ABSTRACT
Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.
ABSTRACT
Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH releasing hormone (GHRH) is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G protein coupled receptor (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.
ABSTRACT
X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.
Subject(s)
Acromegaly , Genetic Diseases, X-Linked , Gigantism , Human Growth Hormone , Pituitary Neoplasms , Adult , Humans , Child , Female , Child, Preschool , Gigantism/genetics , Gigantism/therapy , Gigantism/metabolism , Acromegaly/pathology , Growth Hormone/metabolism , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/therapy , Pituitary Neoplasms/complications , Pituitary Neoplasms/genetics , Pituitary Neoplasms/pathologyABSTRACT
Introduction: Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar). Methods: We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas ("unselected", n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39). Results: AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups. Discussion: AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.
Subject(s)
Pituitary Neoplasms , Prolactinoma , Humans , Male , Dopamine Agonists , Germ Cells , Pituitary Neoplasms/genetics , Pituitary Neoplasms/therapy , Prolactin , Prolactinoma/drug therapy , Prolactinoma/genetics , Receptors, Aryl HydrocarbonABSTRACT
Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
Subject(s)
Pituitary Diseases , Pituitary Neoplasms , Child , Humans , DNA Copy Number Variations , Pituitary Gland , Pituitary Neoplasms/genetics , Mixed Function OxygenasesABSTRACT
Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
ABSTRACT
PURPOSE: Endonasal resection is the first-line treatment for patients harboring growth hormone (GH)-secreting pituitary adenomas. The complexity of the parasellar neurovascular structures makes pre-operative diagnostic imaging essential to understanding the anatomy of this region. We aimed to describe vascular anomalies in acromegalic patients and emphasize their relevance for surgery and preoperative planning. METHODS: A systematic review following the PRISMA statement was performed in July 2021. RESULTS: Thirty-three studies were evaluated. Elevated GH and insulin-like growth factor-1 (IGF-1) levels are linked to the occurrence of cardiovascular risk factors. This is attributed to endothelial dysfunction, mainly caused by changes in flow-mediated dilatation (FMD), which is probably the main cause of vascular anomalies in acromegaly. The occurrence of protrusions of the internal carotid artery (ICA) (35-53%), a narrow intercarotid distance, and an asymmetrical course was described. In 13-18% of acromegalic patients, the presence of an intracerebral aneurysm could be reported (incidence in the general population:0.8-1.3%). The selected studies were however performed with a small patient sample (range:1-257). We present a case report of a 57y/o male patient with anomalies of the ICA ("kissing carotid arteries") harboring a GH-secreting adenoma, which was resected via an endoscopic endonasal approach. CONCLUSIONS: There is an association between acromegaly and endothelial dysfunction, which increases cardiovascular risk factors and vascular anomalies. Preoperative vascular imaging, e.g., CT angiography, should be implemented as a standard to identify patients at risk and estimate surgical morbidity. However, no evidence-based recommendations exist so far, so future studies are necessary.
Subject(s)
Acromegaly , Adenoma , Growth Hormone-Secreting Pituitary Adenoma , Human Growth Hormone , Pituitary Neoplasms , Humans , Male , Acromegaly/surgery , Adenoma/complications , Growth Hormone-Secreting Pituitary Adenoma/complications , Pituitary Neoplasms/complications , Middle AgedABSTRACT
PURPOSE: To study the utility of T2-weighted MRI sequences in the identification of the inferior intercavernous sinus (IICS), a potential source of bleeding during transsphenoidal surgery of pituitary adenomas. METHODS: Pituitary sagittal T1W and coronal T2W MRI sequences were analyzed in 237 consecutive patients, after the exclusion of postoperative MRIs and those revealing an empty sella or a pituitary macroadenoma. Sphenoid sinus pneumatization was defined as incomplete (group 1) if it did not reach the nadir of the sella turcica, as complete (group 2) if it extended beyond the nadir of the sella or asymmetric (group 3), when only one side of the sinus was completely pneumatized. RESULTS: In Group 2 (70% of the patients), the IICS was rarely visualized on coronal T2W MRI (6/167 patients-3.6%), whereas in Group 1 it was identified in nearly all patients (55/57 patients - 96.5%, p < 0.001). In Group 3, the IICS was only visible above the non-pneumatized part of the sphenoid sinus. CONCLUSIONS: The IICS can be identified on coronal T2W images in patients with an incompletely pneumatized sphenoid sinus, but very rarely in patients with a totally pneumatized sinus. This information can help to increase awareness among pituitary surgeons of the need to potentially manage IICS bleeding during transsphenoidal surgery in patients with an incompletely pneumatized sphenoid sinus.
Subject(s)
Empty Sella Syndrome , Pituitary Neoplasms , Surgeons , Humans , Sphenoid Sinus/diagnostic imaging , Sphenoid Sinus/surgery , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/surgery , Sella Turcica/diagnostic imaging , Sella Turcica/surgeryABSTRACT
Background: Our objective was to describe the clinical course and treatment challenges in a very young patient with a pituitary adenoma due to a novel aryl hydrocarbon receptor-interacting protein (AIP) gene mutation, highlighting the limitations of somatostatin receptor immunohistochemistry to predict clinical responses to somatostatin analogs in acromegaly. Case Report: We report the case of a 7-year-old boy presenting with headache, visual field defects, and accelerated growth following failure to thrive. The laboratory results showed high insulin-like growth factor I (IGF-I) (standardised deviation scores ( +3.49) and prolactin levels (0.5 nmol/L), and magnetic resonance imaging identified a pituitary macroadenoma. Tumoral/hormonal control could not be achieved despite 3 neurosurgical procedures, each time with apparent total resection or with lanreotide or pasireotide. IGF-I levels decreased with the GH receptor antagonist pegvisomant. The loss of somatostatin receptor 5 was observed between the second and third tumor resection. In vitro, no effect on tumoral GH release by pasireotide (with/without cabergoline) was observed. Genetic analysis revealed a novel germline AIP mutation: p.Tyr202∗ (pathogenic; class 4). Discussion: In vitro response of tumor tissue to somatostatin may better predict tumoral in vivo responses of somatostatin analogs than somatostatin receptor immunohistochemistry. Conclusion: We identified a novel pathologic AIP mutation that was associated with incipient acrogigantism in an extremely young patient who had a complicated course of disease. Growth acceleration can be masked due to failure to thrive. Tumoral growth hormone release in vivo may be predicted with in vitro exposure to somatostatin receptor analogs, as it cannot be assumed that all AIP-mutated somatotropinomas respond well to pasireotide.
ABSTRACT
CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.
Subject(s)
Acromegaly , Neuroendocrine Tumors , Acromegaly/complications , Acromegaly/diagnostic imaging , Growth Hormone-Releasing Hormone , Humans , Magnetic Resonance Imaging , Neuroendocrine Tumors/complications , Neuroendocrine Tumors/diagnostic imaging , Pituitary Gland/pathology , Retrospective StudiesABSTRACT
All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors.
Subject(s)
Adenoma , Pituitary Neoplasms , Humans , Pituitary Neoplasms/complications , Quality of Life , Adenoma/genetics , Adenoma/complications , Adenoma/metabolism , Biology , HormonesABSTRACT
Pituitary MRI is essential in the diagnosis of ACTH-dependent Cushing's syndrome, but its results are inconsistent. The demonstration of a sellar image compatible with the diagnosis of corticotropinoma varies from 40% to 90%, depending on the centre where the imaging is performed. In fact, the expertise of the neuroradiologist, use of a Tesla 3.0 MRI and choice of sequences are fundamental. The T2 and 3D gradient echo sequences after gadolinium injection are the most informative and today allow the detection of macro- and microadenomas in almost all cases. The diagnosis of numerous picoadenomas (<3-4 mm) is more challenging. The 2D and 3D spin echo or delayed T1 SE or FLAIR sequences after gadolinium can be used as a complement or to confirm a suspicious image. Characterization of corticotropinomas remains problematic. However, the correct assessment of so-called incidentalomas by recognizing artifacts, anatomical variants and frequent Rathke's cleft cysts eliminates around 90% of the incidentalomas that mimic pituitary adenomas, as repetitively reported in the literature. For the time being, there is reason to believe that hybrid imaging combining PET and MRI such as 11C-methionine PET coregistered with volumetric MRI will solve the diagnosis of corticotropinomas in the near future.
Subject(s)
ACTH-Secreting Pituitary Adenoma , Adenoma , Pituitary ACTH Hypersecretion , Pituitary Neoplasms , Adenoma/diagnostic imaging , Gadolinium , Humans , Magnetic Resonance Imaging/methods , Pituitary ACTH Hypersecretion/diagnostic imaging , Pituitary Neoplasms/diagnostic imagingABSTRACT
X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
Subject(s)
Acromegaly , Genetic Diseases, X-Linked , Gigantism , Pituitary Neoplasms , Acromegaly/complications , Acromegaly/genetics , Acromegaly/pathology , Child, Preschool , Chromatin/genetics , Communication , DNA-Binding Proteins/genetics , Genetic Diseases, X-Linked/genetics , Gigantism/complications , Gigantism/genetics , Gigantism/pathology , Humans , Pituitary Neoplasms/genetics , Receptors, G-Protein-Coupled/genetics , Transcription Factors/geneticsABSTRACT
Objective: Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma-paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL. Design: We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors. Methods: Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes. Results: From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients. Conclusions: This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.
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BACKGROUND: The prevalence of thyroid cancer is increasing steadily in most countries, partly due to better, earlier diagnosis. However, there is little data for developing countries, where the technical platform is often very limited, especially in Africa. OBJECTIVES: To assess the frequency of thyroid cancer in the Democratic Republic of the Congo (DRC) and to analyze the epidemiological, clinical, and ultrasound risk factors. MATERIAL AND METHODS: This is a multicenter cross-sectional study of 594 patients operated on for a thyroid mass from 2005 to 2019, in 35 centers in the DRC and for whom histopathological analyses were performed. RESULTS: The frequency of thyroid cancers in our cohort was 20%, mostly in patients over the age of 40 (62% of patients). These cancers were mainly diagnosed at the clinical stage, due to the presence of palpable masses. Papillary cancer was the most common (67.2% of patients), followed by follicular cancer (28% of cases). We found a high prevalence of anaplastic cancer (7.6%). These frequencies are probably the consequence of the fact that histopathological analyses are not systematically performed in the DRC, but mostly on tissues that the thyroid surgeons suspect to be malignant. Age ≥60 years, the presence of adenopathies upon palpation or on ultrasound, the solid nature and hypoechogenicity of nodules, the presence of macronodules and calcifications were the factors independently associated with the diagnosis of cancer in the study population. CONCLUSIONS: In this first study performed in the DRC, we have found that thyroid cancer is common. It is mainly detected at clinical stages, with patients over the age of 40 years and women being the most affected. The histopathology distribution differs from that in developed countries, with a lower prevalence of papillary cancer and a higher prevalence of the anaplastic type. In developing countries, it appears necessary to introduce the use of more precise diagnostic tools for thyroid cancer and also, to reinforce the improvement of known, controllable risk factors such as iodine deficiency.
Subject(s)
Thyroid Neoplasms/epidemiology , Adenocarcinoma, Follicular/epidemiology , Adult , Carcinoma, Papillary/epidemiology , Cross-Sectional Studies , Democratic Republic of the Congo/epidemiology , Female , Humans , Male , Middle Aged , Risk Factors , Thyroid Nodule/pathology , Ultrasonography , Young AdultABSTRACT
OBJECTIVE: Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with a standard of care treatment in a nationwide cohort of MEN1 patients. DESIGN: Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE). METHODS: The GTE database population consists of 1435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports. RESULTS: Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grades III-IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I-II, 4 patients (2.9%) presented tumour progression. CONCLUSION: PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with a standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
Subject(s)
Multiple Endocrine Neoplasia Type 1/pathology , Pituitary Neoplasms/pathology , Adult , Cohort Studies , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective StudiesABSTRACT
Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.
Subject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , GTP-Binding Protein alpha Subunits, Gs/metabolism , Gigantism/metabolism , Growth Hormone/metabolism , Receptors, G-Protein-Coupled/metabolism , Acromegaly/metabolism , Acromegaly/pathology , Animals , Body Composition , Cell Line , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gs/genetics , Gigantism/pathology , Growth Hormone-Secreting Pituitary Adenoma/genetics , Growth Hormone-Secreting Pituitary Adenoma/metabolism , Growth Hormone-Secreting Pituitary Adenoma/pathology , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Pituitary Gland/metabolism , Protein Kinase C/metabolism , Rats , Receptors, G-Protein-Coupled/geneticsABSTRACT
The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
Subject(s)
Acromegaly/therapy , Consensus , Dopamine Agonists/therapeutic use , Neurosurgical Procedures , Patient Care Team , Practice Guidelines as Topic , Radiotherapy , Receptors, Somatotropin/antagonists & inhibitors , Somatostatin/analysis , Acromegaly/diagnosis , Humans , Neurosurgical Procedures/methods , Neurosurgical Procedures/standards , Radiotherapy/methods , Radiotherapy/standardsABSTRACT
Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIPmut+ vs AIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed in AIPmut+ vs AIPmut- somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip-/- mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and antiproliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ vs AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.