MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing's disease? A personal view.

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist.

From benign adrenal incidentaloma to adrenocortical carcinoma: an exceptional random event.

New European guidelines for the management of adrenal incidentalomas were recently released. One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically, he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT scan, it was a 6 cm heterogeneous tumor. On hormonal work-up, there was no secretion. The patient was operated of an adrenalectomy, and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge, this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma.

MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. OBJECTIVE: To improve the knowledge of MEN1 natural history before 21 years old. METHODS: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. RESULTS: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. CONCLUSIONS: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients.

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Local and distant recurrences occur in a subset of tumors classified as 'aggressive' ACC (aACC), as opposed to 'non-aggressive' ACC (naACC). In this study, we investigated whether tissue and serum microRNAs (miRNAs) are predictive of ACC prognosis. Tissue miRNA expression profiles were determined using microarrays in a test series of six adrenocortical adenomas (ACAs), six naACCs, and six aACCs. Eight miRNAs were selected for further validation by quantitative RT-PCR (ten ACAs, nine naACCs, nine aACCs, and three normal adrenals). Serum levels of five miRNAs were measured in samples from 56 subjects (19 healthy controls (HC), 14 ACA, nine naACC, and 14 aACC patients). MiR-195 and miR-335 levels were significantly decreased in both tumor and serum samples of ACC patients relative to ACA patients or HC. MiR-139-5p and miR-376a levels were significantly increased in aACC compared with naACC patients in tumor samples only. Tissue miR-483-5p was markedly upregulated in a majority of ACC compared with ACA patients or HC, but most importantly, serum miR-483-5p was detected only in aACC patients. High circulating levels of miR-483-5p or low circulating levels of miR-195 were associated with both shorter recurrence-free survival (P=0.0004 and P=0.0014 respectively) and shorter overall survival (P=0.0005 and P=0.0086 respectively). In conclusion, this study reports for the first time that circulating miR-483-5p and miR-195 are promising noninvasive biomarkers with a highly specific prognostic value for the clinical outcome of ACC patients.

No evidence for relevant QT interval prolongation in mitotane-treated patients with adrenocortical carcinoma.

OBJECTIVE: We designed a single-center retrospective study to assess the QT interval duration and to describe cardio vascular events among patients treated with mitotane for a adrenocortical carcinoma (ACC). DESIGN: We selected 14 patients (6 males and 8 females) that met the following criteria: ACC treated with mitotane, for whom an electrocardiogram (ECG) at baseline (before mitotane initiation) was available and for whom at least one ECG was available during the course of mitotane therapy together with a concomitant mitotane plasma level determination. RESULTS: Mean mitotane plasma level at baseline and after treatment showed a significant increase (mean level increased from 0 to 14.9±2 mg/l). At baseline and before mitotane was initiated all QTc intervals were <450 msec for men and <460 msec for women. During the treatment phase with mitotane, no QTc>470 msec was found in any patients respectively for men and women. In addition, no patient showed any significant QTc prolongation (>5% or >10 msec) at any time during mitotane treatment. During a mean follow-up of 15.9±3.5 months (range 2-45 months). No cardiovascular deaths or hospitalization for cardiovascular events was documented. No torsades de pointes were documented on ECG. No syncope, dizziness, heart failure were observed during follow up. Six out of 14 patients died during the follow-up, in five cases due to the progression of the disease, one patient died suddenly at home during followup. CONCLUSION: This short and retrospective series shows no evidence that mitotane induce any QT prolongation, even when plasma levels are well above the therapeutic window.

Risk factors for conversion and complications after unilateral laparoscopic adrenalectomy.

BACKGROUND: Laparoscopic adrenalectomy (LA) is the procedure of choice for surgical management of most benign adrenal tumours, with a reported overall complication rate around 10 per cent. The aim of this study was to determine predictive factors for postoperative complications and conversion to open surgery after unilateral LA. METHODS: From 1994 to 2009, consecutive patients undergoing unilateral LA by the lateral transabdominal approach were analysed from a prospectively maintained database. A mass larger than 12 cm in diameter and suspected primary adrenal carcinoma were considered contraindications to LA. Predictive factors for postoperative complications and conversion to open surgery were analysed. RESULTS: Some 462 patients were analysed. There were no postoperative deaths. Postoperative complications occurred in 53 patients (11·5 per cent), medical complications in 28, and surgical complications in 33 patients. Six patients underwent reoperation for complications. Multivariable logistic regression analysis showed that conversion to open surgery (odds ratio (OR) 6·20, 95 per cent confidence interval 2·08 to 18·53; P = 0·001) and left-sided tumour (OR 1·89, 1·02 to 3·52; P = 0·044) were independent predictive factors for overall complications. Conversion to open surgery was the only independent predictive factor for medical complications (OR 12·88, 4·21 to 39·41; P = 0·001), and left-sided LA was the only predictive factor for surgical complications (OR 2·22, 1·01 to 4·89; P = 0·047). No factor was predictive of conversion to open surgery. CONCLUSION: In this single-institution study, conversion to open surgery and left-sided tumours were independent predictive factors for overall complications, but none of the variables analysed was predictive of conversion.

[Manifestations and prognosis of thyrotropin-secreting pituitary adenomas: a case series of three patients]. / Présentation et pronostic des adénomes thyréotropes: à propos de trois observations.

INTRODUCTION: Among pituitary adenomas, thyrotropinomas were previously considered as extremely rare and resistant to therapy. However, the common use of the sensitive TSH measurement and the improvement of pituitary imaging have modified their clinical and hormonal presentation. CASE REPORTS: We here report three cases of TSH secreting pituitary adenoma that highlight the great diversity of the clinical, hormonal and morphological presentation, and their better prognosis. In the presence of an inappropriate TSH secretion, the main differential diagnosis is the syndrome of thyroid hormone resistance. The role of somatostatin analogue prior to the surgical treatment of TSH secreting pituitary adenoma is also underlined in this report. CONCLUSION: The increasing frequency and early diagnosis of TSH secreting pituitary adenoma may be explained by ultrasensitive methods now used for TSH measurement and progress in pituitary imaging, mainly with MRI. This changing spectrum in the presentation and the excellent response to somatostatin analogues improved in the prognosis of the disease.

[Biology of primary hyperparathyroidism: selective venous sampling]. / Biologie de l'hyperparathyroïdie primaire: prélèvements veineux étagés.

The diagnosis of primary hyperparathyroidism (PHP) is chemical: high level of Parathormone (PTH) in conjunction with hypercalcaemia. In borderline cases with sub-normal plasma PTH and calcium, an oral calcium load test could allow a differential diagnosis from other causes of high PTH. Imaging is required only for PHP. Selective venous sampling can help in localizing a parathyroid adenoma in difficult cases by PTH cartography in the following situations: imaging in favour of an ectopic mediastinal gland or a deep cervical adenoma, persistent or recurrent PHP after first failed surgery with negative neck exploration or unsatisfactory in case of another hypersecreting gland, PHP well diagnosed with indeterminate imaging, symptomatic PHP with normal PTH and negative imaging. Venous blood sampling performed in a vascular radiological department with a quick PTH assay can reveal an area of maximum secretion potentially linked to a nodule localized by previous ultrasound coupled to scintigraphy, giving thus a "biological imaging" study. The association of imaging and biology is an efficient procedure enabling localization of an area of abnormal PTH secretion and characterization of the level of PTH secretion. The area with the highest gradient of PTH concentration can help to protocol CT and MR examination.

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

OBJECTIVE: The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics. METHODS: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured. RESULTS: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%+/-4 vs 100%+/-19, P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37+/-0.31 vs 1.00+/-0.20, P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors. CONCLUSION: This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

[Management of hypercortisolism]. / Prise en charge d'un hypercorticisme.

PURPOSE: Cushing's syndrome is a rare but frequently considered disease. Its diagnosis can lead to some difficulties, including confirming the effective endogenous hypercortisolism and determining its cause. The severity of this disease, the diversity of its complications and the multiple therapeutic options make its management challenging. The aim of this review is to present the most recent data about management of Cushing's syndrome, especially diagnostic approaches and therapeutic options. Our references were obtained by screening MEDLINE database from 1996 to 2006. We also included some anterior reviews and consensus statements. MAIN POINTS: We retained the following points: midnight salivary cortisol is a useful tool in the diagnosis of Cushing's syndrome; the desmopressin test can help to distinguish between Cushing's syndrome and "pseudoCushing's" due to alcohol consumption or psychiatric disorders; cavernous sinus and inferior petrosal sinus sampling is indicated in the evaluation of ACTH-dependent Cushing's syndromes when pituitary imaging is normal or equivocal or when dynamic tests are contradictory; multislice computed-tomography of the chest and the abdomen and somatostatin analogue scintigraphy, eventually combined, are the best imaging procedures in occult ectopic ACTH syndromes; patients with Cushing's disease should be referred to a neurosurgeon experienced in corticotroph adenomas surgery; metabolic consequences of Cushing's syndrome, such as cardiovascular risk factors and osteoporosis need an aggressive treatment. PERSPECTIVES: The incidence of Cushing's syndrome is only 1/100000 per year. However, hypercortisolism is diagnosed by systematic evaluation in 2 to 5% of patients with poorly controlled type 2 diabetes and adrenal incidentalomas. Endocrinological management of the disease improves metabolic disorders in these patients. If these results are confirmed, screening for Cushing's syndrome should be systematically performed in these populations.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome.

OBJECTIVE: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus. DESIGN: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome. METHODS: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms. RESULTS: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in approximately 50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) gamma2 were expressed in 50% of the tumours of each group whereas PPARgamma1 was expressed in almost every tumour. CONCLUSIONS: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.

[Cushing's syndrome and adrenal adenoma. Two surprising associations]. / Maladie de Cushing et adénome cortico-surrénalien. Deux associations étonnantes.

INTRODUCTION: Cushing's syndrome has a very low incidence (1-10 cases/million/year), and familial cases are even more rare. We report on two situations involving different causes of Cushing's syndrome. CASES: In the first case, we describe the case of a patient with an adrenal adenoma 20 years before the occurrence of Cushing's disease related to the pineal gland. In the second case, two members of the same family were diagnosed almost simultaneously with adrenal cortical adenoma (mother) and Cushing's disease (daughter). DISCUSSION: These cases lead us to consider the known causes of familial Cushing's syndrome, which were not found here.

Video-assisted thoracoscopic surgery as a first-line treatment for mediastinal parathyroid adenomas: strategic value of imaging.

OBJECTIVE: To present first-line thoracic surgery made possible by localization studies in three patients with ectopic parathyroid adenomas. DESIGN AND METHODS: Three patients with ectopic parathyroid tissue in the mediastinum were examined by ultrasound, technetium-99m sestamibi scintigraphy, computed tomography (CT), and venous catheterization with measurement of parathyroid hormone. Without previous cervical exploration, video-assisted thoracic surgery (VATS) was used in all cases to avoid the need for thoracic open surgical procedures. RESULTS AND CONCLUSIONS: The mediastinal parathyroid glands were all detected at scintigraphy, and CT and venous catheterization were helpful in anatomic and functioning characterization. All pathologic glands were successfully resected, with only one minor complication. VATS can safely remove a deep mediastinal parathyroid adenoma and avoid more aggressive open approaches. In an experienced referral center, systematic and sophisticated imaging studies may accurately identify and localize rare ectopic parathyroid adenomas, and avoid cervical surgery.