Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

[Acromegaly and pregnancy: report of six new cases]. / Acromégalie et grossesse: six nouvelles observations.

INTRODUCTION: Pregnancies in acromegalic women are rare. Data from the literature indicate absence of congenital malformation in newborns, an increase of pituitary adenoma volume rarely clinically symptomatic, an increased risk of gestational diabetes and gravid hypertension in women with non-controlled GH/IGF-1 hypersecretion before gestation. The changes of somatotroph function are rarely described. AIM OF THE STUDY: Report of six new pregnancies in five women with acromegaly. PATIENTS AND METHODS: Before pregnancy three women had incomplete surgical resection of GH-secreting pituitary adenoma, all were treated with somatostatin analogues, and the medical treatment was withdrawal at the diagnosis of gestation. We studied clinical (blood pressure, headaches, visual field), biological (blood glucose concentration) signs, GH and IGF-1 levels were measured during each trimester of pregnancy as well as in post-partum and were compared with pregestational values, MRI of the pituitary performed during the second trimester and in the post-partum were compared with MRI examen before pregnancy. RESULTS: All those pregnancies were normal without gestational diabetes, gravid hypertension and pituitary tumor syndrome. Clinical signs of acromegaly improved in 50 % of the patients, and IGF-1 decreased (22 %) in comparison of pregestational value without significant change in GH levels. No newborn had congenital malformation. CONCLUSION: Pregnancies in those women with acromegaly are uneventful without obstetrical or foetal complication, but a maternal follow-up is necessary in order to diagnose gravid hypertension and gestational diabetes. On the other hand, a clinical monitoring of pituitary tumor syndrome is necessary in women with non-operated GH-secreting macroadenoma before pregnancy. During the first trimester of gestation, an improvement of acromegalic signs can be due to a decrease of IGF-1 levels related to hepatic GH-resistance state secondary to physiological secretion of estrogens during gestation.

[Carcinological results of laparoscopic adrenalectomy for adrenal metastasis]. / Résultats de la chirurgie des métastases surrénaliennes par voie laparoscopique.

INTRODUCTION AND OBJECTIVES: Indication of laparoscopic adrenalectomy for adrenal metastasis remains debated. Our aim was to analyze its carcinological results. MATERIAL AND METHODS: In a series of 332 laparoscopic adrenalectomies, 13 were for adrenal metastasis (kidney=5, lung=3, melanoma=3, breast=1, eye=1). The indication was curative (single metastasis) in nine cases (69%), the four other patients (31%) having a polymetastatic disease. All alive patients were interviewed in August 2010. Survival was estimated using the Kaplan-Meyer method, with comparisons using the log rank test. RESULTS: Mean operative time was 174.2 ± 102 minutes. Blood loss was 351 ± 136 mL. Three conversions (23%) were necessary, for gastric perforation, wound of vena cava and inability to dissect the adrenal. Surgical margins were positive in six cases (46%). The risk of positive margin was lower in case of metastasis of renal cell carcinoma (Fischer, p=0.02). The median of overall survival was 14 months (3-45). Survival was significantly higher in metastases of renal cell carcinoma (p=0.035) than in metastases of other tumors, 24 months (11-36) vs six months (3-45), respectively. There was no difference according to the laparoscopic technique used, neither according to the age, nor according to the tumoral size. CONCLUSIONS: Laparoscopic surgery did not offer sufficient guarantee to be considered as the standard treatment in case of adrenal metastasis. However, with a survival rate of 60%, a lower rate of surgical margins, metastases of renal cell carcinoma seem to be the better candidates for laparoscopic adrenalectomy.

Treatment with somatostatin analogs and chemoembolization of liver metastases for severe hypoglycemia in malignant insulinomas.

BACKGROUND: Preventing hypoglycemia is of vital importance and a major challenge in patients with severe symptomatic hypoglycemia related to malignant unresectable insulinomas, but there is no consensus treatment. PATIENTS: Five patients with malignant unresectable insulinomas were referred to our department for severe hypoglycemia. At referral the five patients were dependent on iv infusion of glucose solution. Patient 1 had a locally invasive 5-cm insulinoma, patients 2, 3 and 4 had multiple liver metastases and patient 5 had a 2.5-cm pancreatic tumor with multiple liver and lung metastases. Before referral to our department, 4/5 patients had been administered systemic chemotherapy and 3/5 therapeutic doses of radiolabeled octreotide without any benefit on blood glucose levels. Octreoscan scintigraphy was positive in 4 patients (patients 1-4). Diazoxide alone or combined with glucocorticoids had failed to control hypoglycemia. Continuous sc administration of octreotide (up to 1500 µg/day) resulted in normalization of blood glucose levels in patient 1. Chemoembolization of liver metastases normalized blood glucose levels in patient 2, minimized hypoglycemia in patients 3 and 4, and normalized blood glucose levels in patient 5 when followed by subcutaneous administration of octreotide (2000 µg/day). Chemoembolization had to be repeated four times in patient 3 to control blood glucose levels. CONCLUSION: Chemoembolization of liver metastases and high-dose octreotide in responsive patients (alone or combined with chemoembolization) can control severe hypoglycemia in patients with symptomatic malignant unresectable insulinomas; the efficacy of octreotide can be improved after chemoembolization of liver metastases.

Carney complex: Clinical and genetic 2010 update.

First described in the mid 1980s, Carney complex is a rare dominantly heritable multiple endocrine neoplasia syndrome that affects endocrine glands as the adrenal cortex, the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation or myxomas of the skin. The Carney complex gene 1 was identified 10 years ago as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. An inactivating heterozygous germ line mutation of PRKAR1A is observed in about two-thirds of Carney complex patients. This last decade many progresses have been done in the knowledge of this rare disease and its genetics. This review outlines the current state of this knowledge on Carney complex.

Chromogranin A assay in clinical practice.

Chromogranins belong to the family of secretory chromogranin and secretogranin proteins. They are found in secretory vesicles throughout the neuroendocrine system. Chromogranin A (CgA) is the main component. CgA acts as a prohormone submitted to processes of degradation through which active peptides are generated. CgA has auto, para and endocrine functions. It is widely used as an immunohistochemical marker. Despite the lack of international standardization, and the lack of an accurate definition of the diagnostic cut-off levels, some CgA assays are reliable. Numerous studies have suggested that CgA determination may be of interest for the diagnosis and the follow-up of various endocrine tumors. Plasma levels of this general marker are proportional to tumor mass. The localization of the primitive tumor, the presence of associated hormonal secretions and possible renal failure and/or hypergastrinemia must be taken into consideration for proper interpretation of CgA levels. New clinical indications are emerging for the evaluation of stress in intensive care units and the assessment of cardiovascular risk. New assays estimating the concentration of active peptides are under development.

Multiple endocrine neoplasia type 2a and germ line C634G RET mutation diagnosed in an 80-year-old patient.

An 80-year-old man presented with progressive fatigue. Blood tests showed that serum calcium was increased (2.93 mmol/l, normal range 2.20-2.55 mmol/l) and serum concentration of intact parathyroid hormone (iPTH) inappropriately high (198 pg/ml, normal range 15-85 pg/ml). Neck ultrasonography and Tc-MIBI scintigraphy revealed a right parathyroid adenoma and a multinodular goiter. Serum calcitonin was significantly increased (220 pg/ml, normal range<10 pg/ml). Concomitantly, a chest-abdominal computed tomography was performed and revealed a 22 mm right adrenal incidentaloma. The urinary catecholamines and metabolites were two-fold above the upper limit of normal. After right adrenalectomy which confirmed the diagnosis of pheochromocytoma, the patient underwent total thyroidectomy with dissection of the central lymph node compartment and right parathyroidectomy. On histopathologic examination, both thyroid lobes presented 13 foci of MTC without lymph node metastasis and the parathyroid gland presented a benign adenoma without hyperplasia. The patient underwent screening and genetic testing revealing a germ line C634 G RET mutation. The diagnosis of Men2a at the age of 80 years and the absence of lymph node metastasis of the multiple MTC in a carrier of C634G mutation were unusual and argued for the possible role of genetic modifier(s) in this MEN 2a patient.

[Retroperitoneal laparoscopic adrenalectomy in a pregnant woman presenting MEN2a with a pheochromocytoma: case report and review of the literature]. / Surrénalectomie par coelioscopie rétropéritonéale au cours de la grossesse chez une patiente présentant un phéochromocytome dans le cadre d'une NEM2a: un nouveau cas et revue de la littérature.

The diagnosis of pheochromocytoma during pregnancy is uncommon and is at high risk for both mother and baby. We report the case of a 22-year-old woman with MEN2a (mutation C634Y in exon 11 of RET) who had undergone surgery for medullary carcinoma of the thyroid and hyperparathyroidism when she was 18. She was asymptomatic when she was seen at 22 weeks of gestation because of increased urinary metanephrine levels. A 24-h blood pressure monitoring was normal. Abdominal magnetic resonance imaging (MRI) revealed a right-sided, 34x31x28mm, well-limited, adrenal mass with high signal intensity on T2-weighted images; the contralateral adrenal was normal. At 26 weeks of gestation and after an adequate labetalol preparation, a retroperitoneal laparoscopic right-sided adrenalectomy was performed without maternal or foetal complications. Pathohistological examination confirmed the presence of a 3cm pheochromocytoma in the right adrenal gland, with no sign of malignancy. The levels of urinary methoxylated metabolites were normal two months after surgery. The pregnancy progressed normally and the patient delivered a healthy child without complications. In conclusion, firstly, all MEN2a women should be screened for a pheochromocytoma with a 24-h urinary metanephrine and normetanephrine evaluation before or early during pregnancy, even with normal blood pressure; secondly, pheochromocytoma diagnosed during pregnancy should be operated on during pregnancy because of the risks for both mother and baby; thirdly, after medical therapy, retroperitoneal laparoscopic adrenalectomy can be performed during the second trimester of pregnancy.

Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism.

BACKGROUND: The long-term efficacy of somatostatin analogues on insulinomas has not been studied. DESIGN: A prospective study to evaluate the response of octreotide in 21 patients with hypoglycaemia related to endogenous hyperinsulinism who were not treated by surgery. RESULTS: Reasons for not undergoing surgery were: refusal (n = 3), old age with multiple diseases (n = 5), unlocalized insulinomas (n = 2), malignant unresectable insulinomas (n = 5), multiple insulinomas (n = 3) and diffuse beta-cell disease (n = 3). Hypoglycaemia was responsive to octreotide in 14 of the 21 patients. A short 100-microg octreotide test correctly predicted the efficacy of treatment in six patients with benign insulinomas. Octreoscan scintigraphy was positive in 6 of the 16 patients of whom three were responsive and three unresponsive to octreotide. Octreoscan scintigraphy was negative in 10 of the 16 patients, eight of whom were responsive to octreotide. Subcutaneous octreotide treatment was prolonged for > 6 months (7-144 months, 67 +/- 47 months) in 11 responsive patients. No tachyphylaxis was observed. However, the octreotide dose had to be increased in two patients after 3 and 18 months, respectively. Only one patient suffered from symptomatic biliary lithiasis after 3 years of treatment. CONCLUSION: Long-term octreotide treatment can be used to control hypoglycaemia in patients with endogenous hyperinsulinism who are not eligible for surgery; octreotide efficacy on hypoglycaemia could be predicted by a short 100 microg-octreotide test in patients with benign insulinomas, but was not correctly predicted by Octreoscan scintigraphy.

Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism.

OBJECTIVE: We evaluated the respective value of insulin, C-peptide and proinsulin levels in 33 patients with endogenous hyperinsulinism and in 67 controls to determine the best parameters and thresholds to make or to rule out the diagnosis of endogenous hyperinsulinism. RESULTS: When blood glucose levels were below 2.5 mmol/l, insulin was <21 pmol/l in 8-35% of the patients and in all controls; C-peptide was >0.2 nmol/l in all insulinomas but not in the nesidioblastosis or in the controls; proinsulin was >5 pmol/l in all patients but not in the controls. When fasting blood glucose levels reached 2.5-3.3 mmol/l, proinsulin was <22 pmol/l in all the controls and >22 pmol/l in 74% of the patients. Proinsulin after an overnight fast was below 22 pmol/l in all non-obese controls and above 22 pmol/l in 73% of non-obese patients. CONCLUSION: Proinsulin levels above 5 pmol/l with blood glucose levels below 2.5 mmol/l during a 72 h fast test represent the best criterion for the diagnosis of endogenous hyperinsulinism, reaching 100% diagnostic specificity and sensitivity. Concomitant C-peptide levels above 0.2 nmol/l also make the diagnosis of all our insulinoma patients, not the diagnosis of nesidioblastosis, while insulin levels have much less diagnostic accuracy. Whether proinsulin levels above 22 pmol/l could also make the diagnosis of endogenous hyperinsulinism in part of the patients at the time of fasting blood glucose levels between 2.5 and 3.3 mmol/l or after an overnight fast in non-obese subjects needs further study.

Recent advances in treatment of medullary thyroid carcinoma.

Medullary thyroid carcinoma accounts for 5-10% of all thyroid cancers. It is sporadic in 75% of cases and familial in 25% of cases. Germ-line REarranged during transfection (RET) proto-oncogene mutations are detected in more than 95% of patients with familial medullary carcinoma whereas somatic RET mutations are detected in 40-70% of sporadic medullary carcinomas. Surgery is the only curative treatment and should consist of total thyroidectomy with central and ipsilateral or bilateral lateral lymph node dissection. Surgery provides successful cure in almost 100% of patients when tumor size measures a few millimeters, in almost 90% of patients with a tumor measuring less than 1 cm, and in only 50% of patients with a tumor larger than 1 cm. Alternative forms of treatment involving radiotherapy or chemotherapy provide little benefit. A perspective of recent trials and research into novel treatment of medullary thyroid carcinoma is summarized in the following paper. In this review we examine immunotherapy, radioimmunotherapy, therapy targeting the RET gene or protein, suicide gene therapy, cyclooxygenase inhibitors and radioiodine therapy following sodium iodide symporter gene expression.

Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors.

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is rare and generally presents as a sporadic disease. We describe a familial case of AIMAH with in vivo and in vitro demonstration of aberrant 5-HT4 and vasopressin adrenal receptors. Two sisters presented with clinical and biological features of mild Cushing's syndrome with bilateral macronodular adrenal enlargement on computerized tomography (CT)-scan evaluation. In vivo pharmacological tests showed a significant increase in plasma cortisol after terlipressin and metoclopramide administration. Unilateral adrenalectomy was performed in one of these patients. Reverse transcriptase-PCR analysis of the hyperplastic tissue revealed expression of 5-HT4 receptor isoforms (a), (b), (c), (i), and (n), and of vasopressin receptors, V1 and V2. Their father and brother were overweight, had easy bruisability and presented with biological features of subclinical Cushing's syndrome. CT scan showed moderate adrenal enlargement. In vivo pharmacological screening tests for the detection of adrenal aberrant receptors in the brother were negative. Finally, three out of the two sisters' children were evaluated. They had neither clinical nor biological features of Cushing's syndrome. Their adrenal glands were normal on CT-scan evaluation. In vivo evaluation for the detection of aberrant adrenocortical receptors performed in one of these subjects was negative. In conclusion, this study shows that (i) familial AIMAH could be an autosomal dominantly inherited disorder; (ii) aberrant 5-HT4 serotonin and vasopressin receptors can be expressed in familial AIMAH; and (iii) phenotypic expression of familial AIMAH could be varied in a same family and more pronounced in female than in male patients.

Persistent and moderate hypercalcemia related to an ovarian clear cell adenocarcinoma: Pre- and postoperative parathyroid hormone related-peptide and 1,25-dihydroxyvitamin D3 levels.

OBJECTIVE: To evaluate the role of PTH-related peptide (PTH-rP) and 1,25-dihyhydroxyvitamin D3 in a case of hypercalcemia related to an ovarian adenocarcinoma. DESIGN: We report a case of humoral hypercalcemia in a patient aged 74 yr with a clear cell adenocarcinoma of the right ovary at an early stage of its development (stage T1aN0M0) revealed by moderate and persistent hypercalcemia (variable level between 2.7 and 3.2 mmol/l without any treatment) over six months. METHODS: PTH-rP and 1,25-dihydroxyvitamin D3 were measured in blood samples taken before and after hysterectomy and bilateral salpingooophorectomy and in blood samples taken intraoperatively from the right ovarian vein and a peripheral vein. RESULTS: High levels of plasma PTH-rP and 1,25-dihydroxyvitamin D3 concomitant with high serum calcium and low PTH levels were found before surgery, which was followed by normalisation of all parameters studied. A concentration gradient was found regarding plasma PTHrP (right ovarian vein 60.4 pmol/l, peripheral vein 4.5 pmol/l), not 1,25-dihydroxyvitamin D3. CONCLUSION: 1) moderate and persistent hypercalcemia can be observed at an early stage of an ovarian carcinoma; 2) the gradient of PTH-rP concentration between the samples taken from the right ovarian vein and a peripheral vein provides evidence for a direct secretion of PTH-rP by the ovarian tumor; 3) the increased 1,25-dihydroxyvitamin D3 level is not related to a direct ovarian production, but is a consequence of PTH-rP secretion.

Normal pregnancy in a woman with nesidioblastosis treated with somatostatin analog octreotide.

OBJECTIVE: We report the case of a 36-yr-old woman with nesidioblastosis treated throughout pregnancy with high doses of octreotide. We studied the course of blood glucose, foetal growth and development. METHODS: Blood samples were obtained every month throughout pregnancy and taken at birth from the umbilical cord. Sonography was performed repeatedly to monitor foetal growth. RESULTS: The daily dose of octreotide was adapted to blood glucose levels: a dose of 1000 microg was infused during the first part of pregnancy, then it was decreased step by step during the last trimester of gestation. An elective cesarean section was performed at 32 weeks of gestation. High octreotide concentrations were obtained during the first part of gestation (range 2888-5021 pg/ml). During the third trimester of pregnancy blood glucose increased despite high insulin levels attesting physiological insulin-resistance. Plasma levels of placental GH and IGF-1 levels were similar to those observed in a normal pregnancy. Despite the presence of octreotide in the umbilical cord, TSH, free T4, PRL and pituitary GH concentrations were normal at birth. The female newborn (weight 3520 g, length 52 cm) had no malformation, and presented with normal postnatal development. CONCLUSION: Our study demonstrates that: 1) octreotide treatment can be effective in controlling endogenous hyperinsulinism during pregnancy; 2) octreotide does not affect physiological changes during pregnancy such as insulin-resistance or placental GH level; 3) exposure of the foetus to octreotide throughout pregnancy does not induce any malformation and does not affect foetal development.