Localisation of mesenchymal tumours by somatostatin receptor imaging

Oncogenic osteomalacia, an acquired hypophosphataemic syndrome associated with mesenchymal tumours, is characterised by hypophosphataemia secondary to inappropriate phosphaturia, reduced concentrations of serum calcitriol, and defective bone mineralisation. Removal of these tumours results in complete reversal of these biochemical defects. However, because these tumours are small, slow-growing, and frequently situated in unusual anatomical sites, conventional imaging techniques often fail to detect them. Since mesenchymal tumours express somatostatin receptors, we postulated that somatostatin analogues would be able to detect these tumours. We did Indium-111 labeled pentetreotide imaging in seven patients with oncogenic osteomalacia. In five patients, we identified a mesenchymal tumour, and clinical improvement occurred after tumour resection. Our findings suggest that 111In-pentetreotide imaging effectively detects occult mesenchymal tumours and facilitates surgical treatment of oncogenic osteomalacia.     

Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with (111)In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and gamma-emitter (111)In-diethylenetriaminepenta-acetic acid (DTPA)(0),octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with (90)Y, a pure beta-emitter, (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid (DOTA)(0),Tyr(3),octreotide ((90)Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. (111)In- and (90)Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with (177)Lu-DOTA(0),Tyr(3)octreotate ((177)Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both (90)Y-DOTATOC and (177)Lu-DOTA(0),Tyr(3)octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on (111)In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.     

Nuclear medicine in the detection, staging and treatment of gastrointestinal carcinoid tumours

Carcinoid tumours belong to the family of neuroendocrine tumours with a capacity to take up and concentrate amines and precursors as well as peptides, and can thereby be detected by nuclear medicine techniques. These rare tumours are difficult to diagnose at earlier stages because of small size and multiplicity. Computed tomography (CT) and magnetic resonance imaging (MRI) are mostly of benefit for detection of larger primary tumours (1-3 cm) and liver and lymph-node metastases. A majority of carcinoid tumours express somatostatin receptors, particularly receptor type 2, and thus somatostatin receptor scintigraphy (SRS) can be used for detection and staging of carcinoid tumours. The detection rate of carcinoid tumours has been reported to be somewhere between 80 and 100% in different studies. The scintigraphy gives a good staging of the disease and detection of unexpected tumour sites, which were not determined by conventional imaging. This method also indicates content of somatostatin receptors, which might indicate efficacy of treatment with octreotide or other somatostatin analogues. Another new non-invasive technique for detection of carcinoid tumours is positron emission tomography (PET). The biological substance for study can be labelled for radioactive imaging with radionuclears, such as (11)C, (15)O and (18)F, with emission of positrons. More than 95% of patients studied displayed high tracer uptake from PET with (11)C-5HTP (5-hydroxytryptophan), which is significantly higher compared to both computer tomography and somatostatin receptor scintigraphy. MIBG has been used for decades to visualize carcinoid tumours, because MIBG is concentrated in the endocrine cells. It was initially developed to detect phaeochromocytomas of the adrenal with reported high sensitivity (87%) and specificity as high as 99%. The method can be used when other methods fail to localize carcinoid tumours and particularly when treatment with (131)I-MIBG is being considered. Tumour-targeted treatment for malignant carcinoid tumour is still investigational, but has become of significant interest with the use of radiolabelled somatostatin analogues. Since a majority of carcinoid tumours present somatostatin receptors and can therefore be visualized in vivo by using radiolabelled somatostatin analogues, it seems logical to try to target these tumours with radioactive substances, not only for visualization but also for treatment. (111)Indium-DTPA-octreotide has been used as the first tumour-targeted treatment, with rather low response rates (in the order of 10-20%) and no significant tumour shrinkage. The second radioactive analogue which has been applied in the clinic is (90)yttrium-DOTA-Tyr3-octreotide, which has given partial and complete remissions in 20-30% of patients. The most significant side-effects have been kidney dysfunction, thrombocytopenia and liver toxicity. The most recent compound is (177)lutetium-DOTA-Tyr3-octreotate, which has been applied by the Rotterdam group and has been reported to give partial remission in about 40% of the patients. In the near future, combined treatment with both (90)yttrium and (177)lutetium coupled to a somatostatin analogue might come into clinical trials. (177)Lutetium may be more effective for smaller tumours whereas (90)yttrium may be more effective for larger tumours.     

The role of octreoscan in thyroid eye disease

Until recently there was no imaging technique available which could demonstrate pathological changes in orbital tissues and could be regarded as a reliable measure of inflammation in thyroid eye disease (TED). Pentetreotide (a synthetic derivative of somatostatin) labelled with 111In has been used to localize tumours which possess surface or membrane receptors for somatostatin in vivo using a gamma camera (1). This technique visualizes somatostatin receptors in endocrine-related tumours in vivo and predicts the inhibitory effect of the somatostatin analogue octreotide on hormone secretion by the tumours (1). By applying 111In-DTPA-d-Phe octreotide scintigraphy (octreoscan), accumulation of the radionuclide was also detected in both the thyroid and orbit of patients with Graves' disease (2-4). If peak activity in the orbit 5h after injection of radiolabelled octreotide is set at 100%, a decrease to 40+/-4% is found at 24h, significantly different from the decrease in blood pool radioactivity, which is 15+/-4% at 24h. Accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somatostatin receptors (5). Alternative explanations are binding to receptors on other cell types (e.g. myoblasts, fibroblasts or endothelial cells) or local blood pooling due to venous stasis by the autoimmune orbital inflammation.     

Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma

OBJECTIVE  Octreotide scintigraphy has been reported to visualize chromaffine tumours. This study in patients with malignant phaeochromocytoma was designed to assess octreotide in comparison with standard m -iodobenzylguanidine (MIBG) scintigraphy and to study functional activity of somatostatin receptors. Finally, two cases of octreotide treatment are reported.
DESIGN  Open, prospective clinical trial.
PATIENTS  In 12 patients with histologically proven malignant phaeochromocytoma, ¹¹¹In-octreotide scintigraphy, ¹²³I-MIBG scintigraphy and computed tomography were performed. In ten patients plasma catecholamine response to a single dose of octreotide (200 μg i.v.) was monitored up to 5 hours after injection. Two patients were treated with octreotide over several months.
MEASUREMENTS  Plasma catecholamines were measured by high performance liquid chromatography (HPLC). Scintigraphy was performed using a large field gamma camera and SPECT technique where appropriate.
RESULTS  At least one metastatic lesion was visualized by octreotide scintigraphy in eight patients while the remaining four patients had negative findings. In total, 43 out of 54 known metastases (79.6%) were detected by MIBG, 24 (44.4%) by octreotide. Nevertheless, octreotide scintigraphy detected six metastases that were negative by MIBG. There was no correlation between the results of octreotide scintigraphy and catecholamine suppression after i.v. octreotide. In two patients on octreotide treatment, symptomatic improvement, but not mass reduction, could be documented.
CONCLUSIONS  Octreotide scintigraphy behaves in part complementary to MIBG, thus increasing diagnostic sensitivity. Presence of somatostatin receptors, as demonstrated by octreotide scintigraphy, does not necessarily predict functional activity or therapeutic response.     

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Oncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.     

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.     

Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours

Five somatostatin receptor (sst) subtype genes, sst(1), sst(2), sst(3), sst(4) and sst(5), have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive tract tumours also express multiple sst subtypes, but sst(2) predominance is generally found. However, there is considerable variation in sst subtype expression between the different tumour types and among tumours of the same type. The predominant expression of sst(2) receptors on pancreatic endocrine or carcinoid tumours is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues such as octreotide and lanreotide. Somatostatin and its octapeptide analogues are also able to inhibit proliferation of normal and tumour cells. The high density of sst(2) or sst(5) on pancreatic endocrine or carcinoid tumours further allows the use of radiolabelled somatostatin analogues for in vivo visualisation. The predominant expression of sst(2) receptors in these tumours and the efficiency of sst(2) receptors to undergo agonist-induced internalisation is also essential for the application of radiolabelled octapeptide somatostatin analogues. Currently, [(111)In-DTPA(0)]octreotide, [(90)Y-DOTA(0),Tyr(3)]octreotide, [(177)Lu-DOTA(0)Tyr(3)]octreotate, [(111)In-DOTA(0)]lanreotide and [(90)Y-DOTA(0)]lanreotide can be used for this purpose.     

Localization of neuroendocrine tumours and insulinomas using radiolabeled somatostatin analogues, 123 I-Try3-octreotide and 111in-pentatreitide

OBJECTIVE A number of neoplasms are known to express somatostatin receptors; the use of somatostatin receptor imaging in their localization has recently been described, but the resolution and discrimination of the isotopes used remains sub-optimal. We have looked at the use of a new” In-labelled analogue of somatostatin, pentatreotide, in the visualization and functional characterization of a number of neoplastic conditions. PATIENTS Thirteen patients with proven neoplasms were scanned using this agent. Planar and single-photon-emission computerized tomographic (SPECT) images of the relevant part of the body were obtained using a gamma-camera at 10 minutes and 4 and 21 hours after injection of the radiopharmaceutical. In six patients (three carcinoid, three insulinomas) scanning was also performed using ¹²³l-Tyr-3-octreotide. RESULTS Primary tumours or metastases were visualized in six of the seven patients with neuroendocrine tumours, and three of six patients with insulinoma. One patient with an insulinoma who had a positive scan showed absent uptake when rescanned after tumour removal. A rise In blood glucose (more than twice basal) in response to octreotide was seen only in those insulinoma patients with positive scans. In cases where both ¹¹¹ln-pentatreotide and ¹²³l-Tyr-3-octreotide scans were performed, both radiopharmaceuticals identified the same 4/ 6 tumours; however, tumour definition (reflecting high tumour to background ratio) was better with pentatreotide on the 21-hour images with minimum biliary and gut activity, allowing better resolution of the tumour image. CONCLUSION It appears that ¹¹¹ln-pentatreotide scintigraphy is a rapid and safe procedure for the visualization of neuroendocrine tumours possessing somatostatin binding sites. A positive scan may be predictive of neuroendocrine responsiveness to octreotide therapy. In addition, it also appears that¹” In-pentatreotide has superior kinetics compared to ¹²³I-Tyr-3-octreotide, typically achieving more satisfactory tumour to background ratios, and may thus be more useful in the localization of endocrine tumours.     

The diagnostic utility of somatostatin receptor scintigraphy in oncology

Somatostatin receptor scintigraphy (SRS) with the diethylenetriaminopentaacetic-acid-conjugated somatostatin analogue [¹¹¹In-DTPA-d-Phe¹] octreotide, also known as¹¹¹In-pentetreotide, is a new non-invasive modality for the evaluation of tumours that express receptors for somatostatin. These receptors are present on neuroendocrine and other tumours including lymphomas and some breast cancers. In oncology SRS is a promising diagnostic tool for localizing primary tumours, staging, control and follow-up after therapy, and for identification of patients who may benefit from therapy with unlabelled octreotide or, in the future, with radiolabelled octreotide. In the past few years many small and large studies investigating various aspects of SRS have been reported. In this review the value of SRS in the management of individual tumour types is explored. For many tumours the best sensitivity in lesion detection is only achieved by very careful imaging after the administration of at least 200 MBq¹¹¹In-pentetreotide. On the basis of the current experience the main value of SRS in oncology is in the staging and evaluation of gastroenteropancreatic tumours, paragangliomas, small-cell lung cancer and lymphomas. Promising areas for SRS are the evaluation of breast cancer, non-medullary thyroid cancer and melanoma, and initial results with targeted radionuclide therapy using radiolabelled octreotide have been reported.Abbreviations SRS somatostatin receptor scintigraphy - DTPA diethylenetriaminopentaacetic acid - SPET single-photon-emission tomography - CT computed tomography - MRI magnetic resonance imaging - TSH thyroid-stimulating hormone - MIBG m-iodobenzyl-guanidine - MTC medullary thyroid carcinoma - SCLC small-cell lung carcinoma - EGF epidermal growth factor     

Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma

OBJECTIVE: Somatostatin receptors are present on human phaeochromocytomas. Catecholamine concentrations may decrease following short-term administration of somatostatin agonists to patients with phaeochromocytomas. We carried out a prospective study on 10 patients with malignant or recurrent phaeochromocytomas to examine the clinical and hormonal effects of three monthly intramuscular injections of 20 mg slow-release octreotide. DESIGN AND MEASUREMENTS: Patients underwent somatostatin receptor scintigraphy using 111In-pentetreotide before slow-release octreotide was administered. The patients' symptoms, blood pressure, blood glucose concentrations, glycosylated haemoglobin concentra-tions, plasma insulin and noradrenaline concentrations, and the levels of two putative markers of tumour burden, urinary metanephrine excretion and plasma chromogranin A concentration, were recorded before the first injection and 28 days after the third injection. RESULTS: Slow-release octreotide did not significantly alter symptoms, blood pressure, blood glucose concentrations, plasma catecholamine and chromogranin A concentrations or metanephrine excretion. Median glycosylated haemoglobin concentrations increased from 5.3% to 6.0% (P = 0.03). Patients whose tumours took up 111In- pentetreotide did not differ from those whose tumours did not after slow-release octreotide treatment in terms of symptoms, blood pressure, blood glucose, plasma catecholamine and chromogranin A concentrations or metanephrine excretion. CONCLUSION: Our data suggest that slow-release octreotide is of limited value for the long-term treatment of patients with malignant or recurrent benign phaeochromocytomas.     

Nuclear medicine in the detection and management of pancreatic islet-cell tumours

Over the last decade somatostatin receptor scintigraphy using various derivatives of long-acting somatostatin analogues has gained its place in the management of pancreatic islet-cell tumours. Scintigraphy is based on the high-affinity binding of such somatostatin analogues to receptors over-expressed by these tumour types. Following the introduction of (111)In-DTPA-D-Phe(1)-octreotide, clinical studies with radiolabelled DOTA-Tyr(3)-octreotide and DOTA-Tyr(3)-octreotate derivatives have shown considerable improvement of imaging results with increased tumour uptake. One of the newer developments, (68)Ga-labelled DOTA-Tyr(3)-octreotide, has shown promising results in patients with pancreatic islet-cell tumours, based on the high-affinity binding to the somatostatin receptor subtype 2 in combination with positron emission tomography (PET) technology. Other peptides--such as ligands for the gastrin/CCK2 receptors or vasoactive intestinal peptide (VIP)--have also been studied for imaging pancreatic cell tumours. Whereas small-sized gastrinoma, somatostatinoma, glucagonoma, carcinoid and VIPoma are frequently detected by somatostatin receptor scintigraphy, insulinoma may escape detection due to reduced receptor expression. Following peptide receptor scintigraphy, a change in patient management is reported in up to 30% of patients. When labelled with (90)Y or (177)Lu, some somatostatin analogues have been applied to patients in advanced stages of the disease. Despite positive response data in 50% of patients, long-term results and survival rates are lacking.     

A human TSH-secreting adenoma: endocrine, biochemical and morphological studies. Evidence of somatostatin receptors by using quantitative autoradiography. Clinical and biological improvement by SMS 201-995 treatment.

An invasive TSH-secreting adenoma inducing mild hyperthyroidism was diagnosed in a 16-year-old male. Initial surgical treatment led to a temporary clinical and biological improvement. Recurrence of the thyrotoxicosis was treated with the somatostatin analogue, SMS 201-995 (octreotide) with normalization of the serum thyroid hormone levels with a dose of 200 micrograms per day. With immunoelectron microscopy, the tumour cells appeared poorly granulated with small secretory granules located at the periphery of the cells; only part of those were immunoreactive with an anti-TSH beta monoclonal antibody. No specific TRH binding site was found in a tumour membrane preparation. By quantitative autoradiography, somatostatin specific binding sites were as numerous in the TSH-secreting tumour as in control GH-secreting tumours. Binding kinetics and guanosine triphosphate dependency of the binding were equivalent in the TSH and GH tumours tested. Although all of the tumour cells displayed the same ultrastructural features, some were non-immunoreactive, suggesting that they could secrete an altered form of TSH. The absence of TRH receptors in the tumour cells is in accordance with previous reports on this type of tumour. We confirm the efficiency of octreotide treatment in this case of neoplastic TSH inappropriate secretion. The therapeutic effect of octreotide goes along with the presence of a high density of guanine nucleotide-dependent somatostatin binding sites in the tumour cells.     

Somatostatin receptor scintigraphy and octreotide treatment in patients with thyroid eye disease

OBJECTIVE Octreotide, a potent long-acting synthetic somatostatin analogue, has been reported to have a beneficial effect in thyroid eye disease (TED), but the precise mechanism of action remains unexplained. ¹¹¹ In-DTPA-D-Phe¹ -octreotide (Octreoscan-111) has been used to localize a number of endocrine tumours and visualize somatostatin receptors in the retrobulbar tissue of patients with TED. Furthermore, this technique can predict the inhibitory effect of octreotide on hormone secretion by endocrine tumours, as there is a close relation between the clinically observed Inhibition and visualization of the tumour using Octreoscan-111. The alms of the present study were to confirm the beneficial effect of octreotide in patients with TED, to investigate the presence of somatostatin receptors In the orbital area and also, if possible, to ascertain whether this technique could select those patients with TED who might benefit from treatment with octreotide. DESIGN A prospective study. SETTING An endocrine clinic of a national hospital. PATIENTS Twenty treated thyrotoxic patients with TED, 5 treated thyrotoxic patients without TED and 5 normal Individuals were studied. In 12 patients with TED, 5 without TED and 5 normal individuals, Octreoscan-111 scintigraphy of the orbits was performed. The remaining 8 patients with ophthalmopathy served as controls. In patients with TED who were Investigated with Octreoscan-111, 300 μg octreotide dally was given for 12 weeks. RESULTS Six patients In both eyes and one patient In one eye showed an improvement In ocular manifestations as assessed by clinical criteria and changes in the NOSPECS score, while the rest showed no Improvement. The patients who showed an Improvement had a high number of somatostatin receptors and positive orbital scans, while with one exception the patients who did not respond had a low number of receptors and negative orbital scans (P<0.02). None of the 5 patients without TED nor the normal individuals had a positive orbital scan. Seven out of 8 control patients with TED showed no change in the disease during the trial, while 1 deteriorated. CONCLUSIONS We conclude that octreotide has a beneficial effect in thyroid eye disease and that Octreoscan-111 could predict those patients with thyroid eye disease who might benefit from this treatment.     

Regulatory peptide receptors in human hepatocellular carcinomas

BACKGROUND: Overexpression of regulatory peptide receptors in selected human tumours is of diagnostic and therapeutic relevance. AIMS: To evaluate the expression of somatostatin, vasoactive intestinal peptide (VIP), substance P, cholecystokinin (CCK) A and B, and neurotensin receptors in hepatocellular carcinoma (HCC). METHODS: In vitro receptor autoradiography for the various peptide receptors using selective iodinated radioligands on tissue sections in 59 cases of HCC. RESULTS: 41% of HCC expressed somatostatin receptors; 47% expressed VIP receptors. VIP receptors were always identified in non-neoplastic liver tissue. Substance P receptors were only identified in 5% of HCC but in the majority of their peritumorous and intratumorous vessels. CCK-A and -B and neurotensin receptors were not detected in HCC. The somatostatin receptors showed high affinity for somatostatin and octreotide. The VIP receptors had high affinity for VIP, pituitary adenylate cyclase activating peptide (PACAP) 27, and a VIP1 selective analogue, suggesting the presence of VIP1/PACAP II type receptors. PACAP I receptors were identified in two cases. Substance P receptors were all of the NK1 subtype. The density of somatostatin receptors in HCC was low compared with the density found in liver metastases of neuroendocrine tumours. The VIP receptor density was always lower in HCC than in adjacent liver tissue. CONCLUSIONS: Somatostatin, VIP, and substance P may have a receptor mediated role in HCC. Substance P receptors may be involved in regulation of tumour associated blood flow; somatostatin receptors and VIP receptors may mediate tumour growth. Diagnostic and therapeutic evaluation of somatostatin and VIP analogues may be of interest in receptor positive HCC.     

Detection of a mesenchymal tumor responsible for hypophosphatemic osteomalacia using FDG-PET

We report a case of oncogenic osteomalacia (OO) in a 71-year-old man. The tumor, which was localized in the left lower mandible, was not found by CT, MRI, or 111-indium octreotide scintigraphy but was easily detected by FDG-PET. The use of this technique in OO has never been reported.     

Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy

The stable somatostatin analog octreotide has been successfully used for imaging and treatment of a variety of human tumors. In pheochromocytoma, data on somatostatin receptor subtyping have thus far been sparse. Pheochromocytomas often express more than one somatostatin receptor, and it is uncertain by which receptor subtype the functional responses of octreotide are mediated. Here, we have examined somatostatin receptor protein expression in a panel of 52 pheochromocytomas from 35 randomly selected patients by immunostaining with specific polyclonal anti-sst(1-5) and monoclonal mouse anti-SS-14 antibodies. Staining pattern, distribution and subcellular localization of somatostatin receptor subtypes were investigated. Seventeen patients received (111)In-octreotide scintigraphy. Although the vast majority of tumors (90%) showed positive immunohistochemical staining for sst(3), immunoreactive sst(2A) receptors were only seen in 13 tumors (25%). All other somatostatin receptor subtypes were less frequently detected. Interestingly, among sst(3)-positive tumors strikingly different subcellular distributions of immunoreactive sst(3) receptors were observed. In most cases, immunoreactive sst(3) receptors were distributed throughout the cytosol. Scintigraphic localization of tumors larger than 1 cm in diameter was always successful in the presence of immunoreactive sst(2A) receptors. In the absence of sst(2A), true-positive octreotide scintigraphy was only seen in the presence of membrane-associated sst(3) immunoreactivity. Our findings suggest that selective expression of functional membrane-associated sst(3) receptors is sufficient for high tracer uptake during octreotide scintigraphy in a subgroup of human pheochromocytomas. These tumors may represent a potential target treatment with somatostatin receptor agonists with improved sst(3) activity.     

Imaging of neuroendocrine gastro-entero-pancreatic tumours using radiolabelled somatostatin analogues

Neuroendocrine tumours of the gastro-entero-pancreatic tract are an uncommon clinical entity and are believed to arise from the endocrine cells of the gastrointestinal tract. Somatostatin receptor imaging is a diagnostic tool which allows visualization of somatostatin receptor bearing tumours. This scintigraphic procedure is performed with indium-111 labelled octreotide, a somatostatin analogue, chelated with diethylene triamine penta-acetic acid. Radionuclide imaging consists in detecting the biodistribution of somatostatin receptors, normally expressed on the cell surface of neuroendocrine gastro-entero-pancreatic tumours. To date, five types of this receptor have been cloned: indium-111-labelled-pentetreotide can visualize tumours expressing type 2 and 5 receptors. The results of our study, which involved 81 neuroendocrine gastro-entero-pancreatic tumour patients, confirm the superior sensitivity of somatostatin receptor imaging (61%) for primary tumour evaluation with respect to conventional imaging modalities such as computed tomography (40%) or ultrasound (28%). Scintigraphic findings in metastatic liver disease proved to have a sensitivity of 89% for somatostatin receptor imaging, versus 81% and 88% for computed tomography and ultrasound, respectively. In 23% of patients, lesions were found with somatostatin receptor imaging which had been missed using the other diagnostic modalities; in 26% of the patients the therapeutic approach was modified after somatostatin receptor imaging.     

Therapeutic and diagnostic implications of the somatostatin system in gastroenteropancreatic neuroendocrine tumour disease

Somatostatin exerts its actions through interaction with specific heptahelical G-protein coupled plasma membrane receptors. Five different somatostatin receptor subtypes have been cloned in man. Different receptor subtypes are coupled to different intracellular transmission cascades in a cell type-dependent manner. In general, somatostatin affects cell proliferation either directly: reducing mitogen-activated protein kinase cascade, activating phosphoproteinphosphatase, stimulating EGF-receptors and adenylate cyclase activity; or indirectly reducing the release of autocrine- and/or paracrine-acting growth factors. Somatostatin can exert cytotoxic (G1 phase cell arrest) or cytostatic (apoptosis induction) effects, also depending on the receptor subtype expressed on the target cell. In gastroenteropancreatic neuroendocrine tumours predominance of sst1 and sst2 with a lesser extent of sst3 and sst5 subtype receptors have been demonstrated using sensitive methods. Synthetic analogues with specific decreasing affinity for sst2 > sst5 > sst3 receptor subtypes have been used as antiproliferative drug in the treatment of gastroenteropancreatic tumours. These compounds (octreotide, lanreotide) resulted in a modest growth-inhibition activity either in functioning or in non-functioning tumours. Combination of somatostatin analogues with alpha-interferon produced a more pronounced antiproliferative effect overcoming therapy resistance developed to either single drug. Finally, the development of radio-labelled somatostatin analogue scintigraphy has contributed to gastroenteropancreatic-tumours lesion localization and future more detailed knowledge of somatostatin receptor mechanisms could improve both the diagnostic and therapeutic application of somatostatin analogues.