Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.
Introduction
In NF1 patients, guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, that may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NET) and their differential diagnosis, gastro-intestinal stromal tumors (GIST). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases. This study aimed to describe prevalence and clinical presentation of these manifestations through a systematic screening in a large cohort of patients.
Patients and Methods
In this monocentric retrospective study, 108 NF1 patients were included and screened for endocrine manifestations and GIST. Clinical, laboratory, molecular profile, pathology and morphologic (abdominal CT-scan and/or MRI) and functional imaging were collected.
Results
Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42 to 63 years) presented with well-differentiated GEP-NET, and four (3.7%) with GIST. One patient had primary hyperparathyroidism, one patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients.
Discussion
The pheochromocytoma prevalence in this NF1 cohort was higher (> 20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NET and GIST was about 3%, respectively. No phenotype-genotype correlation was observed.
Introduction: Immune checkpoint inhibitors (ICI) are used to treat cancers including metastatic melanomas and can induce endocrine side effects. Thyroid is frequently affected with classically transient thyrotoxicosis followed by hypothyroidisms. The evolution of thyroid nodules and goiters under ICI therapy is poorly described.
Case presentation: A 72-year-old male presenting with hyperthyroidism due to toxic nodule in a multinodular goiter (MNG) started ICI therapy combining ipilimumab and nivolumab to treat a metastatic melanoma. After an initial worsening of thyrotoxicosis, treated with carbimazole, he developed a profound hypothyroidism, persisting after carbimazole discontinuation, needing a long-term levothyroxine supplementation. Ultrasound control performed 6 months after ICIs treatment initiation revealed a diffuse thyroid atrophy with involution of all nodules. 123I-scintigraphy confirmed a destructive mechanism.
Discussion: The evolution of MNG and toxic nodule is poorly described in patients treated with ICI since systematic US evaluations are lacking. We describe for the first time a toxic nodule cured by ICI therapy inducing destructive thyroiditis.
Conclusion: Pre-existing nodules and multinodular goiter, even if toxic, are not a contraindication for ICI treatment provided the patients are carefully monitored.
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