Updates on the genetics of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.

Genetic testing in prolactinomas: a cohort study.

BACKGROUND: Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on hereditary predisposition to prolactinoma. OBJECTIVE: We studied the prevalence of germline mutations in a large cohort of patients with isolated prolactinomas. MATERIALS AND METHODS: A retrospective study was performed combining genetic and clinical data from patients referred for genetic testing of MEN1, AIP, and CDKN1B between 2003 and 2020. SF3B1 was Sanger sequenced in genetically negative patients. RESULTS: About 506 patients with a prolactinoma were included: 80 with microprolactinoma (15.9%), 378 with macroprolactinoma (74.7%), 48 unknown; 49/506 in a familial context (9.7%). Among these, 14 (2.8%) had a (likely) pathogenic variant (LPV) in MEN1 or AIP, and none in CDKN1B. All positive patients had developed a macroprolactinoma before age 30. The prevalence of germline mutations in patients with isolated macroprolactinoma under 30 was 4% (11/258) in a sporadic context and 15% (3/20) in a familial context. Prevalence in sporadic cases younger than 18 was 15% in men (5/33) and 7% in women (4/57). No R625H SF3B1 germline mutation was identified in 264 patients with macroprolactinomas. CONCLUSIONS: We did not identify any LPVs in patients over 30 years of age, either in a familial or in a sporadic context, and in a sporadic context in our series or the literature. Special attention should be paid to young patients and to familial context.

Molecular Basis and Natural History of Medullary Thyroid Cancer: It is (Almost) All in the RET.

Medullary thyroid cancer (MTC) is a rare disease, which can be either sporadic (roughly 75% of cases) or genetically determined (multiple endocrine neoplasia type 2, due to REarranged during Transfection RET germline mutations, 25% of cases). Interestingly, RET pathogenic variants (mainly M918T) have also been reported in aggressive forms of sporadic MTC, suggesting the importance of RET signalling pathways in the pathogenesis of MTC. The initial theory of RET codon-related MTC aggressiveness has been recently questioned by studies suggesting that this would only define the age at disease onset rather than the aggressiveness of MTC. Other factors might however impact the natural history of the disease, such as RET polymorphisms, epigenetic factors, environmental factors, MET (mesenchymal-epithelial transition) alterations, or even other genetic alterations such as RAS family (HRAS, KRAS, NRAS) genetic alterations. This review will detail the molecular bases of MTC, focusing on RET pathways, and the potential mechanisms that explain the phenotypic intra- and interfamilial heterogeneity.

Real-life clinical impact of a five-tiered classification of pituitary tumors.

Introduction: Usually benign, pituitary tumors (PT) can be invasive and aggressive with a propensity to progress and/or recur. Trouillas's clinicopathological classification attempts to predict the evolutionary risk of a PT. In this study, we assessed the prognostic value of this classification in an independent patient cohort and analyzed its impact on treatment strategies. Patients and methods: In this study, 607 patients operated on between 2008 and 2018 for a PT were included. Grading was established based on invasion, proliferative activity (Ki-67, mitotic index) and p53 positivity. The therapeutic management following surgery was analyzed. Progression-free survival (PFS) of the graded tumors was estimated (Kaplan-Meier method and log-rank test) and a multivariate analysis was performed (Cox regression model). Results: Grading identified non-invasive PT without (grade 1a: 303 cases) or with proliferative activity (grade 1b: 53 cases) and invasive PT without (grade 2a: 202 cases) or with proliferative activity (grade 2b: 49 cases). The mean follow-up was 47 ± 30 months (median: 38 months). Progression/recurrence occurred in 127 cases. Grades were significant and independent predictors of PFS (P < 0.001) with a 4.8-fold higher risk of progression/recurrence in grade 2b as compared to grade 1a. As second-line therapy, gamma knife or conventional radiotherapy controlled tumor growth in 91.6 and 100% of cases, respectively, irrespective of the grade. Proliferative tumors exposed the patient to a 9.5-fold higher risk of having ≥3 adjuvant therapeutic lines as compared to non-proliferative tumors. Discussion: Grading of a PT according to Trouillas's classification predicts its risk of progression and should advocate for a personalized therapeutic approach in invasive and proliferative tumors. Significance statement: This is the first study to assess, on a cohort of 607 well-characterized patients, the real-life therapeutic impact of the five-tiered clinicopathological classification of pituitary tumors. First, we validate that pituitary tumor grades predict the evolutionary risk of the tumor, with a significant higher risk of progression/recurrence in invasive and/or proliferative tumors (mean follow-up: 47 ± 30 months, median: 38 months). Moreover, our study provides evidence that patients with proliferative tumors have a higher risk to be retreated after primary surgery and point toward the fact that radiotherapy can successfully control tumor growth in case of progression or recurrence. Our findings advocate for a personalized therapeutic approach in clinically aggressive pituitary tumors.

18F-DOPA PET/CT at the Forefront of Initial or Presurgical Evaluation of Small-Intestine Neuroendocrine Tumors.

Our objective was to compare the respective value of 68Ga-DOTATOC and 18F-DOPA PET/CT for initial staging or presurgical work-up of patients with small-intestine neuroendocrine tumors (SiNETs). Methods: This was a retrospective, multicenter, noninterventional investigation involving 53 non-surgically treated SiNET patients who underwent both 68Ga-DOTATOC and 18F-DOPA PET/CT within a 6-mo interval without surgical intervention or therapeutic change between the 2 PET/CT studies. Percentage detection rate was calculated according to per-region and per-lesion analyses. Sensitivity for primary tumor detection was assessed in 37 surgically treated patients, taking surgical results (76 SiNETs) as the diagnostic gold standard. Results: 68Ga-DOTATOC PET/CT and 18F-DOPA PET/CT individually identified at least 1 primary SiNET in 92% (34/37) of the patients. Intestinal tumor multifocality was confirmed by histology in 8 patients. 68Ga-DOTATOC and 18F-DOPA PET/CT were concordantly positive for tumor multifocality in 5 patients, discordantly positive in 2 patients, and concordantly negative in 1 patient. The detection rate for subdiaphragmatic nodal metastases on per-region-based analysis was 91% and 98% for 68Ga-DOTATOC and 18F-DOPA PET/CT, respectively (P = 0.18). 18F-DOPA PET/CT detected a higher number of abnormal subdiaphragmatic nodes (P = 0.009). Regarding mesenteric nodes only, 18F-DOPA PET/CT detected more positive regions (P = 0.005) and nodal lesions (P = 0.003) than 68Ga-DOTATOC PET/CT, including nodes at the origin of mesenteric vessels. For detection of distant metastases, 68Ga-DOTATOC and 18F-DOPA PET/CT performed equally well on a per-region-based analysis. As compared with 68Ga-DOTATOC, 18F-DOPA PET/CT detected more hepatic (P < 0.001), peritoneal (P < 0.001), and lung metastases (P < 0.001). Conclusion: 18F-DOPA PET/CT detected more lesions than 68Ga-DOTATOC PET/CT in the studied patients. The respective roles of the two should be discussed in terms of disease staging and treatment selection.

Current and Emerging Medical Therapies in Pituitary Tumors.

Pituitary tumors (PT) represent in, the majority of cases, benign tumors for which surgical treatment still remains, except for prolactin-secreting PT, the first-line therapeutic option. Nonetheless, the role played by medical therapies for the management of such tumors, before or after surgery, has evolved considerably, due in part to the recent development of well-tolerated and highly efficient molecules. In this review, our aim was to present a state-of-the-art of the current medical therapies used in the field of PT and the benefits and caveats for each of them, and further specify their positioning in the therapeutic algorithm of each phenotype. Finally, we discuss the future of PT medical therapies, based on the most recent studies published in this field.

Value of 68Ga-DOTATOC and Carbidopa-Assisted 18F-DOPA PET/CT for Insulinoma Localization.

Our objective was to assess the value of 68Ga-DOTATOC and carbidopa-assisted 18F-fluorodihydroxyphenylalanine (18F-DOPA) in 21 hypoglycemic patients. Methods: All patients who underwent 68Ga-DOTATOC or carbidopa-assisted 18F-DOPA PET/CT for suspicion of insulinoma from January 2019 to January 2021 were retrospectively analyzed. A final diagnosis of insulinoma was determined by pathologic reports or consensus. Results: During the study period, 21 patients underwent both 68Ga-DOTATOC and 18F-DOPA PET/CT. A final diagnosis of insulin-secreting tumor was reached in 12 cases, including 11 insulinomas and 1 small mixed neuroendocrine/nonneuroendocrine neoplasm. 18F-DOPA and 68Ga-DOTATOC PET/CT were positive in 5 (45%) and 7 (64%) of 11 cases, respectively, with 4 concordant positive findings. Moreover, 1 insulinoma was visualized exclusively by 18F-DOPA PET/CT and 3 by 68Ga-DOTATOC PET/CT only. 18F-DOPA and 68Ga-DOTATOC PET/CT were falsely positive in 1 nonfunctioning pancreatic neuroendocrine tumor. Conclusion: When 68Ga-exendin-4 is not available, 68Ga-somatostatin receptor PET/CT should be the first choice for insulinoma functional imaging.

SGLT2 inhibitors as potentially helpful drugs in PI3K inhibitor-induced diabetes: a case report.

BACKGROUND: Hyperglycemia is the most common side-effect of phosphatidylinositol 3-kinase (PI3K) inhibitors that are approved for the treatment of some advanced or metastatic breast cancers. This side-effect is likely due to the central role of PI3K in insulin signalling. Here we report the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to manage severe hyperglycemia. CASE PRESENTATION: We describe a 74-year-old woman who developed severe uncontrolled hyperglycemia after commencing alpelisib, a new oral PI3K inhibitor indicated for a metastatic breast cancer, despite taking oral anti-diabetic drugs, metformin and vildagliptin, combined with intravenous insulin infusion of up to 250 units/day. The introduction of the SGLT2 inhibitor dapagliflozin rapidly improved blood glucose with a drastic reduction in insulin dosage, from 250 to 12 units/day, and without significant side-effects. CONCLUSIONS: We report the successful management of hyperglycemia induced by alpelisib using a SGLT2 inhibitor without the need to discontinue effective cancer treatment.

Risk stratification of adrenal masses by [18 F]FDG PET/CT: Changing tactics.

CONTEXT: [18 F]FDG PET/CT improves adrenal tumour characterization. However, there is still no consensus regarding the optimal imaging biomarkers of malignancy. OBJECTIVES: To assess the performance of Tumour standardized uptake value (SUV)max :Liver SUVmax for malignancy-risk and to build and evaluate a prediction model. DESIGN/METHODS: The cohort consisted of consecutive patients with adrenal masses evaluated by [18 F]FDG PET/CT. The gold standard for malignancy was based on histology or a multidisciplinary consensus in nonoperated cases. The performance of the previously reported cut-off for Tumour SUVmax :Liver SUVmax (>1.5) was evaluated in this independent cohort. Additionally, a predictive model of malignancy was built from the training cohort (previous study) and evaluated in the validation cohort (current study). RESULTS: Sixty-four patients were evaluated; 28% of them had a Cushing's syndrome. Fifty-four adrenal masses were classified as benign and 10 as malignant (including 7 adrenocortical carcinomas). Compared to benign masses, malignant lesions were larger in size, had higher unenhanced densities and higher [18 F]FDG uptake. CT-derived anthropometric parameters did not differ between benign and malignant masses. A tumour SUVmax :Liver SUVmax  > 1.5 showed a good diagnostic performance: Se = 90.0%/Sp = 92.6%/PPV = 69.2%/NPV = 98.0% and accuracy = 92.2%. A predictive model based on tumour size and tumour-to-liver uptake SUVmax ratio for malignancy-risk was validated and provides a complementary approach to the ratio. CONCLUSIONS: Tumour SUVmax :Liver SUVmax uptake ratio is a useful biomarker for diagnosis of adrenal masses. Another tactic would be to calculate with the model an individual risk of malignancy and integrate this information into a shared decision-making process.

Intraindividual comparison of 18 F-FDOPA and 68 Ga-DOTATOC PET/CT detection rate for metastatic assessment in patients with ileal neuroendocrine tumours.

INTRODUCTION: In patients with ileal neuroendocrine tumours (ileal NETs), head-to-head evaluation of diagnostic performances of 68 Ga-DOTA-peptides and 18 F-fluorodihydroxyphenylalanine (18 F-FDOPA) positron emission tomography/computed tomography (PET/CT) has been performed in only few small patients' cohorts. The aim of this retrospective study was to compare 68 Ga-DOTATOC and 18 F-FDOPA PET/CT for metastatic disease assessment in a homogeneous large series of patients with well-differentiated ileal NETs. METHODS: All patients with ileal NETs who underwent both 18 F-FDOPA and 68 Ga-DOTATOC PET/CT within a 3-month period and no therapeutic change between the two studies were retrospectively included. The detection rates of both modalities were calculated using per-patient, per-region and per-lesion analyses. RESULTS: Forty one patients with ileal NETs were evaluated. 18 F-FDOPA and 68 Ga-DOTATOC showed similar detection rates according to per-patient (97% for both) and per-region analyses (94% for 18 F-FDOPA vs 88% for 68 Ga-DOTATOC, P = .35). For a total of 605 positive lesions, 458 (76%) were detected by both modalities, 122 (20%) exclusively by 18 F-FDOPA PET/CT, and 25 (4%) by 68 Ga-DOTATOC PET/CT only. In a per-lesion analysis, 18 F-FDOPA PET/CT performed better than 68 Ga-DOTATOC PET/CT (overall detection rates of 96% vs 80%; P < .001). 18 F-FDOPA PET/CT detected significantly more metastases than 68 Ga-DOTATOC PET/CT in the liver, peritoneum, abdominal and supra-diaphragmatic lymph nodes. CONCLUSION: 18 F-FDOPA PET/CT seems not inferior than 68 Ga-DOTATOC PET/CT for the delineation of metastatic spread of ileal NETs. Therefore, according to local expertise and technical availability, 18 F-FDOPA should be considered as a valid clinical diagnostic option for exhaustive metastatic assessment in patients with ileal NETs. Obviously, 68 Ga-DOTATOC PET/CT remains mandatory for PRRT assessment. Further comparative studies are needed to determine the optimal approach in various clinical scenarios such as preoperative staging and primary tumour detection.

Celiac Disease and Obesity: Is Bariatric Surgery an Option?

Celiac disease is an immune-mediated enteropathy associated with malabsorptive syndrome and fat-soluble vitamin deficiencies. Celiac disease affects 1% of individuals but is largely underdiagnosed, as its multifaceted clinical presentations create challenging diagnostic scenarios. With the rise of the obesity epidemic, doctors are increasingly seeing celiac disease patients with overweight or obesity, which raises the question of bariatric surgery. However, few studies so far have investigated bariatric surgery in this patient population. Here, we provide a comprehensive review of the literature on celiac disease, its nutritional consequences and complications, and we discuss the possible impact of bariatric surgery on weight loss, nutritional deficiencies, response to gluten-free diet, and long-term post-operative complications. We also review the effect of bariatric surgery on the incidence of celiac disease.

Clinical management of difficult to treat macroprolactinomas.

INTRODUCTION: Prolactinomas represent the most common pituitary adenomas encountered in the clinic. While a majority of these tumors will be successfully treated by dopamine agonist (DA) such as cabergoline, their management becomes problematic since a resistance to DA can occur and/or if the tumor displays features of aggressiveness, two conditions that are closely related. AREAS COVERED: Epidemiology and medical treatment of prolactinomas; resistance to DA and molecular basis of DA-resistance; therapeutical alternatives in case of DA-resistant Prolactinomas and therapies in development; summarizing conclusions. EXPERT OPINION: The management of DA-resistant prolactinomas requires a multidisciplinary approach by an expert team. Along with discussions about surgery with or without gamma knife radiosurgery, genetic screening for multiple endocrine neoplasia type 1 (MEN1) syndrome is actively discussed in a case-by-case approach. In case of surgery, a careful analysis of the tumor sample can provide information about its aggressivity potential according to recent criteria. Ultimately, temozolomide can be indicated if the tumor is rapidly growing and/or threatening for the patient.