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Keywords
Endoscopic ultrasound, neuroendocrine tumor, pancreatic endocrine tumor.
Introduction
Pancreatic endocrine tumors (PETs) are rare tumors (1 per 100,000 population) thought to originate from immature stem cells that are part of the neuroendocrine system (1, 2). They occur, or are at least discovered, most commonly in the fourth and fifth decade of life with a slight female predominance (3). These tumors may produce a variety of hormones including insulin, gastrin, glucagon, pancreatic polypeptide, vasoactive intestinal peptide, and somatostatin (Table I). They are classified as functioning (70% of cases) if responsible for a clinical syndrome related to hormonal release, or non-functioning if there are no hormone-related symptoms attributable to the tumor (15-30% of cases) (4). The most common PETs are insulinomas and gastrinomas. Insulinomas are found within the pancreas greater than 90% of the time, whereas 80% of gastrinomas are located within the gastrinoma triangle formed by the junction of the cystic and common bile ducts superiorly, the junction of the second and third portions of the duodenum inferiorly, and the junction of the neck and body of the pancreas medially (3,5). In up to 30% of cases, gastrinomas are found in extrapancreatic sites such as the liver, jejunum, lymph nodes, or lung. Insulinomas are rarely malignant (<10% of cases) as compared to other PETs which are malignant in 50-90% of cases (6-8). Despite this high rate of malignancy, the overall prognosis of PETs is more favorable compared to pancreatic adenocarcinoma.
Table 1: Pancreatic Endocrine Tumors
| Tumor Type |
Pancreatic Location (%) |
Duodenal Location (%) |
Other Sites (%) |
Malignancy % |
Signs and Symptoms |
| Insulinomas |
>99% |
|
|
<10% |
Hypoglycemia, bizarre behavior, coma |
Gastrinomas |
25% |
70% |
5% |
60-90% |
Peptic ulcer, steatorrhea |
| VIPomas |
90% |
|
10% |
40-70% |
Diarrhea, hypokalemia, lethargy |
| Somatostatinomas |
55% |
45% |
|
70% |
Diabetes, gallstones, steatorrhea |
| GNRHomas |
30% |
|
70% |
60% |
Acromegaly |
| Glucagonomas |
100% |
|
|
50-80% |
Weight loss, diabetes, rash |
| ACTHomas |
100% |
|
|
>95% |
Cushing's syndrome |
| PPomas |
100% |
|
|
>60% |
Abdominal pain, diarrhea |
If functioning, the clinical presentation of PETs is driven by the individual hormone secreted in excess (Table I). If suspicion warrants, serum hormone levels can be measured, with significant elevations being diagnostic. MEN (multiple endocrine neoplasia) syndromes must also be considered, as PETs are present in 80% of MEN I cases (9). MEN I is comprised of pituitary tumors (90% of cases) and parathyroid tumors (90% of cases) along with PETs. The most common PETs associated with MEN I, in decreasing order of frequency, are non-functioning PETs (80-100%), gastrinomas (54%), and insulinomas (21%). If a PET is found, the possible coexistence of MEN I should be investigated by checking calcium, parathyroid, and prolactin levels. In the case of functioning PETs, once diagnosed based on clinical syndrome and hormone levels, the next step is localization of the tumor.
Localization
The utility and reliability of different imaging modalities depends on the characteristics of PETs, specifically their size. Non-functioning PETs tend to be larger (4-10 cm), heterogenous, and may contain cystic areas of degeneration and necrosis (Figures 1A and 1B, Video Clip 1) (10,11). Given their non-functioning state, they remain insidious until large enough to cause symptoms. Insulinomas and gastrinomas are usually smaller (2-4 cm), homogenous and rarely cystic (12). Other functioning tumors are generally slightly larger, having some of the same characteristics of non-functioning PETs, and therefore are easier to localize.
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Figure 1A |
Figure 1B |
Videoclip 1: EUS-FNA of a pancreatic cystic lesion.
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Figure 2 |
Noninvasive techniques for localizing tumors include ultrasound, computed tomography (CT) scan, magnetic resonance imaging (MRI) and somatostatin receptor scintography (SRS). Sensitivity of transabdominal ultrasound is highly operator dependent and at best, detects 50% of tumors (13-15). Until recently, the sensitivity of CT had been low. Newer multidetector helical CT provides higher resolution and several small studies have shown improved sensitivity (> 80%) in localizing PETs, particularly insulinomas (Figure 2) (16-19). For gastrinomas, a CT's average sensitivity is only 40% (20). Similarly, MRI has greater than 80% sensitivity for detection of insulinomas, but far less for gastrinomas (21-23).
Greater than 80% of gastrinomas, carcinoids, nonfunctioning PETs and glucagonomas possess somatostatin receptors. Octreotide, a synthetic somatostatin analog, can be labeled and injected for tumor localization using nuclear imaging. SRS is able to localize 88% of carcinoids, 77% of gastrinomas, 83% of non-functioning PETs and 100% of glucagonomas (24-27). SRS is also highly effective in detecting distant metastases, particularly in lymph nodes, bone, and liver (28). SRS has only a 63% sensitivity rate for detecting insulinomas, since only half of these tumors possess somatostatin receptors (29,30). Others limitations of SRS include an inability to localize the tumor to a specific region of the pancreas, and to differentiate uptake from pancreatic glandular tissue versus an adjacent lymph node.
Arterial stimulation with venous sampling (ASVS) is an invasive technique, now rarely employed, to localize functioning PETs. ASVS involves injecting secretagogues into the arterial supply of the pancreas and sampling the hepatic vein for increase in the culprit peptide level. Calcium gluconate is used for stimulating insulinomas whereas secretin is used for gastrinomas. ASVS combined with angiography achieves a detection rate of greater than 80% for localizing insulinomas, but only 41% for gastrinomas (31-33).
Although the most invasive, intraoperative ultrasound (IOUS) and intraoperative endoscopic transillumination are still employed to localize PETs. IOUS is successful in detecting 85% of PETs when localized to the pancreas or liver (34,35). However, when PETs are found in extrapancreatic sites, the sensitivity of IOUS falls to less than 50% (36). In contrast, intraoperative endoscopic transillumination has been shown to be highly effective (80%) for detection of duodenal gastrinomas. Extrapancreatic gastrinomas can appear as duodenal nodules in up to 50% of cases. Frucht et al. found endoscopic transillumination significantly more sensitive (83%) in detecting duodenal gastrinomas compared to preoperative imaging (25%) and IOUS (42%) (37). In this study, only 42% of the duodenal gastrinomas were found by routine endoscopy. When specifically evaluating for gastrinomas, initial detailed duodenoscopy with either a forward-viewing or side-viewing endoscope should be performed to search for duodenal nodules (38).
Endoscopic ultrasound (EUS) has become the preferred modality for diagnosis and localization of PETs (39,40). In the largest study to date, Anderson et al prospectively studied 82 patients with clinical, biochemical, and radiologic evidence of neuroendocrine tumors referred for EUS (41). Overall, EUS correctly localized the PET in 93% of cases; 100% of gastrinomas and 88% of insulinomas. The mean tumor diameter was 1.51 cm with 71% of the tumors less than 2 cm in size. Most tumors were hypoechoic, homogenous with distinct margins, and located in the pancreatic head. The four lesions missed by EUS were attributed to procedural inexperience, retroperitoneal fat limiting visualization, and heterogeneity of the pancreatic head.
It has been suggested that EUS may also be helpful in differentiating benign versus malignant non-functioning islet cell tumors. In a small series, malignant non-functioning tumors appeared hypoechoic with an irregular central echogenic area compared to benign non-functioning tumors which were more homogenous. These results should be interpreted with caution given the small number of patients (42). Malignant PETs more commonly are predisposed to necrosis, cystic degeneration and hemorrhage.
EUS detection of PETs is influenced by operator skill and location of the tumor. Tumor detection is more difficult with pedunculated lesions and lesions located in the pancreatic tail and duodenal wall (Figure 3A-C). Specifically, when evaluating for duodenal wall gastrinomas, use of a high-frequency miniprobe may prove valuable (38). EUS has proven cost effective in the evaluation of suspected PETs as compared to other localization techniques (43). EUS combined with other diagnostic techniques such as SRS may further improve sensitivity of detection of both primary and metastatic lesions.
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Figure 3A |
Figure 3B |
Figure 3C |
EUS-guided fine needle aspiration (FNA) allows for accurate preoperative diagnosis, with the ability to sample lesions even smaller than 1 cm (39,40). Cytologic analysis is performed on direct smears and cell block material from aspirated specimens. Intra-procedural cytologic feedback is extremely helpful, as if suggestive of a neuroendocrine tumor, 3 to 4 additional needle passes should be performed with material placed in 50% alcohol to allow for immunostaining from the resultant cell block. Immunostains specific for neuroendocrine tumors include chromogranin, synaptophysin, neurone specific enolase, and alpha-1 antitrypsin (Figure 4A-D).
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Figure 4A |
Figure 4B |
Figure 4C |
Figure 4D |
Treatment
PETs by and large respond poorly to standard chemotherapy regimens. Fortunately, these tend to be indolent tumors and medical therapy mostly consists of octreotide injections to alleviate symptoms and hopefully prevent tumor growth. Surgical resection or debulking, if feasible, is considered primary therapy. Two studies demonstrated that complete excision or debulking of metastatic PETs resulted in a 74% 5-year survival with 90% of the patients having improvement in symptoms (44,45). For functioning gastrinomas greater than 2 centimeters, as in Zollinger-Ellison syndrome, surgical enucleation is recommended. However, in MEN I when small or multiple tumors are present, surgery should be deferred.
The diagnostic and localizing capability of EUS has greatly influenced surgical management of PETs. Prior to EUS, up to 50% of insulinomas and gastrinomas were not imaged before proceeding to the operating room. With a firm preoperative diagnosis via FNA and accurate localization, EUS has enabled surgeons to perform laparoscopic enucleation and laparoscopic distal pancreatectomy for appropriate lesions (46). This improved localization with resultant minimally invasive surgery will hopefully translate to less morbidity and mortality.
At the University of Pittsburgh Medical Center, 22 PETs have been diagnosed via EUS-FNA over the past 2 years. We have seen a shift from the reported literature regarding prevalence of functioning vs non-functioning PETs. Only 4 of 22 tumors have been functioning (3 insulinomas, 1 gastrinoma). The remainder have been non-functioning tumors, with 5/18 being metastatic (Video Clip 2). We have also found the average size of non-functioning PETs to be smaller than previously reported, with an average size of 24 x 17 mm. We believe this predominance of smaller non-functioning PETs is due to widespread use of abdominal imaging and resultant detection of incidental lesions (similar to the phenomenon occurring with incidental pancreatic cysts). Accurate localization and preoperative diagnosis via EUS-guided FNA has directed surgical approach, allowing our surgeons to more frequently enucleate or laparoscopically resect the tumor. Operative time is also decreasing, as intra-operative frozen histologic assessment is unnecessary. Therefore, the accuracy and safety profile of EUS-guided FNA places it at the forefront for the evaluation of suspected PETs and incidental pancreatic lesions.
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