Abnormalities of proinsulin processing in functioning insulinomas: clinical implications

OBJECTIVE: Abnormal proinsulin processing in insulinomas may result in secretory granules containing both insulin and proinsulin, a finding not encountered in healthy beta-cells. The aim of this study was to test whether such abnormalities in the proinsulin to insulin conversion have clinical implications in patients with hypoglycaemic disorders. DESIGN: Case-series. PATIENTS AND METHODS: Fifteen patients with histologically confirmed insulinoma and two patients with islet cell hyperplasia were included. The immunohistochemical distribution pattern of proinsulin within the tumour cells was classified as Golgi pattern (predominantly perinuclear immunolabelling) or diffuse pattern (immunolabelling in the periphery of the cells, indicating the presence of proinsulin in secretory granules). Data obtained from the 72-h fast and arterial calcium stimulation and hepatic venous sampling (ASVS) test were related to the morphological classification. RESULTS: Six insulinomas exhibited a diffuse proinsulin distribution pattern, while nine insulinomas and two islet cell hyperplasias disclosed a Golgi pattern. Median proinsulin concentrations at the termination of the fast tended to be higher in patients with the diffuse proinsulin distribution pattern than in patients with the Golgi pattern (86.9 vs. 18.8 pmol/l, P = 0.07). Higher insulin (P < 0.005) and proinsulin (P < 0.05) concentrations were significantly correlated with earlier occurrence of hypoglycaemia during the prolonged fast. During the ASVS test, tumours with the diffuse proinsulin distribution pattern exhibited a higher increase in both insulin (median, 37.3- vs. 10.5-fold, P < 0.05) and proinsulin (6.3- vs. 1.6 fold, P < 0.005) concentrations following calcium stimulation than the tumours with the Golgi pattern. CONCLUSIONS: Abnormalities in the proinsulin to insulin conversion in patients with insulinomas and islet cell hyperplasia correlate with impaired regulation of both insulin and proinsulin secretion during the prolonged fast as well as the ASVS test.     

Regionalization of occult pancreatic insulinomas with the arterial stimulation venous sampling (ASVS) technique

Non-invasive modalities (ultrasound, computerized tomography, MRI and somatostatin receptor scintigraphy) often fail to localize insulinomas smaller than 1.5 cm in diameter. Recently, regionalization of such occult insulinomas was facilitated by the arterial stimulation and venous sampling (ASVS) technique, using calcium as the insulin secretagogue. However, so far experience with this technique has been limited to a few tertiary referrals centres worldwide. In these case studies we report our experience in three consecutive patients with occult insulinomas.
Three consecutive patients (all men 34, 51 and 56 years of age) with insulin-mediated hypoglycaemia were studied. Diagnosis of insulin hypersection was established by the finding of a high amended insulin : blood sugar ratio during fasting. Localization of a pancreatic mass lesion was unsuccessful by ultrasound, CT and/or MRI in all patients. Two patients had negative octreotide scans. In all patients after the infusion of calcium sequentially into the gastroduodenal, splenic and the superior mesenteric arteries, insulin levels rose significantly in right hepatic vein samples giving rise to diagnostic gradients from the splenic artery (in 2 patients) and gastroduodenal artery (in 1 patient), regionalizing insulinomas in the tail and head or neck of the pancreas respectively. The simultaneously obtained angiogram was positive in only 1 patient, in whom it corresponded to the insulin gradient. Regionalization of these occult tumours was subsequently confirmed at laparoscopy in the 2 patients operated.
It is concluded, that the arterial stimulation venous sampling technique is an effective method in regionalizing occult insulinomas and should complement invasive angiography whenever the latter procedure is performed.     

Insulin responses to selective arterial calcium infusion under hyperinsulinemic euglycemic glucose clamps: case studies in adult nesidioblastosis and childhood insulinoma

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (approximately 100 microU/ml) euglycemic (approximately 90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.     

Radio-frequency ablation for symptom control in a patient with metastatic pancreatic insulinoma

Malignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51-year-old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio-frequency ablation. He remains symptom-free 18 months later and levels of insulin and pro-insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio-frequency ablation offers an alternative if vascular access to the tumour is no longer possible.     

64-jährige Patientin mit rezidivierenden Hypoglykämien

Insulinomas are the most common pancreatic islet cell tumours and are characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. Diagnosis is usually made by the detection of endogenous hyperinsulinism over a period of fasting. We report the case of a patient with insulinoma without hyperinsulinaemia. A secretion and overexpression of split insulin has to be discussed. The diagnosis was made by endoscopic ultrasound-guided fine-needle aspiration and the immunohistochemical detection of chromogranine. In conclusion, the present report demonstrates that insulinomas should be considered and searched for in every case of hypoglycaemia, even when associated with normal insulin levels. It also confirms the essential role of endoscopic ultrasonography in the diagnosis of insulin-secreting tumors.     

Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours

In patients with gastro-enteropancreatic neuroendocrine tumours the localization of all the neoplastic lesions and an accurate staging of the diseases have important therapeutic implications. Somatostatin receptor scintigraphy with In-111 pentatreotide has proved to be useful in detecting gastro-enteropancreatic tumours; however, the role of abdominal single photon emission computed tomography has not yet been definitively established. In a series of 52 patients with gastro-enteropancreatic tumours (9 non-functioning islet cell carcinomas, 4 insulinomas, 3 somatostatinomas, 2 VIPomas, 1 glucagonoma and 33 carcinoids) we compared somatostatin receptor scintigraphy with the results of computed tomography and magnetic resonance imaging performed within one month. Four and 24-hour total body planar images and 4-hour abdominal single photon emission computed tomography were acquired after the i.v. injection of approximately 250 MBq of In-111 pentatreotide. Only abdominal localizations were considered: planar scans detected 16 extrahepatic lesions in 13 patients and 54 liver sites in 21 patients; single photon emission computed tomography visualized 31 extrahepatic lesions and 89 liver metastases in 27 and 28 patients, respectively; computed tomography and magnetic resonance imaging detected 11 extrahepatic lesions in 10 patients and 73 liver sites in 21 patients. In-111 pentatreotide single photon emission computed tomography was the only imaging method able to localize tumoural lesions in 13 patients; all these localizations were then histologically verified. The scintigraphic positivity did not depend on the site or on the presence of hormonal hypersecretions. In conclusion, our results indicate that single photon emission computed tomography is more sensitive than planar images and computed tomography/magnetic resonance imaging in detecting abdominal gastro-enteropancreatic tumours and their metastases; it is able to increase both the number of visualized lesions and that of patients with positive findings. Single photon emission computed tomography is particularly useful in patients in whom tumoural lesions have not been already localized; it should be the first imaging modality in patients with gastro-enteropancreatic tumours: its initial use will result in more information and proper management.     

Selective intra-arterial calcium injection in the investigation of adult nesidioblastosis: a case report

A 69-year-old man with recurrent hypoglycaemia had inappropriately elevated plasma insulin level during a symptomatic hypoglycaemia, but had a negative prolonged fast. Computerized tomography (CT) of the abdomen revealed a nodular lesion over the body of pancreas, whereas pancreatic arteriography failed to show tumour blush. Hence, arterial stimulation (with calcium) and venous sampling (ASVS) was performed and a brisk response of plasma insulin level was found when calcium was injected both into the splenic and the superior mesenteric arteries. Since no tumour was found during the operation, the patient received subtotal distal pancreatectomy. Pathological examination of the resected tissue disclosed a typical finding of nesidioblastosis. We suggest that selective intra-arterial calcium injection with hepatic venous sampling for insulin gradients is useful for the diagnosis of adult nesidioblastosis. © 1997 John Wiley & Sons, Ltd.     

Role of EUS in the preoperative localization of insulinomas compared with spiral CT

BACKGROUND: Preoperative radiologic localization of insulinomas often fails because of the small size of these tumors. Endoscopic ultrasound (EUS) can localize insulinomas in up to 80% of the cases. The aim of this study was to compare EUS and computed tomography (CT) diagnostic accuracy for insulinomas. METHODS: We reviewed medical records from 12 patients (10 women) with a biochemical diagnosis of hypoglycemia and hyperinsulinism from 1 university hospital and 1 community hospital. A diagnosis of insulinoma was ultimately made in all cases and before surgery the patients underwent abdominal US, spiral CT and EUS in an attempt to precisely localize the tumor. Surgery was considered the standard for tumor localization. RESULTS: Ten tumors were benign (83.3%) and 2 were malignant (16.7%). The overall sensitivity of EUS in identifying insulinomas was 83.3% compared with 16.7% for CT. Tumors not detected by EUS had a mean size of 0.75 cm. EUS-guided fine-needle aspiration was possible in only 3 patients, with a positive cytologic diagnosis in 2 (66.6%). Tumors located in the head and body of the pancreas were identified by EUS in all patients, but those located in the tail were diagnosed in only 50% of the cases. CONCLUSIONS: EUS is superior to spiral CT and should replace it for the detection of pancreatic insulinomas. EUS identification depends on the site and size of the tumor.     

Insulinomas in MEN-I patients: early detection and treatment of insulinomas in patients with the multiple endocrine neoplasia syndrome type-I

In the multiple endocrine neoplasia syndrome type I (MEN-I syndrome), periodic screening of patients and their close relatives may improve prognosis and life expectancy. Although there is diffuse involvement of the pancreas with microadenomatosis, insulinomas in the MEN-I syndrome usually occur as single tumours. This is illustrated here by two patients with insulinomas and the MEN-I syndrome. Preoperative localization of the tumours was achieved accurately by digital subtraction angiography combined with dynamic computerized tomography after a bolus injection of contrast medium. At present, two and three years after elective surgery both patients are asymptomatic. The early detection and treatment of insulinomas is extremely important because of the high risk of cerebral damage associated with late diagnosis. Periodic investigation of MEN-I family members can promote the early diagnosis and treatment of insulinomas, especially in young patients, whose life expectancy and quality of life may be improved.     

Somatostatin receptor scintigraphy in gastrinomas

Recent studies report that the radiolabelled synthetic somatostatin analogue, [111In-DTPA-DPhe1]octreotide, is useful for imaging carcinoid tumours and pancreatic endocrine tumours. At present, it is unclear whether this method is superior to conventional imaging studies (computed tomography, magnetic resonance imaging, ultrasound, angiography) and what its role should be, if any, in the management of these patients. The aim of this paper is to review five recent studies performed at the National Institutes of Health in patients with Zollinger-Ellison syndrome to define the role of somatostatin receptor scintigraphy. Patients were from a tertiary referral centre, all had Zollinger-Ellison syndrome. In Study n. 1: the sensitivity of somatostatin receptor scintigraphy was assessed compared to conventional studies in 80 patients. Study n. 2: the effect of somatostatin receptor scintigraphy on management was determined in 122 patients. Study n. 3: ability of somatostatin receptor scintigraphy and other conventional methods to distinguish small hepatic metastases (< 2 cm) from hepatic haemangiomas was assessed in 29 patients. Study n. 4: somatostatin receptor scintigraphy, magnetic resonance imaging and bone scanning were compared in 115 consecutive patients to detect bone metastases. Study n. 5: ability of somatostatin receptor scintigraphy to detect gastrinomas found at surgery in 35 patients and its effect on cure rate and determinants of detection of gastrinomas by somatostatin receptor scintigraphy were analysed. Briefly, results showed: Study n. 1: somatostatin receptor scintigraphy is the most sensitive modality for detection of primary or metastatic gastrinomas; Study n. 2: somatostatin receptor scintigraphy changes management in 47% of cases; Study n. 3: somatostatin receptor scintigraphy is the only method to distinguish small liver metastases from small haemangiomas; Study n. 4: somatostatin receptor scintigraphy and magnetic resonance imaging have higher sensitivity and predictive values for bone metastases than bone scanning; Study n. 5: somatostatin receptor scintigraphy misses 33% of gastrinomas found at surgery, primarily small duodenal tumours. Size is the important factor. The use of somatostatin receptor scintigraphy does not increase cure rate. In conclusion, Somatostatin receptor scintigraphy is now the imaging method of choice in patients with Zollinger-Ellison syndrome for preoperative primary tumour localization, detection of bone or liver metastases, and to distinguish small liver metastases from small hepatic haemangiomas. Its specificity appears to be high but has been poorly studied as has the use of it in combination with endoscopic ultrasound. Studies by others suggest these recommendations will apply to carcinoid tumours and other pancreatic endocrine tumours except insulinomas.     

Gastrointestinal/pancreatic hormone concentrations in the portal venous system of nine patients with organic hyperinsulinism

Percutaneous transhepatic sampling of blood in the portal venous system (TPVS) was used to; (1) localize hormone secreting tumors and help in differentiating tumors from diffuse disease (nesideoblastosis and hyperplasia with adenomata) in 9 patients with fasting hypoglycemia and hyperinsulinism, and (2) study the concentration an distribution of the immunoreactive peptides: insulin (IRI), gastrin (IG), glucagon (IRG), pancreatic polypeptide (hPP), and somatostatin (SRIF-LI), in the venous drainage of the uninvolved portion of the pancreas and GI tract. Localized elevations of IRI (64-920 microunits/ml) predicted tumor localization in 6 patients with single tumors that were not demonstrable angiographically. In one patient with nesideoblastosis and another with islet cell hyperplasia with adenoma, elevated IRI concentrations at multiple locations suggested a diffuse or multicentric process. Elevations of SRIF-LI in the same region as IRI elevations in one patient and of IRG in another patient suggested that these tumor produced two hormones. Some problems in the interpretation of portal venous insulin concentrations are discussed. The locations of maximum portal venous system plasma concentrations and portal-arterial gradients (mean +/- SE pg/ml) in five patients with small single insulinomas were: IG, gastrocolic trunk (126 +/- 27, 46 +/- 22); IRG, proximal splenic vein (130 +/- 30, 47 +/- 13) and gastrocolic trunk (131 +/- 23, 60 +/- 13); hPP, portal vein (164 +/- 48, 49 +/- 22); SRIF-LI, superior mesenteric vein (186 +/- 50, 57 +/- 20) and gastrocolic trunk (178 +/- 59, 55 +/- 21). It is concluded; (1) TPVS can be used successfully to localize single insulin-secreting tumors of the pancreas and to help distinguish them from diffuse disease but problems in such differentiation do occur, (2) circulating SRIF-LI and IRG are derived from both the pancreas and the gut, IG predominantly from the proximal gut and hPP from the head of the pancreas, and (3) The data provide new information for the interpretation of portal insulin concentrations in patients with organic hyperinsulinism and of hormone concentrations for localization of peptide-producing tumors of the pancreas other than insulinomas.     

Localization of islet-cell hyperplasia: value of pre- and intraoperative arterial stimulation and venous sampling

Arterial stimulation and venous sampling was effective in the localization of β‐cell hyperplasia of the pancreas in the islets of Langerhans in an 84‐year‐old woman. The patient presented with repeated episodes of unconsciousness and hypoglycemia. She was first suspected of having insulinoma, but diagnostic imaging failed to reveal any tumors. Arterial stimulation and venous sampling (ASVS) and percutaneous transhepatic portal venous sampling (PTPS) were performed to localize the tumor. By ASVS, increases in immuno reactive insulin (IRI) were noted in renal vein blood samples (because a splenorenal shunt was present) after splenic arterial stimulation and venous sampling, and PTPS revealed a stepup in IRI from splenic venous blood samples. Preoperative diagnosis suggested β‐cell hyperplasia in the pancreas tail. Intraoperative ultrasound failed to find a tumor. Intraoperative ASVS showed the site of increase IRI as the pancreas tail, so distal pancreatectomy and splenectomy were performed. However, hypoglycemia was observed constantly after this operation. Relaparotomy, causing additional resection, was conducted to confirm the precise location and to remove the residual β‐cell hyperplasia of the pancreas. At the second resection, the existing part of β‐cell hyperplasia was confirmed through intraoperative ASVS, and additional resection of the pancreas body and neck was performed. At this time, complete removal of the residual β‐cell hyperplasia was confirmed through ASVS. The hypoglycemia and impaired consciousness disappeared after the operation, and the patient's blood sugar level was maintained at a normal level. Pathological findings revealed islets of Langerhans hyperplasia extending to 1 cm in the pancreas tail region. We conclude that pre‐ and intraoperative ASVS is a useful test for β‐cell hyperplasia, which is difficult to diagnose through ordinary imaging techniques.     

New therapeutic options for metastatic malignant insulinomas

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.     

Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies

OBJECTIVE: We studied the efficacy of octreotide treatment on hypoglycaemia in patients with insulinoma and its relationships with Octreoscan scintigraphy and the presence of tumoral somatostatin receptors sst2A and sst5. DESIGN AND METHODS: 17 patients with insulinoma were evaluated using (i) evaluation of blood glucose, insulin and C-peptide during a short 100 mug octreotide test in fasting patients and/or treatment over 8 days-8 months with octreotide, (ii) Octreoscan scintigraphy and (iii) immunostaining of the tumor with anti-sst2A and anti-sst5. RESULTS: Octreotide was effective on hypoglycaemia in 10/17 patients. Octreoscan scintigraphy detected 4/17 insulinomas. sst2A receptor was detected in 7/17 insulinomas and sst5 in 15/17 insulinomas. Octreotide was effective on hypoglycaemia in those seven patients with sst2A receptor-expressing insulinoma, and in three patients with undetectable sst2A receptor and detectable sst5; it was ineffective in six patients whose tumor expressed the sst5 receptor with undetectable sst2A and in one patient with undetectable sst2A and sst5 receptor. CONCLUSIONS: Octreotide is an effective treatment of hypoglycaemia in more than 50% of patients with insulinoma. Detection of responsive patients was better based on a positive short test with subcutaneous octreotide than on the results of Octreoscan scintigraphy. Positive anti-sst2 receptor immunostaining is associated with efficacy of octreotide treatment, but does not account for all cases of responsiveness to octreotide. Expression of sst5 receptor does not appear to explain per se the efficacy of octreotide on sst2A-negative insulinomas.     

Adrenomedullin, a new peptide, in patients with insulinoma

BACKGROUND: It has been demonstrated that adrenomedullin, a newly discovered peptide, affects the release of insulin from pancreatic islets cells, suggesting a role in the insulin-regulating system. OBJECTIVE: To investigate whether adrenomedullin secretion is modified in patients with insulin-secreting islet cell tumours. DESIGN: The study was performed in nine patients with surgically treated insulinoma. Circulating adrenomedullin was assayed using a specific radioimmunoassay and its localization and distribution in the tumour were determined by means of immunohistochemistry. RESULTS: Adrenomedullin concentrations were significantly greater in patients with insulinoma (6.6 +/- 3.2 fmol/ml) than in controls (2.1 +/- 1.1 fmol/ml). In six patients monitored before and after surgery, plasma adrenomedullin decreased from 6.3 +/- 2.9 fmol/ml to 3.0 +/- 1.6 fmol/ml. Immunoreactive adrenomedullin was localized exclusively in the tumours cells, whereas stroma, surrounding pancreas parenchyma and major ducts were negative for the peptide. CONCLUSIONS: Our findings indicate that circulating adrenomedullin is increased in insulinoma and that this increase is related to the neoplastic phenotype.     

Adult-onset diffuse nesidioblastosis causing hypoglycemia

We report the case of a 32-year-old male with adult-onset diffuse nesidioblastosis causing hypoglycemia. Under the tentative diagnosis of insulinoma, localization procedures were carried out but no tumor was found. The presence of an insulinoma in the tail of the pancreas was suggested by selective intra-arterial calcium stimulation with hepatic venous sampling (ASVS). A distal pancreatectomy was performed under the assumed diagnosis of insulinoma in the tail based upon the ASVS. Diffuse nesidioblastosis was diagnosed by histopathological evaluation. During the post-operative course, the patient’s glucose and insulin levels were well controlled and uneventful without any medications or insulin for 7 months.     

Pancreatic insulinoma:current issues and trends

BACKGROUND:Although insulinomas are very rare tumors, they are the most common pancreatic neuroendocrine neoplasms.The incidence in general population is 1-4 per 1 000 000 yearly but the incidence is higher in autopsy studies. The malignancy of insulinomas is difficult to be predicted on the basis of their histological features,and the current WHO classification has been re-evaluated.This review aimed to summarize classical knowledge with current trends in the diagnosis and treatment of insulinomas. DATA SOURCES:A Medline search using terms"insulinoma", "treatment"and"neuroendocrine tumors"was conducted. Additional references were sourced from key articles. RESULTS:Surgery is the treatment of choice for insulinoma and has an extremely high success rate.Medical treatment is also available but only for patients who are unable or unwilling to undergo surgical treatment.Preoperative localization is necessary for planning the surgical approach.Many methods exist for localization of an insulinoma and can be invasive and non-invasive.The combination of biphasic thin section helical CT and endoscopic ultrasonography(EUS)has an almost 100% sensitivity in localizing insulinomas.Laparoscopic ultrasound is mandatory to localize intraoperatively these tumors.EUS-guided fine needle tattoing is an alternative method of localization in case of lack of laparoscopic ultrasound. CONCLUSION:Laparoscopic resection for benign insulinomas is the procedure of choice,whereas pancreatectomy is reserved for large,potentially malignant tumors.     

Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma

Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumours (NETs), and patients usually present with symptoms secondary to hypoglycaemia. Octreotide has been widely used in the symptomatic treatment of patients with pancreatic NETs, including insulinomas. We describe a case of a patient with a metastatic NET, subsequently identified as a malignant insulinoma, who developed severe hypoglycaemia after treatment with long-acting octreotide.     

An unusual association of neuroendocrine tumors in MEN 1A

Multiple Endocrine Neoplasia type 1 is an autonomic dominant disease with a high degree of penetrance. It is characterized by combinations of over 20 different endocrine and nonendocrine tumors. A 25-year-old woman was referred for 1 year-evolution amenorrhea and bilateral galactorrhea. She also had fasting hypoglycaemia and hypercalcemia, and she was diagnosed of Multiple Endocrine Neoplasia type 1A. Resection of three parathyroid glands was performed showing hyperplasia of principal cells. Post-parathyroidectomy serum levels of calcium and intact PTH were normal but 3 years later serum calcium levels rose again. A 99mTc-sestamibi scan showed increased uptake in the low right area compatible with adenoma. After biochemical test showing probable insulinoma, somatostatin receptor scintigraphy showed a focal captation in head and body of pancreas. MRI found two nodules in the same localization. An antral gastrectomy, total pancreatoduodenectomy, colecistectomy and truncal vagotomy was performed and histopathologic examination revealed a combination of neuroendocrine tumors: gastrinomas, somastotinomas, glucagonomas and insulinomas. After surgery she started with tingling in fingers, toes and lips, and calcium levels was 5.9 mg/dl and PTH intact 3 pg/ml. A new 99m Tc-sestamibi scan showed no captation and cervical ultrasonography was normal. Now, 2 years later, she continues with normal calcium and i-PTH levels. This report represents an unusual case of MEN 1A with association of insulinomas, gastrinomas glucagonomas and somatostatinomas in the same patient.     

Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas

Insulinomas are rare endocrine neoplasias that constitute the most frequent islet cell tumours. Somatostatin (SST) analogs are tentatively used to inhibit insulin secretion and control tumour growth in patients with local invasion or inoperative metastasis, but variable responses have been reported. Data regarding somatostatin receptor (SSTR) subtypes expression in insulinomas are conflicting. In this study, we evaluated 16 cases of primary insulinomas (including four primary plurihormonal tumours) and two hepatic metastases. Histopathological and immunohistochemical analysis for some features associated with tumour aggressiveness and semi-quantitative RT-PCR for SSTR1-5 and real-time qPCR for SSTR5 were performed. SSTR subtypes 1, 3, and 5 were expressed in 100%, SSTR2 in 89%, and SSTR4 only in 22% of the insulinomas. SSTR5 mRNA was positively correlated with histopathological features related to tumour aggressiveness (large tumour diameter, well-differentiated endocrine tumour with uncertain behaviour and higher number of cells with nuclear atypia). SSTR5 mRNA expression in primary insulinomas was lower than in primary plurihormonal tumours (P < 0.05). The observed positive correlation between SSTR5 expression and tumour size suggests that the use of SST analogues more specific to SSTR5 in the treatment of insulinomas deserves attention.