Primitive pituitary perivascascular epithelioid cell tumor: A challenging diagnosis of melanocytic pituitary lesion.

BACKGROUND: Perivascular Epithelioid cell tumors (PEComa) are rare mesenchymal tumors. They generally occur in the gynecologic or digestive tract. The diagnosis of Central Nervous System PEComa is exceptional and challenging. CASE DESCRIPTION: We report the case of a 46-year-old woman, with no particular medical history, who presented a secondary amenorrhea and a slight hyperprolactinemia. She was diagnosed on MRI with a pituitary tumor showing spontaneous hypersignal in T1-weighted images. After failure of medical treatment with cabergoline, surgical resection was required due to progressive tumor growth. Macroscopic aspect and initial immunohistochemical features were in favor of a primitive hypophyseal melanocytoma. However, molecular and transcriptional study through targeted exome- and RNA-sequencing led to the exceptional diagnosis of pituitary Perivascular Epithelioid Cell Tumor (PEComa). Three-years of postoperative radio-clinical follow-up showed an asymptomatic non-evolutive small remnant. CONCLUSION: PEComa is an exceptional diagnosis among pituitary tumors. It should be evoked as a potential differential diagnosis in case of primitive melanocytic lesion of the pituitary gland. Specific molecular analysis is mandatory to confirm the diagnosis and exclude differential diagnosis.

Graves' orbitopathy post-SARS-CoV-2 vaccines: report on six patients.

CONTEXT: Autoimmune and inflammatory thyroid diseases (Graves' disease, subacute thyroiditis, chronic autoimmune thyroiditis) have been reported following SARS-CoV-2 vaccines but Graves' orbitopathy (GO) post-COVID-19 vaccination is uncommon. METHODS: We describe six new patients seen in Endocrinology Departments with Outpatient Clinics for GO following SARS-CoV-2 vaccines in France. RESULTS: After COVID-19 vaccination, GO was observed in six patients (three men, three women, mean age 53 ± 6 years) with a personal past history of Graves' disease (5/6) or orbitopathy (4/6). New-onset (n = 2) or recurrence (n = 4) of GO was observed following mRNA vaccines after the first (3/6) or second (3/6) dose, with the mean time from vaccination to GO at 23.8 ± 10.4 days. In one patient, thyrotoxicosis was confirmed by increased free T4 and low TSH concentrations while others had normal TSH levels, during chronic levothyroxine treatment in three patients. Four patients had significant anti-TSH receptor antibodies levels. According to the severity and activity of GO, the patients were treated using selenium (n = 2), intravenous glucocorticoids (n = 2), teprotumumab (n = 1), tocilizumab (n = 2) and orbital decompression (n = 1) with a significant improvement in GO signs and symptoms observed by most patients. CONCLUSION: In this study, we report the main data from six new patients with GO following SARS-CoV-2 vaccines. Clinicians need to be aware of the risk of new-onset or recurrent GO in predisposed patients with autoimmune thyroid diseases after COVID-19 vaccination. This study should not raise any concerns regarding SARS-CoV-2 vaccination since the risk of COVID-19 undoubtedly outweighs the incidence of uncommon GO after SARS-CoV-2 vaccination.

Pituitary metastasis of malignant melanoma misdiagnosed as pituitary adenoma: A case report and systematic review of the literature.

We report a case of malignant melanoma revealed by a metastasis to the pituitary gland. The tumor was misdiagnosed as a pituitary adenoma and aggressive transsphenoidal surgery was complicated by a cerebrospinal fluid fistula. Nine weeks later, the patient presented multiple leptomeningeal and brain metastases spreading from the sellar region. Regarding these observations, we conducted a systematic review of the literature in order to investigate clinicoradiological features that should lead clinicians to suspect pituitary metastasis and how it should impact the surgical management.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Nodular recurrence and hypothyroidism following partial thyroidectomy for benign nodular thyroid disease in children and adolescents.

OBJECTIVES: Diagnostic and therapeutic processing of a thyroid nodule in children and adolescents may require lobectomy-isthmusectomy (LI) or nodule-resection (NR). Very few data in the literature report the long-term evolution of the remaining thyroid lobe in a defined pediatric population. In this study, we aimed to answer the following questions: Does a nodule recurrence occur in the remainder lobe? Is a post-operative thyroxine treatment necessary? MATERIAL AND METHODS: This retrospective study describes 28 patients under 18 who underwent LI (22 cases) or NR (6 cases) from January 2004 to March 2012. Ten of them were lost to follow up, 18 could be assessed (4 NR (22%) and 14 LI (78%) - mean follow-up 45±31 months). All patients benefited of post-operative thyroid ultrasonography, and regular endocrinologic follow-up. The following data were analysed: emergence of new thyroid nodules, evolution of pre-existing nodules, occurrence of post-operative hypothyroidism and requirement for completion thyroidectomy. RESULTS: The mean age at the time of surgery was 14.3±1.9 years. Two patients (11%) had pre-existing nodules in the remaining thyroid gland, none of which showed an increase in size after surgery. De novo nodules developed in five patients (27.8%). Three patients who underwent LI (21.4%) needed thyroxine treatment for post-operative hypothyroidism. One patient (5.5%) needed completion thyroidectomy. CONCLUSIONS: In this children and adolescents population, after performing LI or NR, remaining thyroid tissue stays free of nodules in 72.2% of the cases. A post-operative thyroxin treatment is necessary in 21.4% of cases after LI.

Thyroid surgery in children and adolescents: a series of 65 cases.

OBJECTIVES: To describe the specificities and complications of thyroid surgery in children and adolescents. MATERIAL AND METHODS: This retrospective study was based on 64 patients under the age of 18 who underwent thyroid surgery between January 2004 and March 2012, with two operations in one case. The following data were analysed: anatomical variants of the recurrent laryngeal nerve, postoperative recurrent laryngeal nerve paralysis rate, postoperative hypoparathyroidism rate, and histological results. RESULTS: Two cases of right non-recurrent inferior laryngeal nerve were observed (2.2% of the 93 recurrent laryngeal nerves dissected). One case of persistent left recurrent laryngeal nerve paralysis was observed (1.1%) despite intraoperative recurrent laryngeal nerve monitoring. Eight cases of immediate postoperative hypocalcaemia were observed (23.5% of the 34 total thyroidectomies) and permanent hypocalcaemia was observed in 5 cases (14.7%) with a significantly lower immediate postoperative serum calcium than in the case of transient hypocalcaemia (P=0.035). Among the 11 patients operated for familial medullary thyroid carcinoma (MTC), 36.3% presented one or more sites of C-cell carcinoma. Among the 32 patients operated for thyroid nodule, 6.3% presented papillary adenocarcinoma. Histological results were benign in all other cases. CONCLUSIONS: Thyroid surgery in children and adolescents is part of global multidisciplinary management of thyroid disorders in children. Recurrent laryngeal nerve paralysis is a rare complication, but may occur despite the use of intraoperative recurrent laryngeal nerve monitoring. Permanent hypoparathyroidism is the most common complication and is correlated with immediate postoperative serum calcium. Systematic prophylactic total thyroidectomy in patients with a RET proto-oncogene mutation allowed early diagnosis of MTC in one-third of cases. In view of the low rate of malignant nodules in our series, the malignant thyroid nodule rates reported in children in the literature may be overestimated.

Patients lost to follow-up in acromegaly: results of the ACROSPECT study.

OBJECTIVE: The complex management of acromegaly has transformed this disease into a chronic condition, with the risk of patients being lost to follow-up. The objective of this study was to estimate the proportion of acromegalic patients lost to follow-up in France and to determine the impact that abandoning follow-up has on the disease and its management. DESIGN: ACROSPECT was a French national, multicentre, cross-sectional, observational study. METHODS: Acromegalic patients were considered lost to follow-up if no new information had been entered in their hospital records during the previous 2 years. They were traced where possible, and data were collected by means of a recall visit or questionnaire. RESULTS: In the study population, 21% of the 2392 acromegalic patients initially followed in 25 tertiary endocrinology centres were lost to follow-up. At their last follow-up visit, 30% were uncontrolled, 33% were receiving medical therapy and 53% had residual tumour. Of the 362 traced, 62 had died and 77% were receiving follow-up elsewhere; the leading reason for abandoning follow-up was that they had not been informed that it was necessary. Our analysis of the questionnaires suggests that they were not receiving optimal follow-up. CONCLUSIONS: This study underlines the need to better inform acromegalic patients of the need for long-term follow-up, the absence of which could be detrimental to patients' health, and to develop shared care for what must now be regarded as a chronic disease.

Positron emission tomography-computed tomography evaluation for recurrent differentiated thyroid carcinoma.

OBJECTIVES: Recurrence is observed in 15-20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography-computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC. METHOD: A comprehensive review and discussion of the medical literature was carried out. RESULTS: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck. CONCLUSION: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence.

[The multifaceted TSH receptor]. / Diverses facettes du récepteur de la TSH.

The TSH receptor is a key element of thyroid homeostasis and many gain or loss of function mutations have been described since its cloning in 1989. Behind classical and severe forms like toxic adenomas, non-autoimmune familial or sporadic hyperthyroidism or inversely complete TSH resistance syndromes, new methodological approaches allow now the functional characterization of milder clinical situations : linear regression analysis of activating mutations can differentiate mutations with moderate constitutive activity and non functional receptor's variants ; the early oligomerization of wild-type and mutated receptors in intracellular compartments explain the dominant inheritance of mild form of TSH resistance. However many aspects of TSH receptor signalization remain to be explored, for example its persistent activity after internalization, and their clinical implications to be determined. Finally, new modulators of TSH receptor with attractive therapeutic potential are being developed.

Guidelines of the French society of endocrinology for the management of thyroid nodules.

The present document is a follow-up of the clinical practice guidelines of the French Society of Endocrinology, which were established for the use of its members and made available to scientific communities and physicians. Based on a critical analysis of data from the literature, consensuses and guidelines that have already been published internationally, it constitutes an update of the report on the diagnostic management of thyroid nodules that was proposed in France, in 1995, under the auspices of the French National Agency for Medical Evaluation (l'Agence nationale d'évaluation médicale). The current guidelines were deliberated beforehand by a number of physicians that are recognised for their expertise on the subject, coming from the specialities of endocrinology (the French Thyroid Research Group) and surgery (the French Association for Endocrine Surgery), as well as representatives from the fields of biology, ultrasonography, cytology and nuclear medicine. The guidelines were presented and submitted for the opinion of the members of the Society at its annual conference, which was held in Nice from 7-10 October 2009. The amended document was posted on the website of the Society and benefited from additional remarks of its members. The final version that is presented here was not subjected to methodological validation. It does not claim to be universal in its scope and will need to be revised in concert with progress made in technical and developmental concepts. It constitutes a document that the Society deems useful for distribution concerning the management of thyroid nodules, which is current, efficient and cost effective.

[Cowden syndrome, or multiple hamartomatous tumor syndrome, in clinical endocrinology]. / Le syndrome de Cowden ou syndrome des hamartomes multiples en endocrinologie clinique.

Cowden syndrome (CS) is the prototypic PTEN hamartoma tumor syndromes (PHTS), rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. CS is characterized by association of macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, with increased risk for breast, thyroid and endometrial cancer. PTEN, which is located on chromosome 10q23, regulates negatively the prosurvival PI3K/Akt/mTOR pathway through a lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. CS diagnosis is clinical, based on the association of pathognomonic, major and minor criteria. The association in a patient with thyroid cancer, rarely with multinodular goiter, of typical dermatological manifestations, easily identifiable by clinical examination (papillomatous papules, acral keratoses, trichilemmomas), with a history of breast, endometrial, or renal cancer, or hamartomatous tumors presence, should alert the clinician. Clinical management of patients with CS is multidisciplinary, to include early and frequent screening, surveillance, and preventive care for associated malignancies. The development of antineoplastic agents targeting PI3K/Akt/mTOR pathway, such as rapamycin, may be the opportunity of treatment in PHTS and CS patients, for whom no specific medical treatment exist.

An unusual succinate dehydrogenase gene mutation C in a case of laryngeal paraganglioma.

OBJECTIVE: To report a rare case of a laryngeal paraganglioma related to succinate dehydrogenase gene mutation C. METHOD: A case report and a review of the world literature concerning succinate dehydrogenase mutations and laryngeal paraganglioma are presented. RESULTS: We identified a laryngeal paraganglioma in a 38-year-old woman, related to a very rare, deleterious in exon 4 of the succinate dehydrogenase mutation C. This mutation was a non-sense mutation: c.183G >A leading to p.Trp61X. No other neuroendocrine tumour was identified in this case, but a thyroid papillary carcinoma was concomitantly discovered and cured. CONCLUSION: To our knowledge, this is the first report in the world literature of laryngeal paraganglioma related to a succinate dehydrogenase mutation C. The case presented underlines the fact that every patient with paraganglioma should be tested for succinate dehydrogenase genetic mutations, even if a family history of paraganglioma is absent, in order to enable appropriate clinical management and to improve our knowledge of familial paraganglioma.

Surgical management of carotid body tumors.

BACKGROUND: Carotid body tumors (CBT) should be considered when evaluating every lateral neck mass. METHODS: A retrospective study was conducted of 52 patients with 57 CBT. The surgical approach and complications were reviewed. All patients were operated on without preoperative embolization. RESULTS: Multifocal paraganglioma (PG) were detected in six cases. A succinate dehydrogenase subunit D (SDHD) mutation was discovered in four patients. Vascular peroperative complication occurred in one case. Vascular reconstruction was decided peroperatively in five cases (8.8%). Vascular reconstruction was 0% for Shamblin 1 or 2 tumors, but 28.5% for Shamblin 3. A postoperative nerve paresis was reported in 24 patients (42.1%) and vagal nerve paralysis persisted in four cases (7.01%). The rate of serious complications, e.g., permanent nerve palsy, preoperative and postoperative complications, was 14.03%; it was 2.3% for Shamblin 1 or 2 tumors and 35.7% for Shamblin 3. One patient had malignant PG with node metastasis and was not referred for radiotherapy. No recurrence or metastasis was reported after 6-year follow-up. CONCLUSION: Early surgical treatment is recommended in almost all patients after preoperative evaluation and detection of multifocal tumors. Surgical excision of small tumors was safe and without complication, but resection of Shamblin 3 tumors can be challenging. Routine preoperative embolization of carotid body paragangliomas is not required.

Optimizing the outcome of pregnancy in obese women: from pregestational to long-term management.

The obesity epidemic is of some concern in women of reproductive age. Maternal obesity is associated with many pregnancy complications, especially gestational diabetes and hypertensive disorders of pregnancy. Delivery in obese women is characterized by a high caesarean-section rate and an increased risk of anaesthetic and postoperative complications. Weight retention after birth may increase the risk of type 2 diabetes in the long term. Foetal risks include macrosomia, malformations and increased perinatal mortality, with the long-term infant health marked by a higher risk of obesity and metabolic disorders. Optimal management includes preconception counselling, pregravid weight-loss programmes, monitoring of gestational weight gain, repeated screening for pregnancy complications and long-term follow-up to minimize the social and economic consequences of pregnancy in overweight women.

[Long-term risks of polycystic ovaries syndrome]. / Risques à long terme du syndrome des ovaires polykystiques.

The prevalence of the polycystic ovaries syndrome (PCOS) is high but it is a heterogeneous disorder with implications in numerous medical domains. Abdominal obesity and insulin resistance, which are the main metabolic disorders, are strong links between hormonal abnormalities and long-term medical consequences. The latter begin to be better understood. Some studies suggest that PCOS may increase the risk for several conditions, including type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease and some cancers.

[Menopause: towards treatment "à la carte" ]. / Ménopause: vers un traitement << à la carte >>.

In spite of questioning and doubt arising from WHT study hormone substitution therapy (HST) has proven efficacy on climacteric symptoms and certain short-term and long-term consequences of menopause. Among 1000 women taking HST for ten years, eight supplementary cases of breast cancer and 6 fewer cases of colonic cancer are observed. No cardiovascular protection has been demonstrated. A history of coronary artery disease, vascular disease, stroke or thromboembolism are contraindications for HST. The vascular impact of estradiol administered via an extra-digestive route in women with a low vascular risk cannot be extrapolated from the HERS and WHI trials because these trials were conducted is high-risk women, using specific types of steroids given orally. Tibolone has demonstrated efficacy and in an alternative to HST after more than one year of menopause. The usefulness of phytoestrogens remains to be determined, particularly due to the wide individual variability of their effects on climacteric symptoms and the low level of proof provided by epidemiological or clinical studies conducted to study the prevention of osteoporosis and the risk of breast cancer. Most of the analyses present methodological biases. Currently, the most widely accepted notion is that there is a beneficial effect on cardiovascular risk. To date, SERMs have selective indications and cannot be prescribed for all women: raloxifen is used for the prevention and treatment of menopause-related osteoporosis. The relative risk of venous thromboembolism with SERMs (raloxifen and tamoxifen) is comparable to that observed with HST. HST or any other treatment given for menopause must be an individual decision balancing the benefits against the risks and taking into account the desires of the patient perfectly informed of the currently available evidence. Prescriptions should be part of an overall scheme including nutritional advise and physical exercise aimed at preserving quality of life and preventing age-related effects which largely depend on genetic predisposition and the psycho-affective environment.

[Therapeutic strategies in somatotroph adenomas with extrasellar extension: role of the medical approach, a consensus study of the French Acromegaly Registry]. / Stratégies thérapeutiques dans les adénomes somatotropes avec extension extrasellaire. Place du traitement médical. Etude consensus du Répetoire français de l'Acromégalie.

UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.

[Insulin sensitivity and polycystic ovarian syndrome]. / Insulinosensibilité et syndrome des ovaires polykystiques.

Insulinresistance, commonly associated with polycystic ovarian syndrome (PCOS), raises many unresolved debates about its prevalence, mechanism and true pathological role. Low insulin sensibility may have multiple origins among them genetic molecular defects in pathways of cellular insulin effects. A weight gain and android distribution of fat mass may reveal or increase insulin resistance and hyperinsulinemia. The preexisting unbalanced ovarian steroidogenesis secondary to abnormalities in gene coding for enzymes of P450C17 alpha might be the necessary support facilitating the stimulatory effect of hyperinsulinemia or other factors (LH, IGF1) on ovarian androgens. In practice, the phycisian has to know how to evaluate and to treat insulin resistance in view of its implication in dysovulation and, later on, metabolic and cardiovascular risks. Nutritional education and regular physical exercice are the necessary approaches. The efficacy and indications of metformin and thiazolidinediones have to be further evaluated.

[Which contraception to choose for the diabetic woman?]. / Quelle contraception choisir pour la femme diabétique?

Low-dose oral contraceptives can be used by a great number of women with IDDM or a previous gestational diabetes mellitus. Others hormonal contraceptives (progestogen-only preparations) are less convenient and the compliance is poor with an increasing risk of gynaecologic side effects. The safety of this contraceptives as regards vascular diabetic complications is not evaluated well. Nulliparous patients with progressive complications can use barrier methods of contraception after education. Macroprogestative contraception is a adequate choice for women within forties. For multiparous diabetic women, intra-uterine devices represent the first choice.