H. Vierhapper

Anaplastic (undifferentiated) thyroid carcinoma (ATC)

Background: Old age, reduced general condition and far advanced tumor stage associated with poor prognosis induced the belief that, apart from verifying the diagnosis of anaplastic thyroid carcinoma (ATC) by biopsy, no additional surgery would be justified. However, in some cases, an ultraradical approach was recommended in order to improve the quality of life and survival. Methods: These are the results of a retrospective analysis involving 120 patients subjected to restricted radical surgery (excising as much as possible of the tumor and local metastases, foregoing ultraradical removal of vital organs such as esophagus, larynx and trachea). Results: Irrespective of the surgical approach used, 6±2% of the patients were alive after 5 years (median survival time: 3.1 months). Patients without tumor residues (R0-resections; extending to soft tissue only; Kaplan-Meier estimate – cumulative survival 15±5%) had a significantly better prognosis than patients with tumor residues (R1/R2-resections; no patient survived 5 years; P<0.001). Tumor morphology (spindle cells, giant cells, mixed cells) or differentiated parts of the tumor as well as lymph-node involvement had no statistically significant impact on the prognosis. Conclusions: In ATC, the objective should be to remove as much of the carcinoma as possible (in the ideal case, a thyroidectomy); if lymph nodes are affected, neck dissection should be the goal, if possible (restricted radical approach, improving quality of life). Ultradical surgery to include segmental resection of larynx, trachea or esophagus do not seem to be indicated, as prolonged survival is questionable and quality of life is certainly diminished.

C-cell hyperplasia and medullary thyroid carcinoma in patients routinely screened for serum calcitonin.

Routine screening of calcitonin serum levels in patients with nodular thyroid disorders has led to an increased rate of total thyroidectomies. We investigated prevalence and interrelationship of C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients with thyroid and parathyroid disorders that showed increased calcitonin serum levels detected by routine screening. Within two years, 30 (mean age, 60 +/- 14 years) of 667 patients had a pentagastrin-stimulated calcitonin level of more than 100 pg/mL. All 30 underwent total thyroidectomy and were tested for germ-line mutations of the ret protooncogene. Entire surgical specimens were blocked, and C-cell disorders were assessed using conventional histology and immunohistochemistry. C-cell hyperplasia was defined by the presence of more than 50 C cells/l low-power field in both lobes and was classified as focal, diffuse, nodular, or neoplastic. Nineteen patients (female/male = 14/5) had MTC, and 11 males but no females had CCH only. Six of 16 patients with sporadic MTC had concomitant CCH. Three patients were index cases of new MTC families. We conclude that MTC with concomitant CCH is an unreliable marker for hereditary MTC risk and that CCH has a preneoplastic potential in the absence of germ-line mutations. In this series, CCH alone was not found in females.

Positron emission tomography imaging of adrenal masses: 18F-fluorodeoxyglucose and the 11β-hydroxylase tracer 11C-metomidate

Purpose11C-metomidate (MTO), a marker of 11β-hydroxylase, has been suggested as a novel positron emission tomography (PET) tracer for adrenocortical imaging. Up to now, experience with this very new tracer is limited. The aims of this study were (1) to evaluate this novel tracer, (2) to point out possible advantages in comparison with 18F-fluorodeoxyglucose (FDG) and (3) to investigate in vivo the expression of 11β-hydroxylase in patients with primary aldosteronism.Methods Sixteen patients with adrenal masses were investigated using both MTO and FDG PET imaging. All patients except one were operated on. Five patients had non-functioning adrenal masses, while 11 had functioning tumours(Cushing’s syndrome, n=4; Conn’s syndrome, n=5; phaeochromocytoma, n=2). Thirteen patients had benign disease, whereas in three cases the adrenal mass was malignant (adrenocortical cancer, n=1; malignant phaeochromocytoma, n=1; adrenal metastasis of renal cancer, n=1).ResultsMTO imaging clearly distinguished cortical from non-cortical adrenal masses (median standardised uptake values of 18.6 and 1.9, respectively, p<0.01). MTO uptake was slightly lower in patients with Cushing’s syndrome than in those with Conn’s syndrome, but the difference did not reach statistical significance. The expression of 11β-hydroxylase was not suppressed in the contralateral gland of patients with Conn’s syndrome, whereas in Cushing’s syndrome this was clearly the case. The single patient with adrenocortical carcinoma had MTO uptake in the lower range.ConclusionMTO could not definitely distinguish between benign and malignant disease. FDG PET, however, identified clearly all three study patients with malignant adrenal lesions. We conclude: (1) MTO is an excellent imaging tool to distinguish adrenocortical and non-cortical lesions; (2) the in vivo expression of 11β-hydroxylase is lower in Cushing’s syndrome than in Conn’s syndrome, and there is no suppression of the contralateral gland in primary aldosteronism; (3) for the purpose of discriminating between benign and malignant lesions, FDG is the tracer of choice.

Hyperprolactinaemia in hypothyroidism: clinical significance and impact of TSH normalization

objectives Menstrual irregularities in hypothyroidism have been reported to occur less frequently than previously described. We therefore studied the influence of serum PRL in patients with newly diagnosed subclinical and overt hypothyroidism and in hyperprolactinaemic patients treated with T4 to distinguish the impact of hypothyroidism from that of confounding drugs on hyperprolactinaemia and menstrual irregularities.

Production rates of testosterone in patients with cushing's syndrome

Testosterone production rates were determined in 16 patients with Cushings syndrome (4 men and 12 women) using the stable-isotope dilution technique and mass spectrometry. 1alpha,2alpha-D-Testosterone was infused for 10 hours at a dose of 20 microg/h (men) and 0.4 microg/h (women) and blood samples were obtained at 20-minute intervals during the last 4 hours of the observation period. Estimated production rates in men with Cushings syndrome were 27, 73, 150, and 180 microg/h (mean, 106 +/- 70 microg/h; healthy men [n = 12], 210 +/- 70 microg/h). In the 12 women with Cushings syndrome, testosterone production rates were 0.3 to 22.3 microg/h (healthy women [n = 5], 4.3 +/- 1.9 microg/h). There was no difference in testosterone production rates in female patients with central (n = 8) versus adrenal (n = 4) Cushings syndrome. In summary, testosterone production rates are subnormal or low-normal in male patients with endogenous hypercortisolism, but not in female patients with the same disorder. We conclude that testosterone production in men, but not in women, is predominantly of gonadal origin and hence susceptible to a glucocorticoid-induced suppression of gonadotropin secretion.

Sex-specific differences in cortisol production rates in humans

Production rates of cortisol were determined in healthy men (n = 7) and in healthy women during the follicular phase of their menstrual cycle (n = 7) using the stable-isotope dilution technique and analysis by gas chromatography/mass spectrometry (GC/MS). 1Alpha,2alpha-D-Cortisol was infused for 10 hours (116 +/- 6 microg/h; 8 AM to 6 PM). Blood samples obtained at 20-minute intervals during the last 4 hours (2 PM to 6 PM) were pooled and used for analysis. Estimated production rates of cortisol were 0.94 +/- 0.15 mg/h and 0.38 +/- 0.14 mg/h in healthy men and women, respectively. Even when corrected for body-surface area, production rates of cortisol in men (0.48 +/- 0.09 mg/m2 x h) were higher (P < .001) than in women (0.22 +/- 0.08 mg/m2 x h). An increased production rate of cortisol was seen in 12 patients with Cushings syndrome, although in four of nine female patients, it was within the range considered normal for healthy men. It is concluded that women have a lower production of cortisol than men and that this sex-specific difference is of clinical relevance in patients with endogenous hypercortisolism.

Effects of islet amyloid polypeptide on hepatic insulin resistance and glucose production in the isolated perfused rat liver

SummaryThe impact of (pancreatic) islet amyloid polypeptide on glucose metabolism and insulin sensitivity was examined in isolated rat livers perfused in a non-recirculating system. Continuous infusion of 10−7mol/l islet amyloid polypeptide affected neither basal nor glucagon (10−9 mol/l)-stimulated glucose output by livers from fed rats, but it did increase the hepatic cyclic AMP release within 44 min (7.91±12.07 vs control: 0.07±0.03 pmol·100 g body weight−1). The effect of the peptide on the ability of insulin to inhibit glucagon-induced hepatic glycogenolysis was measured in three experimental groups (n = 6). As expected glucagon (7×10−11 mol/l) increased integral hepatic glucose release within 84 min (763.4±161.7 vs −25.7±73.2 μmol · 100 g body weight−1 in the control group, p<0.001), while insulin (100 mU/l) decreased the glucagon-stimulated glucose production (395.2±180.0 μmol·100 g body weight−1, p<0.01). Simultaneous infusion of 10−7 mol/l islet amyloid polypeptide however, was not able to reverse insulin-dependent inhibition of glucagon-stimulated hepatic glucose output (370.0±102.5 μmol·100 g body weight−1, NS) or to enhance lactate-induced gluconeogenesis of livers from 24 h fasted rats (n = 8). The glucose production stimulated by 10−9 mol/l glucagon was slightly greater in islet amyloid polypeptide-pre-treated livers than in a control group without addition of islet amyloid polypeptide (5 min: 3.60±3.36 vs 1.67±1.28 μmol·min−1·100 g body weight−1). These results suggest that islet amyloid polypeptide neither directly affects hepatic glycogenolysis nor causes insulin resistance to hormone-sensitive glucose production, but may increase the size of the hepatic glycogen pool by enhancing gluconeogenesis.

Increased prevalence of heterozygous 21-OH germline mutations in patients with adrenal incidentalomas.

objective As a result of the widespread use and the enhanced quality of high‐resolution radiological techniques [computed tomography (CT), magnetic resonance imaging (MRI)] a high frequency (4–10%) of adrenal incidentalomas has been detected in the general population. It is still debated whether undiagnosed 21‐hydroxylase (21‐OH) deficiency, accounting for more than 90% of congenital adrenal hyperplasia (CAH) cases, predisposes for adrenal tumours. We therefore performed an analysis of the prevalence of 21‐OH germline mutations in patients with non‐functional adrenal incidentalomas.

Can dynamic gadolinium-enhanced magnetic resonance imaging with chemical shift studies predict the status of adrenal masses?

Endoscopic adrenalectomy represents the new gold standard in the surgical treatment of benign adrenal lesions up to 6 cm. In some cases lesions larger than 10 cm have been removed laparoscopically to offer the patient the advantages of the minimally invasive technique. The larger the diameter of an adrenal lesion, the greater the probability of malignancy. In a prospective study 130 consecutive patients (88 women, 42 men; mean age 47.8 years) with 137 adrenal lesions earmarked for surgery underwent preoperative gadolinium-enhanced magnetic resonance imaging (MRI) with chemical shift studies (CSS). The aim of this study was to predict the status (benign, borderline, malignant) of adrenal lesions by MRI irrespective of tumor size. There were 14 patients with malignant tumors, 3 had borderline tumors (epithelial tumors with high malignant potential), and the remaining 120 had benign adrenal lesions. Five malignant lesions (36%) had a diameter < 6 cm. MRI correctly predicted 11 of 14 malignant tumors (1 malignant pheochromocytoma and 2 adrenocortical carcinomas had false-negative results), 117 of 120 benign lesions, and 2 of 3 borderline lesions. All but two malignant tumors were operated on using open surgery; 82 (68%) of 120 benign adrenal lesions were treated using the transperitoneal laparoscopic approach. Tumor size alone is not suitable for predicting the status of adrenal lesions. Dynamic gadolinium-enhanced MRI with CSS can predict the status of at least 95% of adrenal lesions. Tumors > 6 cm classified as benign by preoperative MRI may be removed laparoscopically by endocrine surgeons experienced in endoscopic adrenalectomy.

Effect of endothelin-1 in man--impact on basal and stimulated concentrations of luteinizing hormone, follicle-stimulating hormone, thyrotropin, growth hormone, corticotropin, and prolactin.

The effect of endothelin-1 on basal and stimulated serum (plasma) concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), prolactin (PRL), growth hormone (GH), and corticotropin was investigated in healthy male volunteers (n = 5). Intravenous (IV) administration of endothelin-1 (5 ng/kg/min for 15 minutes, followed by 2.5 ng/kg/min for 105 minutes) induced an increase in basal plasma concentrations of corticotropin. Serum concentrations of PRL, TSH, LH, FSH, and GH remained unchanged. The increase in serum concentrations of these pituitary hormones induced by IV administration of LH-releasing hormone ([LH-RH] 100 micrograms), thyrotropin RH ([TRH] 400 micrograms), GH-RH (100 micrograms), and corticotropin-releasing factor ([CRF] 100 micrograms) was suppressed in regard to PRL (P < .01) and GH (P < .01) and enhanced in regard to corticotropin (P < .01). Stimulated serum concentrations of LH and FSH also tended to be higher following administration of endothelin-1 (P < .05), whereas the increase in serum concentrations of TSH remained unchanged. Thus, when administered in pharmacological doses, endothelin-1 influences pituitary hormone secretion in man.