Somatostatinoma is a rare tumor of the gastroenteropancreatic neuroendocrine axis, representing 4% of gastrointestinal neuroendocrine tumors (NET). (Kloppel 2005) Somatostatinoma syndrome consists of diabetes mellitus, diarrhea/steatorrhea, gallbladder disease, hypochlorhydria and weight loss (332-334), but is present in less than 10% of cases and depends on the location of the tumor. This chapter will review the salient features, diagnosis and treatment of somatostatinomas.

Somatostatin (SRIF) is a tetradecapeptide that inhibits numerous endocrine and exocrine secretory functions. Almost all gut hormones that have been studied are inhibited by SRIF, including insulin, PP, glucagon, gastrin, secretin, GIP, and motilin (330). In addition to inhibition of the endocrine secretions, SRIF has direct effects on a number of target organs (331). For example, it is a potent inhibitor of basal and prostaglandin-stimulated gastric acid secretion. It also has marked effects on GI transit time, intestinal motility, and absorption of nutrients from the small intestine. The major effect in the small intestine appears to be a delay in the absorption of fat and reduced absorption of calcium.

The first cases of the somatostatinoma syndrome were reported in 1977 by Ganda and colleagues (332). We have examined the cases reported since 1977 and describe here the features now recognized to be a part of the syndrome. For convenience, we have divided the cases into those arising from the pancreas, the intestine, and extrapancreatic tumors. It appears that the syndrome differs among tumors arising from the pancreas and the intestine or extrapancreatic sites. Therefore, these will be considered separately.

Tumor Location

Of the reported cases, 60% of somatostatinomas were found in the pancreas and 40% in the duodenum or jejunum. Of the pancreatic tumors, 50% were located in the head, and 25% in the tail, and the remaining tumors either infiltrated the whole pancreas or were found in the body. Regarding extrapancreatic locations, approximately 50% originate in the duodenum, approximately 50% originate in the ampulla, and, rarely, one is found in the jejunum. Thus, approximately 60% of somatostatinomas originate in the upper intestinal tract, which probably is a consequence of the relatively large number of D cells in this region.

Tumor Size

Somatostatinomas tend to be large, similar to glucagonomas,(344) but unlike insulinomas and gastrinomas, which, as a rule, are small (345-347). Duodenal tumors tend to be smaller averaging between 15-20 mm compared to pancreatic tumors with a median size of 42.5 mm. (Garbrecht et al.) Symptoms associated with somatostatinomas and glucagonomas are less pronounced and probably do not develop until very high blood levels of the respective hormones have been attained. As a result, somatostatinomas and glucagonomas are likely to be diagnosed later.

Clinical Features

Most patients are between 40 and 60 years of age. There is a 2:1 ratio of female to male patients, which contrasts with the equal sex incidence for other islet cell tumors (335). The most common symptom for all somatostainomas is abdominal pain, occurring in 53% of pancreatic somatostatinomas and 39% of intestinal tumors (Garbrecht et al. 2008). Duodenal tumors can also present with jaundice (23%) and gastrointestinal bleeding (22%), while pancreatic tumors are found incidentally in 35% of cases.

Somatostatinoma syndrome classically is described as a triad of diabetes mellitus, diarrhea and gallstones, but also includes weight loss and hypochlorhydria. Contemporary case series report the incidence of the syndrome in less than 10% of patients and it more commonly occurs in pancreatic somatostatinomas as opposed to intestinal tumors.

Diabetes Mellitus and Hypoglycemia

Seventy-five percent of patients with pancreatic somatostatinomas have diabetes mellitus. In contrast, diabetes occurs only in 11% of patients with intestinal tumors. In all instances, the diabetes has been relatively mild and can be controlled with diet and/or oral hypoglycemic agents or with small doses of insulin. It is not clear, however, whether the differential inhibition of insulin and diabetogenic hormones can explain the usually mild degree of diabetes and the rarity of ketoacidosis in patients with somatostatinoma. Replacement of functional islet cell tissue by pancreatic tumor may be another reason for the development of diabetes in most patients with pancreatic somatostatinoma, contrasting with the low incidence in patients with intestinal tumors. These usually large tumors can destroy substantial portions of the pancreas.

Gallbladder Disease

Fifty-nine percent of patients with pancreatic tumors and 27% of patients with intestinal tumors have gallbladder disease. The high incidence of gallbladder disease in patients with somatostatinoma and the absence of such an association in any other islet cell tumor suggests a causal relationship between gallbladder disease and somatostatinoma. Infusion of somatostatin into normal human subjects has been shown to inhibit gallbladder emptying,(331;336) suggesting that somatostatin-mediated inhibition of gallbladder emptying may cause the observed high rate of gallbladder disease in patients with somatostatinoma. This thesis is supported by the observation of massively dilated gallbladders without stones or other pathology (337;338) in patients with somatostatin-secreting tumors.

Diarrhea and Steatorrhea

Diarrhea consisting of 3 to 10 frequently foul-smelling stools per day and/or steatorrhea from 20 to 76 g of fat per 24 hours is common in patients with pancreatic somatostatinoma. This could result from the effects of high levels of somatostatin within the pancreas, serving as a paracrine mediator to inhibit exocrine secretion or, alternatively, from the somatostatinoma’s causing pancreatic duct obstruction. Somatostatin has been shown to inhibit the pancreatic secretion of proteolytic enzymes, water, bicarbonate, (339) and gallbladder motility (340). In addition, it inhibits the absorption of lipids (341). All but one patient with diarrhea and steatorrhea had high plasma somatostatin concentrations. In some cases, the severity of diarrhea and steatorrhea parallels the course of the disease, worsening as the tumor advances and metastatic disease spreads, and improving after tumor resection. The rarity of diarrhea and/or steatorrhea in patients with intestinal somatostatinomas may result from lower somatostatin-like immunoreactivity (SLI) levels.

Hypochlorhydria

Infusion of somatostatin has been shown to inhibit gastric acid secretion in human subjects (342). Thus, hypochlorhydria in patients with somatostatinoma in the absence of gastric mucosal abnormalities likely results from elevated somatostatin concentrations. Basal and stimulated acid secretion was inhibited in 87% of patients with pancreatic tumors tested but in only 12% of patients with intestinal tumors.

Weight Loss

Weight loss ranging from 9 to 21 kg over several months occurred in one-third of patients with pancreatic tumors and one-fifth of patients with intestinal tumors. The weight loss may relate to malabsorption and diarrhea, but in small intestinal tumors, anorexia, abdominal pain, and yet unexplained reasons may be relevant.

Associated Endocrine Disorders

Of great interest is the presence of associated disorders in patients with intestinal somatostatinomas. Approximately 50% of all patients have other endocrinopathies in addition to their somatostatinoma. Duodenal and periampullary tumors have been associated with neurofibromatosis, gastrointestinal stromal tumors, tuberous sclerosis, von Hippel-Lindau disease and MEN-1. (Chetty 2009, Sreenarasimhaiah 2009, Lubensky et al. 1998, Lévy-Bohbot 2004) While the association of somatostatinomas with these inherited disorders is intriguing, a link between the known gene mutations of these disorders with the development of somatostatinomas has not been clearly established. Secretion of different hormones by the same islet cell tumor, sometimes resulting in two distinct clinical disorders, is now being recognized with increasing frequency(343). These possibilities should be considered during endocrine work-ups of patients with islet cell tumors and their relatives.

Somatostatin-Containing Tumors Outside the GI Tract

Somatostatin has been found in many tissues outside the GI tract. Prominent among those are the hypothalamic and extrahypothalamic regions of the brain, the peripheral nervous system (including the sympathetic adrenergic ganglia), and the C cells of the thyroid gland. Not surprisingly, therefore, high concentrations of somatostatin have been found in tumors originating from these tissues. Sano and colleagues (348) and Saito and colleagues (349) reported seven patients with medullary carcinoma of the thyroid (MTC) who had high basal plasma SLI concentrations and high tumor SLI concentrations. Roos and colleagues (350) reported elevated plasma SLI concentrations in three of seven patients with MTC and high tissue SLI concentrations in three of five MTC tumors. Some, but not all, of these patients exhibited the clinical somatostatinoma syndrome.

Elevated plasma SLI concentrations also have been reported in patients with small cell lung cancer (350). One case of metastatic bronchial oat cell carcinoma caused Cushing’s syndrome, diabetes, diarrhea, steatorrhea, anemia, and weight loss and had a plasma SLI concentration 20 times greater than normal (351). A patient with a bronchogenic carcinoma presenting with diabetic ketoacidosis and high levels of SLI (> 5,000 pg/mL) has been reported (352). Pheochromocytomas (343;353) and catecholamine-producing extra-adrenal paragangliomas (350) are other examples of endocrine tumors producing and secreting somatostatin in addition to other hormonally active substances. One-quarter of 37 patients with pheochromocytomas had elevated SLI levels (350).

Diagnosis

In the reported series cited, somatostatinomas often were found more or less incidentally. In most cases, the tumors were found either during exploratory laparotomy or upper GI radiographic studies, CT, or ultrasound, or endoscopy performed because of various symptoms, including unexplained abdominal pain, melena, hematemesis, persistent diarrhea, or in search of insulinomas or ACTH-secreting tumors. Once found, the tumors were identified as somatostatinoma by the demonstration of elevated tissue concentrations of SLI and/or prevalence of D cells by immunocytochemistry or demonstration of elevated plasma SLI concentrations. Thus, events leading to the diagnosis of somatostatinoma usually occur in reverse order. In other islet cell tumors, the clinical symptoms and signs usually suggest the diagnosis, which then is established by demonstration of diagnostically elevated blood hormone levels, following which efforts are undertaken to localize the tumors. It can be expected that the same sequence of diagnostic procedures will be followed in the future for the diagnosis of somatostatinoma, mainly for two reasons: (a) the increasing familiarity of physicians with the clinical somatostatinoma syndrome (this symptom complex, although not pathognomonic, is nevertheless sufficiently characteristic of somatostatinoma to suggest the correct diagnosis) and (b) the greater availability of reliable radioimmunoassays for the determination of SLI in blood has increased the yield. Presently, these assays are complicated by the need for cumbersome extraction procedures and are not readily available. (Assay available at Inter Science Institute-800-255-2873). It should be recognized, however, that the syndrome is rare. Of 1,199 cases screened for somatostatinoma at the University of Michigan between 1982 and 1986, only 8 cases had diagnostic serum levels.

The mean (SLI) concentration in patients with pancreatic somatostatinoma is 50 times higher than normal (range, 1–250 times), while intestinal somatostatinomas have only slightly elevated or normal SLI concentrations. The diagnosis of somatostatinoma at a time when blood SLI concentrations are normal or only marginally elevated, requires reliable provocative tests. Increased plasma SLI concentrations have been reported after intravenous infusion of tolbutamide and arginine, and decreased SLI concentrations have been observed after intravenous infusion of diazoxide. Arginine is a well-established stimulant for normal D cells and thus is unlikely to differentiate between normal and supranormal somatostatin secretion. The same may be true for diazoxide, which has been shown to decrease SLI secretion from normal dog pancreas as well as in patients with somatostatinoma (354). Tolbutamide stimulates SLI release from normal dog and rat pancreas,(339;340;354) but no change was found in the circulating SLI concentrations of three normal human subjects after intravenous injection of 1 g of tolbutamide (355). Therefore, at present, tolbutamide appears to be a candidate for a provocative agent in the diagnosis of somatostatinoma, but its reliability must be established in a greater number of patients and controls. Until then, it may be necessary to measure plasma SLI concentrations during routine work-ups for postprandial dyspepsia and gallbladder disorders, (333) for diabetes in patients without a family history, and for unexplained steatorrhea as these findings can be early signs of somatostatinomas.

Tumors can be localized radiographically by CT scan, somatostatin receptor scintigraphy and, more recently reported, by PET scan. (Suzuki et al. 2008)

Microscopic Appearance

On light microscopy, most tumors appear to be well-differentiated islet cell or carcinoid-type tumors. Some show a mixed picture, consisting of separate zones of differentiated and anaplastic cells. In the differentiated areas, cells are arranged in lobular or acinar patterns that are separated by fibrovascular stroma. Less well-differentiated areas consist of sheets of cells interrupted by fibrous septa.

Diffuse positive immunoreactivity for somatostatin usually is found, which contrasts with the rarity of somatostatin-positive cells in gastrinomas and other tumors. There is a unique occurrence of psammoma bodies in somatostatinomas localized within the duodenum. In addition, there is abundant immunologic evidence for the presence of cells containing insulin, calcitonin, gastrin and VIP, ACTH, prostaglandin E2, and SP. In tumors with multiple hormones, however, SLI-containing cells represent the large majority of all cells containing hormones detected by immunopathology.

Incidence of Malignancy

Eighty percent of patients with pancreatic somatostatinomas and 50% with intestinal tumors have metastatic disease at presentation. Metastasis to the liver is most frequent, and regional lymph node involvement and metastases to bone are less so. Thus, in approximately 70% of cases, metatastic disease is present at diagnosis. This is similar to the high incidence of malignancy in glucagonoma (345) and in gastrinoma, (346) but it is distinctly different from the low incidence of malignant insulinoma (347). The high prevalence of metastatic disease in somatostatinoma also may be a consequence of late diagnosis but apparently is not dependent on the tissue of origin.

Treatment of Somatostatinomas

Forty percent of patients with somatostatinomas died at intervals ranging from 1 week to 14 months after diagnosis, whereas 60% of patients were alive from 6 months to 5 years after diagnosis. Thus, the syndrome is associated with a high malignant potential, and it is important to be aggressive in management and to attempt to remove all tumor tissue in benign cases. Surgical extirpation of the tumor provides the only chance of cure. As stated earlier, most patients present with liver metastases. Although not curative, surgical debulking of NETs has been shown to provide symptomatic relief and may extend survival, given the slow growing nature of these tumors. Liver resection appears to be most appropriate for solitary lesions and oligometastases. Orthotopic liver transplantation has been performed in a small number of institutions with liver-only metastatic islet cell tumors. (Le Truet 2008) More extensive liver metastases can be treated by ablative methods including radiofrequency ablation and cryoablation, either alone or in combination with surgical resection. Hepatic artery embolization or chemoembolization with doxorubicin, cisplatin and mitomycin C of hepatic metastases can result in tumor regression and symptom palliation. Selective intra-arterial irradiation with yttrium labeled microspheres also has been reported with some success. (King et al. 2008) A novel therapeutic approach in NETS is treatment with radiolabeled somatostatin analogs and a recent study reported a complete response rate of 2% and a partial response rate of 28% with a median time to progression of 40 months. (Kwekkeboom et al. 2008)

The somatostatin analog octreotide is standard therapy for those patients with unresectable disease. It provides relief of symptoms initially in many cases of neuroendocrine tumors, but induces objective tumor regression in less than 5%. In one report of three patients, octreotide therapy of 500 micrograms daily improved symptoms of diarrhea, diabetes and weight loss in 2 patients for at least 6 months and induced a decrease in SLI levels of 40-80% at 1 year. (Angeletti et al. 1998) Interferon alpha can also be used alone or in combination with octreotide to control symptoms in patients refractory to octreotide.

The optimal form of chemotherapy remains to be determined.

Additional references

Angeletti S, Corleto V, Schilacci O, et al. Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumors. Gut 1998;42:792-794.

Chetty R, Vajpeyi R. Vasculopathic changes, a somatostatin-producing neuroendocrine carcinoma and a jejunal gastrointestinal stromal tumor in a patient with type 1 neurofibromatosis.Endocrine Pathology2009;20:177-81.

Garbrecht N, Anlauf M, Schmitt A et al. Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocrine-Related Cancer 2008:15;229-241.

King J, Quinn R, Glenn DM, Janssen J, Tong D, Liaw W, Morris DL. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer.2008;113:921-9.

Klöppel G, Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract.Best Practice and Research Clinical Gastroenterology. 2005;19:507-17.

Kwekkeboom DJde Herder W, Kam B, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival.Journal of Clinical Oncology2008;26:2124-30.

Le Treut Y, Grégoire E, Belghiti J, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report. American Journal of Transplantation2008;8:1205-1213.

Lévy-Bohbot N, Merle C, Goudet P, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry.Gastroentérologie Clinique et Biologique. 2004;28:1075-81.

Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients : Histopathological and molecular genetic analysis. American Journal of Pathology 1998 153: 223-231.

Sreenarasimhaiah J, Armstrong LA, Tang SJ, Barnett C. Pancreatic somatostatinoma and tuberous sclerosis: case report of an exceedingly rare association.Gastrointestinal Endoscopy2009;69:379-81.

Suzuki H, Kuwano H, Masuda N, et al. Diagnostic usefulness of FDG-PET for malignant somatostatinoma of the pancreas. Hepatogastroenterology.2008;55:1242-5.