252 ANNALS OF GASTROENTEROLOGYP. ECONOMOPOULOS, 2001, 14(4):252-260 et al Review Somatostatinoma syndrome P. Economopoulos, C. Christopoulos SUMMARY mandatory. The localization of tumor or metastases may be made by imaging methods, mainly by endoscopic U/S Somatostatinomas are extremely rare functioning endocrine (87.2%), and angiography (82.1%) or by surgical explora- tumors of the gastrointestinal tract, occurring with almost tion. Treatment of choice is the surgical removal of tumor equal frequency in the pancreas (mainly in the head) and and, when possible, of metastases, with or without adju- duodenum (periampullary region). The latter are often as- vant chemotherapy. Due to their slow natural course, so- sociated with von Recklinghausen disease (50%). They oc- matostatinomas have a better prognosis than pancreatic or cur sporadically (93.1%) or as part of multiple endocrine biliary duct cancer. neoplasia type 1 (6.9%). The tumors are relatively large (with an average size of 5 cm for those of pancreatic and 2.5 cm for those of duodenal origin) and usually malignant INTRODUCTION (64.7%) with metastases mainly to the lymph nodes (31.2%) The somatostatinoma syndrome is a distinct clinical and liver (27.7%). Duodenal somatostatinomas are charac- entity that can be clearly differentiated from those of the terized by the frequent presence of psammoma bodies. Clin- other neuroendocrine tumors. Tumors (termed as soma- ical manifestations are characterized by two distinct enti- tostatinomas) are the least common among neuroendo- ties, one due to somatostatin hypersecretion (inhibitory crine tumors and are located primarily in the pancreas syndrome) and the other due to tumor location and growth. and duodenum (Table 1). Some of the clinical manifes- The inhibitory syndrome includes diabetes mellitus or glu- tations and biochemical findings reflect the excess of cose intolerance, cholelithiasis, weight loss, diarrhea with somatostatin secretion. It is noteworthy that most duo- or without steatorrhea, and hypochlorhydria or complete denal somatostatinomas were simultaneously diagnosed achlorhydria. Clinical manifestations due to tumor loca- as carcinoid somatostatinomas or somatostatin-secret- tion and growth include mainly obstructive jaundice, duo- ing carcinoids1 and may also be classified as foregut car- denal obstruction, weight loss, and gastrointestinal bleed- cinoids.2 In fact there is considerable confusion surround- ing. Mixed clinical manifestations may occur in cases of ing the term somatostatinoma as well as the histologic multiple hormone secretion by the tumor (e.g. Cushings classification and the spectrum of clinical findings. syndrome, peptic ulcer etc.). The diagnosis is usually acci- dental at the time of laparotomy for cholecystectomy or during gastrointestinal imaging studies for various non- HISTORICAL VIEW specific complaints. For the definitive diagnosis of so- In 1977 Ganda et al,3 and Larsson et al4 independ- matostatinoma histology with immunocytochemistry is ently reported the first two cases of somatostatinoma, while the full biochemical, morphologic and clinical syn- drome was characterized by Krejs et al5 in 1979. The case 1st Department of Internal Medicine, A. FLEMING General of Ganda et al, a 46-year-old woman, had a well estab- th Hospital, 14 25 Martiou str., Melissia Attikis, 151 27 Athens, Greece lished diagnosis of diabetes mellitus of eight year dura- tion and a pancreatic mass fortuitously visualized during Author for correspondence: cholecystectomy for cholelithiasis. The initial impression P. Economopoulos, 1st Department of Internal Medicine, A. FLEMING General Hospital, 14 25th Martiou str., Melissia was that she had a non functioning islet-cell tumor. Attikis, 151 27 Athens, Greece The tumor ultrastructure had a distinctive endocrine mor- Somatostatinoma syndrome 253 phology, resembling D cells, while it contained a large PATHOLOGY quantity of immunoreactive somatostatin. After complete resection of the tumor the patient became euglycemic. Tumor location The case of Larsson et al was a 55-year-old woman with Somatostatinomas are found with almost equal fre- diarrhea and steatorrhea, abdominal pains of long dura- quency in the pancreas (46.8%) and in other sites of the tion, hypochlorhydria and diabetic glucose tolerance. gastrointestinal tract (53.2%) mainly in the duodenum During cholocystectomy, as in the case of Ganda et al, a and particularly in the ampula.17 Other sites such as the tumor located in the head of the pancreas with liver lung,27 the liver,28 or the kidney29 are very rare. The head metastases was detected. Examination of biopsy speci- of the pancreas is the predominant (55.6%) site of so- mens showed the tumor to be of endocrine type and cells matostatinomas followed by the tail (27.2%) (Table 1).1 were indistinguishable from islet D cells. Radioimmu- Size/Malignancy/Metastases. Somatostatinomas are noassay of blood-samples obtained by tumor vein cathe- usually large, ranging from 1 to 10 cm or more in diame- terization revealed very high levels of somatostatin im- ter1,2,30 with a mean size of 5 cm from pancreatic somato- munoreactivity, while tumor extracts inhibited insulin and statinomas and 2.5 cm for those of duodenal origin (Ta- glucagon secretion from isolated perfused porcine pan- ble 2).2 In the majority of cases (>90%) the tumor is sol- creas. Another case, published by Kowacs et al6 in the itary.1,2,4 same year, has been considered by certain authors as com- patible with somatostatinona.7 The malignant nature of the tumors varies with an average of 64.7% of cases. Extreme and constant hyper- somatostatinemia is consistent with a malignant tumor EPIDEMIOLOGY associated with metastases.5 Somatostatinomas occurring Incidence as sporadic cases have a higher rate of malignancy than those occurring as part of multiple endocrine neopla- Somatostatinomas are extremely rare functional en- sia.1 docrine tumors of the gastrointestinal tract with an esti- mated annual incidence of 1 in 40 million.2,8,9 They may The overall rate of metastases is 53% without differ- occur either sporadically (93.1%) or rarely as part of ences between pancreatic and duodenal somatostatino- multiple endocrine neoplasia syndrome type 1 (MEN 1) mas.1 Lymph nodes1,31,32 and liver1,32-37 are the most com- (6.9%).1,10 They also can present in association with phe- mon sites of metastases with some differences in the rate ochromocytoma and neurofibromatosis type I (termed between pancreatic and duodenal somatostatinomas1 also von Recklinghausen disease), in the MEN 2 syn- (Table 3). On the other hand, extraduodenopancreatic drome.2,11-15 It is noteworthy that duodenal somatostati- somatostatinomas appear to have a higher rate of me- nomas are frequently (43.2-50%)1,16 associated with von tastases (89%).1 Metastatization in duodenal somatostat- Recklinghausen disease16-21 and rarely with von Hippel inomas associated with von Recklinghausen disease is Lindau disease.12,22 The relation between somatostatino- relatively rare (27%) and mainly confined to lymph nodes ma and multiple endocrine neoplasia type I and multi- (88%).16 ple neoplasia type II remains unclear. Possibly some cases Tumor histology. The tumors appear as well differ- of somatostatinomas represent manifestations of mixed entiated islet cells with D-cell granules in electron mi- forms of multiple endocrine neoplasia syndromes.23 croscopy.30 Immunohistochemical analysis demonstrates Gender somatostatin-like immunoreactive material in all tu- mors.5,30 Both sexes appear to be affected with almost equal frequency.1,24,25 Psammoma bodies (psammomatous calcifications) are frequently encountered in the glandular lamina of Age duodenal somatostatinomas (49.4-66%), whereas their Statistical evaluation indicated a significant difference presence in other neuroendocrine tumors or in pancre- in age only between female patients with pancreatic and atic somatostatinomas is very rare (2.5%).1,16,38 The his- duodenal somatostatinomas (55.4 years vs 48.7 years).1 tological finding of psammoma bodies is important in Most patients are 40 to 60 years old with a mean age of the diagnosis of duodenal somatostatinomas.39 A review about 51-53 years.26 of the literature reveals that somatostatinomas with psam- moma bodies are found only in the duodenum and do not produce significant amounts of peptides other than 254 P. ECONOMOPOULOS, et al Table 1. Location of somatostatinomas1 Location No % Location No % Pancreas 81 46.8 Head 45 55.6 Body 6 7.4 Tail 22 27.2 Head/Body 1 Body/Tail 2 }6.2 Diffuse/Head+Tail 2 Not srecified 3 Extrapancreatic1 92 53.2 Duodenum 81 88.0 Lungs 2 Gallbladder 1 Choledochus 1 Stomach 1 }9.8 Jejunum 1 Colon 1 Rectum 1 Thyroid 1 Unknown 2 2.2 1: Other sites, as the lung27, the liver28, or kidney29 have also been reported Table 2. Comparative data of size in somatostatinomas1 Size (cm) Pancreatic (No=62) Duodenal (No=70) Overall (No=138) No % No % No % < 1 4 6.5 12 17.1 18 13.0 1.1-2 5 8.1 29 41.4 35 25.4 Subtotal 9 14.5 41 58.6 53 38.4 2.1-5 29 46.5 27 38.6 59 42.8 5.1-10 22 35.5 2 2.9 24 17.9 > 10.1 2 3.2 0 0 2 1.4 Subtotal 53 85.5 29 41.4 85 61.6 Average size 5.11 cm (No=57) 2.41 cm (No=70) 3.57 cm (No=132) somatostatin.40 In general, these tumors are composed cinoma and possibly others.42,43 of regular cells arranged in glands or acini with psam- moma bodies and can be misdiagnosed as adenocarci- CLINICAL MANIFESTATIONS - nomas.41 PATHOPHYSIOLOGY It is noteworthy that a low but variable proportion of In the majority of patients, somatostatinomas are somatostatin-containing cells is present in a number of symptomatic (92.7%, Table 4). Some differences between neoplasms, the majority of which are derived from cells pancreatic and duodenal somatostatinomas appear in the of the neuroendocrine system, such as oat cell carcino- tables 4 and 5.