Neuroendocrine tumor markers.

Tumor markers used in the diagnosis and follow-up of patients with neuroendocrine tumors are in most instances not specific for a given tumor and circulate under normal conditions in the serum, making their use as an early diagnostic tool difficult (low sensitivity). By combining hormone measurements with tissue responsiveness, demonstrations of inappropriate secretions of PTH, insulin, and gastrin during hypercalcemia, hypoglycemia, and hyperacidity, respectively, become highly sensitive and specific diagnostic tests. The application of polyclonal antibodies in RIAs of hormones, such as ACTH, insulin, and gastrin, increase the diagnostic level of hormone measurements in patients with neuroendocrine tumors. Other markers, such as chromogranin A, neuron-specific enolase, and alpha-subunit, as well as peptide receptor visualization, are of increasing importance in the diagnosis and follow-up of neuroendocrine and non-neuroendocrine tumors.

Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma.

OBJECTIVE: This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA). DESIGN: Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment. RESULTS: A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels. CONCLUSIONS: Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.

Chromogranin A: its clinical value as marker of neuroendocrine tumours.

Chromogranin A (CgA) belongs to a family of secretory proteins that are present in densecore vesicles of neuroendocrine cells. Owing to its widespread distribution in neuroendocrine tissues, it can be used as an excellent immunohistochemical marker of neoplasms of neuroendocrine origin. It can also serve as serum marker of neuroendocrine activity because it is co-released with the peptide hormone content of the secretory granules. The serum concentration of CgA is elevated in patients with various neuroendocrine tumours. Elevated levels are strongly correlated with tumour volume. Although its sensitivity and specificity cannot compete with that of the specific hormonal secretion products of most of these tumours, it can nevertheless have useful clinical applications. Neuroendocrine tumours for which no peptide marker is available usually retain the capacity to secrete CgA. CgA can thus be used as serum marker for these so-called 'non-functioning' endocrine tumours. Moreover, in patients with carcinoids and phaeochromocytomas, CgA is a more stable and thus more easily manageable marker than plasma levels of respectively serotonin and catecholamines and their urinary metabolites. Its role as an important general neuroendocrine marker may be extended in the future by the development of immunoscintigraphy of membrane-bound CgA, allowing in vivo visualization of neuroendocrine neoplasms.

Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones.

Chromogranin A (CgA) is gaining acceptance as a serum marker of neuroendocrine tumors. Its specificity in differentiating between neuroendocrine and nonneuroendocrine tumors, its sensitivity to detect small tumors, and its clinical value, compared with other neuroendocrine markers, have not clearly been defined, however. The objectives of this study were to evaluate the clinical usefulness of CgA as neuroendocrine serum marker. Serum levels of CgA, neuron-specific enolase (NSE), and the alpha-subunit of glycoprotein hormones (alpha-SU) were determined in 211 patients with neuroendocrine tumors and 180 control subjects with nonendocrine tumors. The concentrations of CgA, NSE, and alpha-SU were elevated in 50%, 43%, and 24% of patients with neuroendocrine tumors, respectively. Serum CgA was most frequently increased in subjects with gastrinomas (100%), pheochromocytomas (89%), carcinoid tumors (80%), nonfunctioning tumors of the endocrine pancreas (69%), and medullary thyroid carcinomas (50%). The highest levels were observed in subjects with carcinoid tumors. NSE was most frequently elevated in patients with small cell lung carcinoma (74%), and alpha-SU was most frequently elevated in patients with carcinoid tumors (39%). Most subjects with elevated alpha-SU levels also had elevated CgA concentrations. A significant positive relationship was demonstrated between the tumor load and serum CgA levels (P < 0.01, by chi 2 test). Elevated concentrations of CgA, NSE, and alpha-SU were present in, respectively, 7%, 35%, and 15% of control subjects. Markedly elevated serum levels of CgA, exceeding 300 micrograms/L, were observed in only 2% of control patients (n = 3) compared to 40% of patients with neuroendocrine tumors (n = 76). We conclude that CgA is the best general neuroendocrine serum marker available. It has the highest specificity for the detection of neuroendocrine tumors compared to the other neuroendocrine markers, NSE and alpha-SU. Elevated levels are strongly correlated with tumor volume; therefore, small tumors may go undetected. Although its specificity cannot compete with that of the specific hormonal secretion products of most neuroendocrine tumors, it can have useful clinical applications in subjects with neuroendocrine tumors for whom either no marker is available or the marker is inconvenient for routine clinical use.

In vivo imaging of pituitary tumours using a radiolabelled dopamine D2 receptor radioligand.

OBJECTIVE: Knowledge of the dopamine D2 receptor status of pituitary tumours may play a predictive role in differential diagnosis and therapeutic decisions. This study was performed to evaluate the value of pituitary dopamine D2 receptor scintigraphy with (S)-2-hydroxy-3-123I-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide (123I-IBZM) in the diagnostic evaluation of patients with pituitary tumours. DESIGN AND PATIENTS: Scintigraphy using 123I-IBZM was performed in 5 patients with PRL-secreting macroadenomas, 2 patients with PRL-secreting microadenomas, 17 patients with clinically non-functioning pituitary adenomas (NFPAs), 12 patients with GH-secreting adenomas and 1 patient with a TSH-secreting macroadenoma. RESULTS: Single-photon emission tomography (SPECT) showed significant uptake of 123I-IBZM in the pituitary region in 3/5 macroprolactinoma patients. These results closely correlated with the response of plasma PRL levels to the dopamine D2 receptor agonist quinagolide. In two scan-positive prolactinoma patients, repeated SPECTs during therapy with quinagolide showed a reduction in the pituitary uptake of 123I-IBZM. Pituitary SPECT was negative in the 2 microprolactinoma patients, who responded to quinagolide administration. In 4/17 patients with NFPA, significant uptake of the radioligand in the pituitary region was observed. In 2/3 scan-positive NFPA patients, who were treated with quinagolide, shrinkage of the pituitary tumours was observed. Treatment with quinagolide resulted in stabilization of tumour growth in the other scan-positive patients. Four out of 17 patients with NFPA and a negative SPECT were treated with quinagolide. Tumour growth was observed in 1 patient, and tumour size did not change in the other 3 patients. The pituitary region of none of the 12 acromegaly patients showed significant uptake of 123I-IBZM. Sensitivity of the GH-secreting adenomas to quinagolide was demonstrated in 8/12 patients in vivo by an acute test, and in 6/9 of the tumours in vitro. Pituitary SPECT was negative in the patient with the TSH-secreting macroadenoma and this tumour also showed no sensitivity to quinagolide in vivo or in vitro. CONCLUSIONS: We conclude that 123I-IBZM is a ligand for in vivo imaging of dopamine agonist- sensitive macroprolactinomas, but not for microprolactinomas or GH-secreting adenomas. The technique potentially provides a means of predicting the dopamine agonist-responses of non-functioning pituitary adenomas in vivo.

Serum chromogranin A in the differential diagnosis of Cushing's syndrome.

We evaluated whether measuring serum levels of chromogranin A, a marker of neuroendocrine tumours, could be useful in the differential diagnosis between pituitary, adrenal and ectopic causes of Cushing's syndrome. Thirty patients with Cushing's syndrome were studied. The localization of the tumours responsible was pituitary in 15, adrenal in 5 and ectopic in 10 patients. Serum concentrations of chromogranin A were measured in all patients. Petrosal sinus sampling for chromogranin A was performed in the cases with pituitary-dependent Cushing's syndrome. Immunohistochemical staining for chromogranin A was carried out on part of the tumour specimens. Slightly elevated serum levels of chromogranin A (range 223-262 micrograms/l) were detected in inferior petrosal sinus and peripheral venous samples from three patients with pituitary-dependent Cushing's syndrome. Serum chromogranin A showed no significant pituitary to peripheral gradient in these patients. Chromogranin A levels were not elevated in cases of adrenal Cushing's syndrome. Markedly elevated concentrations (range 270-13,900 micrograms/l) were shown in seven of 10 patients with neuroendocrine tumours with ectopic adrenocorticotrophin (ACTH) and/or corticotrophin-releasing hormone (CRH) production. Widespread metastasis was present in all these cases. Subjects with "occult" carcinoid tumours, with limited spread, had normal chromogranin A levels. Immunohistochemical staining for chromogranin A was positive in three out of five pituitary adenomas and in all neuroendocrine tumours with ectopic ACTH and/or CRH production, while it was negative in all adrenocortical tumour specimens. It is concluded that elevated serum levels of chromogranin A can serve as markers of neuroendocrine tumours with ectopic ACTH and/or CRH production.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin receptor scintigraphy: its value in tumor localization in patients with Cushing's syndrome caused by ectopic corticotropin or corticotropin-releasing hormone secretion.

PURPOSE: To assess the feasibility of somatostatin receptor scintigraphy for patients with Cushing's syndrome caused by tumors secreting ectopic corticotropin or corticotropin-releasing hormone (CRH). PATIENTS AND METHODS: Ten patients with Cushing's syndrome, nine with ectopic corticotropin-secreting tumors and one with a CRH-secreting tumor, were consecutively studied. For comparison purposes, eight patients with corticotropin-secreting pituitary tumors and one patient with an autonomous adrenal adenoma were investigated. In vivo tumor localization was performed for all patients using a radionuclide-coupled somatostatin analog. The results obtained with this technique were compared with those obtained with conventional imaging techniques. For some patients, the clinical effects of octreotide therapy were evaluated. RESULTS: Somatostatin analog scintigraphy successfully identified the primary ectopic corticotropin-secreting and CRH-secreting tumors or their metastases, or both, in 8 of 10 patients; in 2 patients with corticotropin-secreting bronchial carcinoids, the tumors could not be visualized. Normal scans were obtained for the 8 patients with corticotropin-secreting pituitary tumors and the one patient with an adrenal adenoma. CONCLUSION: Somatostatin analog scintigraphy can be included as a diagnostic step in the workup of Cushing's syndrome patients with a suspected ectopic corticotropin-secreting tumor or a CRH-secreting tumor.

A comparison between the diagnostic value of gonadotropins, alpha-subunit, and chromogranin-A and their response to thyrotropin-releasing hormone in clinically nonfunctioning, alpha-subunit-secreting, and gonadotroph pituitary adenomas.

We tested the hypothesis of whether chromogranin-A (CGA), an immunohistochemical marker of neuroendocrine tumors, could serve as a serum marker for clinically nonfunctioning pituitary adenomas. Basal and TRH-stimulated concentrations of LH, FSH, alpha-subunit, and CGA were measured in 22 patients with clinically nonfunctioning pituitary adenomas and in 20 control patients with other pituitary tumors. The control group consisted of 9 patients with PRL- and/or GH-secreting adenomas and 11 patients with nonendocrine tumors [5 craniopharyngiomas, 2 (dys)germinomas, 1 astrocytoma, 1 meningioma, 1 neurinoma of the acoustic nerve, and 1 dermoid cyst]. Immunohistochemical staining for CGA was performed on tumor tissue obtained at transsphenoidal surgery in 18 study and 12 control patients. Tissue from 19 of the 22 clinically nonfunctioning adenomas was cultured, and concentrations of LH, FSH, alpha-subunit, and CGA were measured. Immunohistochemical staining for CGA was positive in 15 of 18 clinically nonfunctioning adenomas and negative in all examined control tumors (n = 12). CGA was present in the culture medium of 16 of 18 adenomas in vitro. In 3 adenomas it was present in the absence of detectable amounts of gonadotropins or alpha-subunit. Basal serum levels of gonadotropins and/or alpha-subunit were elevated in 7 of 22 patients with clinically nonfunctioning adenomas and in 4 of 9 control patients with PRL- and/or GH-secreting adenomas. Basal CGA was elevated in 2 study patients and 1 prolactinoma patient. Significant increases in serum gonadotropin and/or alpha-subunit levels in response to TRH occurred in 14 of 21 patients with clinically nonfunctioning adenomas and in 13 of 20 control patients. A significant CGA peak after TRH administration was demonstrated in 6 patients with clinically nonfunctioning pituitary tumors and in none of the controls. We conclude that 1) immunohistochemical staining for CGA is an excellent tool to prove the endocrine origin of clinically nonfunctioning pituitary tumors; 2) in vivo, the gonadotroph origin can be recognized in only a minority of patients who have elevated basal levels of LH, FSH, or alpha-subunit; 3) examination of the effect of TRH on CGA release is a rather insensitive, but specific, diagnostic test, allowing differentiation from nonendocrine pituitary tumors; and 4) the responses of gonadotropins and alpha-subunit to TRH, although more sensitive, are not specific for clinically nonfunctioning pituitary adenomas and are probably only reliable in cases of total hypopituitarism.

Current tools in the diagnosis of pituitary tumours.

Pituitary tumours result in hypersecretion of different hormones which can be used in diagnosis. Prolactinomas can be diagnosed by measurement of prolactin serum concentration. Prolactin concentrations of > 150 to 200 micrograms/l are invariably due to macroprolactinoma. Lower levels may indicate microprolactinoma or a peripituitary tumour. Computed tomography scans visualize (micro)prolactinomas of 3 mm. Diagnosis of acromegaly is now based on measurement of serum IGF-I concentration. IGF-I levels correlate with the old test which measured insufficient suppression of GH levels to < 2 micrograms/l in response to oral glucose load. Most endocrine tumours have somatostatin receptors, allowing visualization with radiolabelled somatostatin analogues. 111In-diethylenetriaminopentaacetic acid-octreotide allows normal pituitary and somatostatin positive tumours to be visualized. A positive scan is predictive of good response to octreotide therapy. Cushing's syndrome is diagnosed by ecchymoses, myopathy, hypertension, and by measurement of the overnight 1 mg dexamethasone suppression test, urine cortisol levels and the diurnal cortisol rhythm. Clinically nonfunctioning macroadenomas in post-menopausal women often do not immunostain for gonadotropins. Serum gonadotropin levels are not elevated, although they do release gonadotropins or subunits in vitro. Diagnosis is assisted by TRH administration which increases serum gonadotropins or subunits, especially LH-beta.

Hypertension in obese and non-obese non-insulin dependent diabetics a matter of regional adiposity?

There is growing evidence that differences in fat distribution can be predictive for differences in the prevalence of metabolic disturbances, cardio-vascular disease, stroke and death, independent of commonly used indices of obesity. This study evaluates regional body fat distribution as a possible main reason for hypertension in obese and non-obese type II diabetics. 42% of normal weight diabetics with abdominal obesity are hypertensive versus 47% of obese diabetics; only 5% hypertension could be found when a lower body segment fat distribution is present. A significant (p less than 0.001) correlation exists between fat mass topography and both systolic (r = 0.49) and diastolic (r = 0.49) blood pressure. This correlation remains true after correction for body mass index and percent glycosylated hemoglobin. These results suggest that localization of fat in the upper body segment should be considered as a additive risk for hypertension.