R. Desailloud

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

BACKGROUND Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

CONTEXT Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. OBJECTIVE We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. RESULTS Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Post-surgical management of non-functioning pituitary adenoma.

Post-surgical surveillance of non-functioning pituitary adenoma (NFPA) is based on magnetic resonance imaging (MRI) at 3 or 6 months then 1 year. When there is no adenomatous residue, annual surveillance is recommended for 5 years and then at 7, 10 and 15 years. In case of residue or doubtful MRI, prolonged annual surveillance monitors any progression. Reintervention is indicated if complete residue resection is feasible, or for symptomatic optic pathway compression, to create a safety margin between the tumor and the optic pathways ahead of complementary radiation therapy (RT), or in case of post-RT progression. In case of residue, unless the tumor displays elevated growth potential, it is usually recommended to postpone RT until progression is manifest, as efficacy is comparable whether treatment is immediate or postponed. The efficacy of the various RT techniques in terms of tumor volume control is likewise comparable. RT-induced hypopituitarism is frequent, whatever the technique. The choice thus depends basically on residue characteristics: size, delineation, and proximity to neighboring radiation-sensitive structures. Reduced rates of vascular complications and secondary brain tumor can be hoped for with one-dose or hypofractionated stereotactic RT, but there has been insufficient follow-up to provide evidence. Somatostatin analogs and dopaminergic agonists have yet to demonstrate sufficient efficacy. Temozolomide is an option in aggressive NFPA resistant to surgery and RT.

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas

OBJECTIVES Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. DESIGN Multicenter retrospective study by members of the French Society of Endocrinology. METHODS Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. RESULTS The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. DISCUSSION Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Acromégalie du sujet âgé

L’acromegalie diminue l’esperance de vie. La mortalite est principalement cardiovasculaire. L’âge et la duree d’evolution sont les principaux determinants de la cardiopathie acromegalique. Le traitement efficace permet de ramener la survie a celle de la population generale. Nous traitons ici de la prise en charge de la decouverte d’une acromegalie chez un sujet âge. Les particularites cliniques, biologiques et anatomopathologiques de l’acromegalie du sujet âge sont revues. Les alternatives therapeutiques et leurs possibles contre-indications dues a l’âge sont argumentees.