Follicular nodules (THY3) of the thyroid: we recommend surgery.

OBJECTIVE: To determine the need of total thyrodectomy for patients with follicular nodules of thyroid. SUBJECTS AND METHODS: From January 2005 through June 2008, 2249 consecutive patients (438 males, 1811 females; mean age 54 yr, range 9-87) with thyroid nodules were submitted to 2518 ultrasound-guided fine-needle aspiration (USgFNA) for cytological examination. USgFNA were performed by experienced surgeon (RP) and endocrinologist (RGG) under ultra- sonographyc guidance, using a 10-MHz linear transducer. Liquid-based cytology was used. RESULTS: All cytological samples were classified in 5 diagnostic classes (THY1, THY2, THY3, THY4, THY5) in agreement with the British Thyroid Association (BTA); 1.4% specimen were classified as THY5, 2.1% as THY4, 7.6% as THY3, 79.5% as THY2 and 9.4% as THY1. In 97% of THY5 patients, malignancy was found. Among THY4 patients, 95.5% were positive for thyroid tumor. Among THY3 patients, malignancy was found in 29.1%. THY3 patients with thyroid tumors were younger than those with benign lesions (46 ± 14.1 yr vs 50 ± 13.8 yr; p<0.05, t test). No statistical difference was found neither in malignancy frequency among men and women nor in mean size of nodules (24 ± 11.8 mm malignant vs 23 ± 9.4 mm benign). CONCLUSIONS: this study provides evidence that USgFNA offers a very sensitive and accurate method in reducing THY1 samples and in detecting malignancy (>95% both in THY5 and THY4, and >29% in THY3 lesions). Our proposal is to submit to total thyroidectomy all patients with THY5 and THY4 lesions and THY3 thyroid nodule >1 cm.

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Two-step development of a pituitary adenoma: from hyperprolactinemic syndrome to Cushing's disease.

In this report we describe the case of a young female patient with amenorrhea-galactorrhea syndrome apparently due to pituitary PRL-secreting adenoma who, after three years of dopaminergic therapy without any shrinkage of the tumor, developed true Cushing's disease. Progression from hyperprolactinemia to hypersecretion of ACTH has been rarely described and it may be due to different possibilities. However, histopathological and immunohistochemical studies of the adenoma showed a pattern of PRL negative and ACTH positive cells, excluding mixed pituitary tumor. In order to explain the progression from hyperprolactinemia with amenorrhea-galactorrhea to an ACTH hypersecretion syndrome, it must be hypothesized either pituitary stalk compression or the influence of paracrine regulation factor(s) (such as Galanine) due to an "initially silent" corticotropinoma. This case confirms that the presence of hyperprolactinemia in a patient with pituitary tumor and amenorrhea-galactorrhea syndrome is insufficient to confidently conclude for prolactinoma. Furthermore, it underlines the importance both of clinically monitoring the patient with prolactin pituitary adenoma if dopaminergic therapy does not reduce tumor volume, and of accurately and repeatedly measuring the other pituitary hormonal secretions.

Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group.

OBJECTIVES: Pheochromocytoma (pheo) is the second component of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. Clinical expression is sometimes poor, and chronology between medullary thyroid carcinoma (MTC) and pheo is not well evaluated. Therefore, a retrospective study was done in eight European countries in order to precise the main characteristics of pheo in MEN 2. SUBJECTS: Data from 300 MEN 2 patients with pheo (274 MEN 2 A and 26 MEN 2 B) were obtained from cases registered by the EuroMen study group, and collected by a medical standardized questionnaire. These cases occurred between 1969 and 1992. RESULTS: Mean age at diagnosis of pheo was 39.5 years (range 14-68 years) in MEN 2A and 32.4 years (range 15-41 years) in MEN 2B patients. Pheo occurred first in 25.1% of the cases (2-15 years before diagnosis of MTC) and after MTC in 40.2% (2-11 years). In other cases (34.7%), MTC and pheo were diagnosed at the same time. Involvement was bilateral in 67.8% of cases. Malignancy was only 4%. Thirty-nine deaths occurred in these 300 patients, 64.1% were linked in pheo, 23.1% to MTC and 12.8% to other causes. Surgery was unilateral in 39.7% of the cases and bilateral adrenalectomy was the first procedure in 48.4%. A bilateral adrenalectomy in two steps had to be done in 11.9% of cases. In conclusion, these results justify systematic and prolonged biochemical screening of pheo during follow-up of MTC and address some questions about the best mode of surgery.

Usefulness of early morning urine estrone-3-glucuronide assay in the monitoring ovarian secretory function in precocious puberty.

To evaluate the usefulness of the urinary estrone-3-glucuronide (EI-3-G) in the monitoring of the ovarian function in girls, we studied 11 girls with idiopathic central precocious puberty (ICPP) treated with LHRH analogs (LHRHa) for 2-5 years. Plasma LH, FSH, 17-beta-Estradiol (E2) levels, early morning urine (EMU) E1-3-G concentrations, were assessed before and 3, 6, 12 months after the onset of treatment. As expected, mean basal plasma LH, FSH and E2 concentrations, as well as mean basal EMU E1-3-G levels were significantly (p < 0.01) higher in patients studied than in normal, age matched, prepubertal controls. Three out of the 11 sexually advanced girls showed undetectable (< 15 pg/ml) basal plasma E2 values. On the contrary, in each patient studied, individual basal E1-3-G levels were higher than in normal age-matched prepubertal girls. LHRHa treatment significantly suppressed both basal and peak stimulated plasma gonadotropins, plasma E2 and EMU E1-3-G. However, while serum E2 levels were below the assay detection limit, not allowing to assess the degree of gonadal suppression, E1-3-G urinary concentrations were detectable in each subject treated, in the range of the normal prepubertal values. EMU E1-3-G determination seems to be a very sensitive and reliable approach to the monitoring of the effectiveness of LHRHa treatment in sexually advanced girls, allowing to detect very low estrogen concentrations and to achieve the desired ovarian suppression.

Precocious puberty: auxological criteria discriminating different forms.

It may be possible to recognize different forms of precocious puberty at the first evaluation. In a group of 26 sexually precocious girls we used Bayley-Pinneau predicted adult height (P.A.H.) to discriminate patients with 'poor' or 'good' height prognosis. Patients with evidence of impaired height prognosis (P.A.H. < -1 SDS) (Group 1) were immediately treated with LH-RH analogs, while patients with unimpaired height prognosis (P.A.H. > -1 SDS) (Group 2) were followed without therapy. Two yr of treatment significantly improved P.A.H. in Group 1 patients, from a mean of -1.68 +/- 0.4 to a mean of -0.57 +/- 0.6 (SDS) (p < 0.01). After the 2 yr observation period, Group 2 patients showed no significant variation of P.A.H. (from a mean of 0.45 +/- 0.8 to a mean of 0.33 +/- 0.6). The retrospective analysis of the growth pattern changes in the two Groups seems to indicate that LH-RH agonist treatment improves height potential in girls with initial poor height prognosis and that girls with initial good height prognosis maintain an unimpaired growth potential.

Increased acylphosphatase levels in erythrocytes from hyperthyroid patients.

Acylphosphatase activity and content were measured in erythrocytes from hyperthyroid patients and healthy controls. In addition, the soluble enzymes glucose-6-phosphate dehydrogenase, hexokinase, and the membrane bound (Na+ + K+)-ATPase and Ca2+-ATPase were assayed. Our results confirmed previous studies indicating a decrease of (Na+ + K+)-ATPase and an increase of Ca2+-ATPase activity in hyperthyroid erythrocytes. While glucose-6-phosphate dehydrogenase was not significantly changed, hexokinase and acylphosphatase activities were significantly higher in the hyperthyroid group. Both activities and content of acylphosphatase returned to normal levels in erythrocytes from treated patients, when they were euthyroid. These findings suggest that an excess of thyroid hormones may stimulate acylphosphatase biosynthesis in erythroid cells and indicate a potential clinical usefulness of this enzyme in hyperthyroidism.

A study on human adrenal secretion. Measurement of epinephrine, norepinephrine, dopamine and cortisol in peripheral and adrenal venous blood under surgical stress.

Epinephrine (E), norepinephrine (NE), dopamine (DA) and cortisol (F) were measured in samples drawn simultaneously by direct venepuncture from the brachial and the adrenal vein of 12 patients undergoing surgery for left kidney diseases. In 7 patients the influence of anesthesia on peripheral plasma levels was also assessed. Catecholamines were measured by a radioenzymatic assay and F by radioimmunoassay. Compared to basal values (mean +/- SE) (E: 53.6 +/- 6.2 pg/ml; NE: 209.4 +/- 24.4 pg/ml; DA: 24.5 +/- 3.3 pg/ml; F: 12.9 +/- 1.2 micrograms/dl) only NE peripheral levels were significantly modified by anesthesia (NE: 343.7 +/- 67.4 pg/ml p less than 0.05), whereas under surgery a significant increase in the peripheral levels was found for every substance measured (mean +/- SE) (E: 332.5 +/- 46.6 pg/ml p less than 0.001; NE: 633.6 +/- 114.2 pg/ml p less than 0.005; DA: 85.8 +/- 15.7 pg/ml p less than 0.005; F: 21.3 +/- 1.9 micrograms/dl p less than 0.01). Catecholamine and F levels in adrenal vein showed a high variability suggesting an intermittent secretion. In the adrenal venous blood E levels were, in the mean, 381 times higher, NE levels 45 times, DA levels 27 times and F levels 23 times higher than in peripheral blood. E, NE and DA concentrations in the adrenal vein were all significantly correlated to the others but not to cortisol, suggesting that the medulla secrets E, NE and DA in rather constant ratios and that the cortex and the medulla respond differently to surgical stress.

Thyroxine and triiodothyronine levels in thyroid vein blood and in thyroid tissue of patients with autonomous adenomas.

Thyroxine (T4) and triiodothyronine (T3) concentrations were measured in peripheral and thyroid vein blood and in nodular and extranodular thyroid tissue from twenty-four patients with autonomous thyroid nodules (AFTN); fifteen of these patients showed clinical signs of hyperthyroidism and nine were euthyroid. Thirteen patients with solitary non-functioning thyroid adenomas who were clinically euthyroid, served as controls; samples of thyroid vein blood and normal thyroid tissue being obtained from the contralateral lobe. T4 (189.4 +/- 27.2 nmol/l) and T3 (7.05 +/- 2.03 nmol/l) concentrations were significantly higher in the thyroid vein blood of patients with AFTN compared with controls (T4 = 119 +/- 9.1 nmol/l, P less than 0.05; T3 = 2.3 +/- 0.21 nmol/l, P less than 0.01) whereas peripheral levels in the two groups were similar. The T3 concentrations (10.56 +/- 4.12 nmol/g wet tissue) in autonomously-functioning thyroid nodular tissue were significantly higher than those of extranodular (1.9 +/- 0.62 nmol/g wet tissue, P less than 0.01) and normal thyroid tissue (2.63 +/- 0.43 nmol/g wet tissue, P less than 0.05). The T4 levels were not different in the tissues examined. The concentrations of T4 and T3 in thyroid vein blood did not show any significant correlation with the hormone levels in thyroid tissue.