullary NETs reaches 90% for well-differentiated tumors, but markedly decreases with a lower differentiation of the tumor [4, 11, 24, 27]. The low-grade tumors show 5- and 10-year survival rates of 80% and 71%, respectively, whereas the high-gradeNETs have 10-year survival rates of 15% [11, 27].
Although NET of the ampulla of Vater represents a rare disease and the majority of ampullary NETs is indolent, this neoplasm has been increasingly reported in recent years and is associated with a relatively poor prognosis. NETs without invasion and a diameter of <2 cm seem to have a better prognosis. Radical resection should be the standard approach in most patients with a NET of the ampulla of Vater, due to the poor accuracy of preoperative and intraoperative assessments of lymph node involvement and the high incidence of lymph node metastases, even intumors that are smaller than 2 cm.
The authors declare that they have no competing interests.