Gastroenteropancreatic Endocrine Tumors Research Articles

Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours

Background—Somatostatin receptor scintigraphy (SRS) and octreotide therapy have both changed the management of gastroenteropancreatic endocrine tumours, but very few data are available on the use of SRS and octreotide to...

Cell biology, clinicopathological profile, and classification of gastro-enteropancreatic endocrine tumors.

Recent developments in the field of endocrine cell biology and pathology at both morphological and molecular levels are briefly outlined and discussed as a basis for endocrine tumor characterization. The main tools available for identifying the endocrine nature of the tumors, their pathogenetic interpretation. and experimental reproduction with special emphasis on tumor antecedents are reported. Based on this, classifications of endocrine tumors of the pancreas and gastrointestinal tract are developed, covering most clinical (hyperfunctional syndromes included), pathological, and biological patterns, with special emphasis on tumor prognosis.

Somatostatin-receptor scintigraphy in the management of gastroenteropancreatic tumors

Objectives: This study evaluates the diagnostic and therapeutic implications of somatostatin-receptor scintigraphy in the management of patients with proven or high clinical suspicion of gastroenteropancreatic endocrine tumors. Methods: Forty-one patients were studied by planar and tomographic imaging at 4 h and 24 h after 111In-pentetreotide injection. Scintigraphic findings were compared with computed tomography, and in several patients also with ultrasound, angiography, biopsy, and/or surgery, when performed. Results: Among 23 patients with carcinoid tumor, three of nine primary tumors were initially identified by scintigraphy. Unsuspected mesenteric metastases found on scintigraphy in three patients led to octreotide treatment. Scintigraphic detection of multiple metastases in a patient with thyroid metastasis of bronchial carcinoid spared here an unnecessary total thyroidectomy. Among 18 patients with 19 islet-cell tumors, scintigraphy detected three of five insulinomas, whereas computed tomography identified only one. Receptor positivity in an isle-cell tumor (vipoma?) with no metastases on the scan led to surgical removal of the primary tumor. Receptor-positive metastases of gastrinoma (two of three patients), glucagonoma (two of three patients), and parathyroid hormone—related peptide-producing tumor (one patient) led to octreotide treatment. Nonvisualization of metastases of a glucovipoma led to chemotherapy. Conclusions: Somatostatin-receptor scintigraphy contributes to the management of patients with gastroenteropancreatic tumors in the following ways: 1) localization of a primary occult tumor, allowing surgical removal; 2) staging of the disease for optimal therapy—surgical excision or systemic treatment; and 3) identification of receptor status of the metastases for octreotide treatment or chemotherapy. (Am J Gastroenterol 1998;93:66–70.

Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours.

Somatostatin and its analogues are now of current use in the management of endocrine gastroentero-pancreatic (GEP) tumours for the purpose of inhibiting hormone hypersecretion, carrying scintigraphy imaging and attempting to slow down tumour growth. Recent molecular studies have revealed the existence of up to five membrane somatostatin receptor subtypes termed SSTR1-5. However, whether or not scintigraphy imaging and tumour characteristics are correlated with specific subtype(s) remains unclear. SSTR1-5 messenger RNA (mRNA) transcripts were investigated in 38 endocrine GEP tumours (32 islet cell tumours, six carcinoid) using reverse transcriptase polymerase chain reaction (RT-PCR), and their distribution was analysed with respect to tumour characteristics and scintigraphy imaging. SSTR2, SSTR5 and SSTR4 were detected in most cases of endocrine GEP tumours (92%, 84%, and 82% respectively), but SSTR1 and SSTR3 were less frequently observed (66% and 50% respectively). No clear-cut correlation was found between tumour characteristics and subtype mRNA distribution. Moreover, no differences in mRNA subtype distribution were found between the 17 tumours detected by scintigraphy and the four tumours not detected by this method. Somatostatin receptor mRNA subtypes are widely expressed in endocrine GEP tumours, but their distribution is not correlated with tumour characteristics or scintigraphy positivity.

Somatostatin receptor subtypes sst1, sst2, sst3 and sst5expression in human pituitary, gastroentero‐pancreatic and mammary tumors

Using in situhybridization techniques with selective oligoprobes, the gene expression of sst1, sst2, sst3 and sst5 was studied in a series of 32 human pituitary adenomas, 28 breast tumors and 21 endocrine gastroentero-pancreatic tumors, shown to express somatostatin receptors to variable extents. In most of these tumors the sst2 receptor subtype was abundantly expressed, even though a significant number of pituitary adenomas, breast and gastroentero-pancreatic tumors expressed sst1 and/or sst3 as well. A very high incidence of the sst5subtype was found in growth hormone-producing pituitary adenomas and, to a lesser extent, in inactive pituitary adenomas, whereas breast tumors seldom expressed sst5; gastroentero-pancreatic tumors showed all possible combinations of sst expression, with, however, a predominance of sst2 and sst1. Overall, the presence of sst2 mRNA and/or sst5 mRNA generally correlated with the presence of octreotide binding sites. A lack of octreotide binding sites corresponded with a lack of sst2 mRNA. Several tumors exhibiting a low number of octreotide binding sites had no measurable sst2 mRNA, despite abundance of β-actin mRNA, suggesting in these cases a very low abundance of sst mRNAs or a too low sensitivity of the in situ hybridization methodology. In all other cases, the method allowed precise localization of the respective mRNAs on the tumor tissue, notably in breast tumors with non-homogeneous receptor distribution. Tumors without measurable amounts of somatostatin receptors had no detectable sst mRNA. Our results indicate a highly variable abundance of the various sst mRNAs in individual somatostatin receptor-containing tumors. Int. J. Cancer 70:530–537. © 1997 Wiley-Liss Inc.

Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography.

Using in situ hybridization techniques with selective oligoprobes, the gene expression of sst1, sst2, sst3 and sst5 was studied in a series of 32 human pituitary adenomas, 28 breast tumors and 21 endocrine gastroentero-pancreatic tumors, shown to express somatostatin receptors to variable extents. In most of these tumors the sst2 receptor subtype was abundantly expressed, even though a significant number of pituitary adenomas, breast and gastroentero-pancreatic tumors expressed sst1 and/or sst3 as well. A very high incidence of the sst5 subtype was found in growth hormone-producing pituitary adenomas and, to a lesser extent, in inactive pituitary adenomas, whereas breast tumors seldom expressed sst5; gastroentero-pancreatic tumors showed all possible combinations of sst expression, with, however, a predominance of sst2 and sst1. Overall, the presence of sst2 mRNA and/or sst5 mRNA generally correlated with the presence of octreotide binding sites. A lack of octreotide binding sites corresponded with a lack of sst2 mRNA. Several tumors exhibiting a low number of octreotide binding sites had no measurable sst2 mRNA, despite abundance of beta-actin mRNA, suggesting in these cases a very low abundance of sst mRNAs or a too low sensitivity of the in situ hybridization methodology. In all other cases, the method allowed precise localization of the respective mRNAs on the tumor tissue, notably in breast tumors with non-homogeneous receptor distribution. Tumors without measurable amounts of somatostatin receptors had no detectable sst mRNA. Our results indicate a highly variable abundance of the various sst mRNAs in individual somatostatin receptor-containing tumors.

Diagnosis and treatment of gastroenteropancreatic endocrine tumors

Pancreatic (islet-cell) and gastrointestinal endocrine tumors are quite rare diseases - the incidence of new cases is from 0.4 to 1.5 per 100,000 inhabitants. Instead of the broader term APUDomе, the term gastroenteropancreatic endocrine tumors (GEPET) has recently become more commonly used in clinical literature for practical reasons. As a result of numerous clinical and fundamental studies, about 19 types of GEPET and more than 40 products of their secretion are currently described. Most tumors are characterized by multihormonal secretion, but the development of the endocrine syndrome clinic is determined by the predominance of the production of a single hormone. The main GEPETs are insulinoma, gastrinoma, glucagonoma, VIPoma, tumors causing the development of carcinoid syndrome, and hormone-inactive endocrine tumors. Hormone-inactive GEPET refers to tumors originating from endocrine cells, but lacking the ability to secrete one or another hormone. GEPETs differ not only in the production of a particular hormone, but also in the nature of tumor growth. With the exception of insulin, it is mainly a malignant tumor (see table), but compared with other carcinomas, spontaneous tumor growth is often relatively slow. The essential clinical significance, which largely determines the therapeutic approaches, has a very different rate of tumor growth. Cases of spontaneous course of the process for more than 10 years are described, as well as rapid growth of the tumor, leading to death in literally months. In recent years, interest in GEPET has increased significantly, which is probably due to the creation of more advanced methods of topical diagnosis and treatment, which significantly improved the prognosis.

Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours.

Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients' characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months.

Somatostatin Receptor Localization of Pancreatic Endocrine Tumors

Gastroenteropancreatic endocrine tumors are difficult to localize. At the same time the tumor is localized, though, there is an opportunity for cure or to remove tumor tissue. In this study we have prospectively examined the ability of 111In-octreotide scintigraphy, magnetic resonance imaging (MRI), and computed tomography (CT) to localize tumor lesions in 24 patients with a biochemical or histologic diagnosis of neuroendocrine tumor. In eight patients a surgical assessment of the imaging results was prospectively performed. Planar and abdominal single-photon emission tomography (SPET) images acquired 4 and 24 hours after 180 to 220 MBq of 111In-octreotide injection were evaluated and compared with conventional imaging techniques. SPET scintigraphy visualized more presumed tumor lesions (n = 39) than conventional imaging studies (MRI,n = 25; CT,n = 13); 23 of 24 patients had positive octreotide scintigraphy, 17 of 24 had positive MRI-scans, and 12 of 24 patients had positive CT scans. It was concluded that 111In-octreotide scintigraphy combined with conventional imaging improves the preoperative localization of presumably tumorous lesions in patients with gastroenterohepatic endocrine tumors.

Gastroenteropancreatic tumours and prohormones.

The structures and post-translational maturation of pancreatic and gastrointestinal prohormones are reviewed with emphasis on Danish contributions to today's knowledge. The review describes general, cell-specific, and tumour-specific prohormone-processing patterns. Since prohormone-processing in endocrine tumours is often attenuated, conventional assays that measure only the phenotypic endpoint of hormone gene expression (i.e. the bioactive hormone) do not quantitate tumour activity accurately. In contrast, measurements that include also prohormones and processing intermediates provide more accurate data on hormone synthesis in gastroenteropancreatic endocrine tumours. In order to comply with such demands we have developed a new analytical principle (processing-independent analysis (PIA)) which quantitates the entire translation product irrespective of the degree of processing. The significance of PIA in routine diagnostics awaits prospective evaluation. We hope that the present review illustrates how the tumour biology of endocrine cells in the pancreas and the gut has been an essential research area in Danish gastroenterology and endocrinology--one purpose being improvement of early diagnosis of endocrine tumours in the gut and the pancreas.

Control of growth in neuroendocrine gastro-enteropancreatic tumours.

This paper reviews data on the effect of pharmacological anti-tumour agents on tumour growth in patients with malignant gastro-enteropancreatic (GEP) tumours. Agents include long-acting somatostatin analogues, interferon-alpha, a combination of both, chemotherapy, and chemo-embolisation. Characteristics of tumours are considered which should be taken into account in the management of patients with metastatic endocrine GEP tumours, including growth rate. Tumour type should be matched to the anti-proliferative strategy.

The role of somatostatin analogues in the treatment of gastro-enteropancreatic endocrine tumours.

Neuroendocrine (NE) cells are involved in gastro-enteropancreatic (GEP) neoplasms. Biological markers, such as peptides hypersecreted by biologically active NE tumours, aid in the evaluation of response to treatment. For surgically untreatable NE neoplasms, the therapeutic approach remains undefined. Somatostatin analogues, particularly octreotide, can control the clinical effects of hormone overproduction in NE neoplasms and they have revolutionised individualised treatment, particularly for biologically active tumours. So far, like interferon, octreotide used at standard dosages has failed to control neoplastic growth per se. We gave the somatostatin analogue lanreotide to women with advanced breast cancer and to colorectal carcinoma patients. Results confirmed that inhibition of the production of insulin-like growth factor-1, which plays an important role in neoplastic proliferation, could be obtained using the highest doses. Considering these data, we started a clinical trial of 58 patients affected by NE tumours, treated with two sequential doses (500 and 1,000 micrograms subcutaneously t.i.d.) of octreotide. Long-term disease stabilisation (> 6 months) was achieved in 43% of patients but an objective response in only 3%. Good control of clinical symptoms and markers was obtained in 73 and 77% of cases, respectively. Toxicity was negligible. Somatostatin analogues should be carefully evaluated at high doses for possible anti-proliferative effects. Studies are currently investigating their promising association with interferon.

Glucagon-like peptide 1 immunoreactivity in gastroentero-pancreatic endocrine tumors: a light- and electron-microscopic study

The preproglucagon gene encodes, in addition to glucagon, two smaller peptides with structural similarity: glucagon-like peptides 1 and 2. Glucagon-like peptide 1 (GLP-1) 7-36 amide is the most powerful incretin candidate. In the present study, GLP-1 immunoreactivity was investigated in tissue specimens of various types of gastroenteropancreatic tumors, and the serum-levels of GLP-1 were assayed. Immunohistochemical staining of 88 tumors revealed GLP-1 immunoreactivity in 17 neoplasias (19.3%), viz., in 7 out of 33 non-functioning tumors, 4 out of 20 gastrinomas, 4 out of 13 insulinomas, 1 out of 3 vasoactive-intestinal-polypeptide (VIP)omas and 1 adrenocorticotropic-hormone (ACTH)-producing tumor. In these tumors, GLP-1-immunoreactive cells were distributed either diffusely, arranged in clusters, or as single cells. All GLP-1-positive tumors were immunoreactive for glucagon or glicentin, 10 tumors were immunoreactive for pancreatic polypeptide, and 8 tumors for insulin. Ultrastructural analysis of 8 GLP-1-positive tumors, with the immunogold technique, demonstrated GLP-1 immunoreactivity mainly in cells resembling the A-cells of the pancreas or the L-cells of the gut. Of the 17 GLP-1-immunoreactive tumors, 15 were primarily located in the pancreas. Additionally, 2 non-functioning tumors of the rectum were GLP-1 immunoreactive. Five tumors were GLP-1 immunoreactive from 9 patients with multiple endocrine neoplasia I syndrome. Patients with GLP-1-immunoreactive tumors were characterized by a significantly lower rate of distant metastases (P < 0.01) and a higher rate of curative resections (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Glucagon-like peptide 1 immunoreactivity in gastroentero-pancreatic endocrine tumors: a light- and electron-microscopic study

Glucagon-like peptide 1 immunoreactivity in gastroentero-pancreatic endocrine tumors: a light- and electron-microscopic study

Alpha-subunit and human chorionic gonadotropin-beta immunoreactivity in patients with malignant endocrine gastroenteropancreatic tumours.

In the serum of patients with malignant endocrine gastroenteropancreatic (GEP) tumours, both alpha-subunit (alpha-SU), common to all glycoprotein hormones, as well as free beta-subunit of human chorionic gonadotropin (hCG-beta) have been reported to be elevated in a substantial fraction. Both have been discussed as markers of malignancy in these neoplasms. In the present study we evaluated the diagnostic significance of alpha-SU and hCG-beta as serum markers in patients with malignant endocrine gastroenteropancreatic tumours. The study group consisted of 52 patients with endocrine GEP-malignancies (24 nonfunctioning, 23 carcinoid syndromes, four gastrinoma, one glucagonoma), located in the small intestine (n = 29), pancreas (n = 17), colon or rectum (n = 3), retroperitoneum (n = 2) and stomach (n = 1). alpha-SU and hCG-beta immunoreactivity was also assessed in the serum of patients with benign GEP-tumors (five insulinoma, and three gastrinoma). Concentrations of alpha-SU and hCG-beta were determined using two highly sensitive and specific immunoradiometric assays employing two monoclonal antibodies each. In 19 of 52 patients (37%), either alpha-SU (n = 9), hCG-beta (n = 7) or both subunits (n = 3) were elevated. In the subgroup of 24 patients with nonfunctioning GEP-tumours, increased concentrations of either alpha-SU (n = 6) or hCG-beta(n = 3) or both subunits (n = 1) were found in 10 of 24 patients (42%). In four of 23 patients with carcinoid syndrome (17%), either alpha-SU (n = 2), hCG-beta(n = 1) or both subunits (n = 1) were above the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastroenteropancreatic Endocrine Tumours: Effects of Octreotide Treatment

Octreotide is particularly useful in patients with resistant acromegaly and some gastroenteropancreatic (GEP) tumours, e.g. VIPomas, carcinoids and glucagonomas. The efficacy of octreotide can be attributed to its action regarding somatostatin receptors on GEP tumour cells. The symptoms of these tumours are due to a greater extent to the peptides they secrete than to their actual size. In most patients these symptoms improve or disappear completely with octreotide treatment. Side effects of treatment are mainly mild and do not necessitate withdrawal of the treatment. Octreotide is currently the drug of choice for controlling the symptoms of inoperable GEP tumours.

The Role of Somatostatin Receptor Scintigraphy in Gastroenteropancreatic Endocrine Tumors

In a European multicenter trial, a combination of conventional imaging methods (CIM) detected tumor sites in 88% of patients with gastroenteropancreatic endocrine tumors, whereas [111In-DTPA-D-Phe1]-octreotide scintigraphy was positive in 80% of the patients. The highest success rates of [111In-DTPA-D-Phe1]-octreotide scintigraphy were observed in patients with glucagonomas (100%), vipomas (88%), carcinoids (87%) and nonfunctioning islet cell tumors (82%). In addition to 297 out of 388 localizations found with CIM [111In-DTPA-D-Phe1]-octreotide scintigraphy revealed another 166 unsuspected lesions of which 40% were subsequently confirmed as true-positive findings based on the results of additional imaging procedures or histology obtained during a follow-up period. Overall, the scintigraphic findings led to management changes in 40% of the 235 patients for whom these data were available.

Somatostatin analog sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors.

A prospective study was performed to determine the efficacy of octreotide (Sandostatin; SMS 201-995) 200 micrograms tid in controlling tumor growth. The study included 21 patients with metastasized endocrine GEP tumors: 6 gastrinomas, 8 carcinoid syndromes, 7 nonfunctioning tumors. Treatment was performed for 3 to 59 months (median 15 months). Evaluation of the response to octreotide was facilitated in 12 patients by a pretreatment observation period of 3 to 47 months (median 17 months) during which the natural growth behavior was determined. Based on the presence or absence of a control period prior to treatment, 5 patients were considered to be responders, 7 as questionable responders (no pretreatment phase available), and 9 as nonresponders. None of the 21 patients had documented shrinkage of the tumor mass. The most favorable response was tumor standstill. In all but one responder an escape to an initially favorable response occurred after 6 to 28 months (median 14 months). Proved inhibition of growth was paralleled by a reduction of serum and urine hormone parameters, whereas unaltered progression of tumor growth was observed also in the presence of hormone suppression. Tumor growth and hormone release was inhibited in the absence and presence of somatostatin receptors on the tumor. It is concluded that octreotide exerts a limited effect on metastatic GEP tumor growth. The evaluation of a response to octreotide is facilitated by an observation period prior to the drug that provides information on growth characteristics of the tumor. The presence of octreotide receptors does not predict the success of therapy.

Gastroenteropancreatic Endocrine Tumours: Effect of Sandostatin® on Tumour Growth

One hundred and fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumours entered a prospective multicentre trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumours and 5 with other endocrine GEP tumours) to determine the efficacy of 200 micrograms Sandostatin t.i.d. in the control of tumour growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a 'negative' selection of patients included in the trial and suggesting that Sandostatin is unable to prevent disease progression when it is far advanced. In the evaluation of 68 patients followed up for at least 3 months, partial regression was observed in 4.4%, stable disease in 50% and tumour progression in 45%. An initially favourable response occurred frequently, however, it was followed by a decrease in response, from 54.4% at 3 months to 38% at 12 months, for the whole group of patients. Proven inhibition of tumour growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumour growth in patients with metastatic endocrine GEP tumours. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

The Visualization of Gastroenteropancreatic Endocrine Tumors

In this review, we evaluate radiological techniques currently used to localize gastroenteropancreatic (GEP) endocrine tumors. We also describe the visualization, using intravenous administration of two isotope-labelled somatostatin analogs (123-I-Tyr3-octreotide and 111In-DTPA-octreotide), of islet cell tumors in 25 patients and carcinoids in 39 patients. The primary tumor as well as previously unrecognized distant metastases were visualized in 20 of the 25 patients (80%) and in 37 of the 39 (95%). Parallel in vitro detection of somatostatin receptors on those tumors also visualized in vivo showed that ligand binding to the tumor in vivo represents binding to specific somatostatin receptors. The detection of somatostatin receptors on tumors in vivo predicted a good suppressive effect of octreotide on hormonal hypersecretion by these tumors. It is an easy, quick and harmless procedure, valuable in the localization of primary endocrine pancreatic tumors and their often radiologically and clinically unrecognized metastases. Future prospective controlled studies comparing this procedure with other radiological investigative techniques should demonstrate its sensitivity and specificity and determine the place of somatostatin receptor imaging in the localization of GEP endocrine tumors.