Practice guidelines for the endocrine evaluation and treatment of pituitary incidentalomas are presented, including indications for surgery.
Objective:
The aim was to formulate practice guidelines ...for endocrine evaluation and treatment of pituitary incidentalomas.
Consensus Process:
Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails and one in-person meeting.
Conclusions:
We recommend that patients with a pituitary incidentaloma undergo a complete history and physical examination, laboratory evaluations screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months and yearly) after the initial evaluations. We recommend that patients with a pituitary incidentaloma be referred for surgery if they have a visual field deficit; signs of compression by the tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological compromise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than a prolactinoma.
Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and ...their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.
Clinical Biology of the Pituitary Adenoma Melmed, Shlomo; Kaiser, Ursula B; Lopes, M Beatriz ...
Endocrine reviews,
12/2022, Letnik:
43, Številka:
6
Journal Article, Web Resource
Recenzirano
Odprti dostop
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.
Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as ...it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.
Abstract
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 (
Ghrhr
Gpr101
)
. Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic
Ghrhr
Gpr101
mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only G
s
, but also G
q/11
and G
12/13
, 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.
Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia type 1 (MEN1) and Carney's complex (CNC), which occur due to mutations in the genes MEN1 and PRKAR1A respectively. ...Isolated familial somatotropinoma (IFS) is also a well-described clinical syndrome related only to patients with acrogigantism. Pituitary adenomas of all types--not limited to IFS--can occur in a familial setting in the absence of MEN1 and CNC; this phenotype is termed familial isolated pituitary adenomas (FIPA). Over the past 7 years, we have described over 90 FIPA kindreds. In FIPA, both homogeneous and heterogeneous pituitary adenoma phenotypes can occur within families; virtually all FIPA kindreds contain at least one prolactinoma or somatotropinoma. FIPA differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. A minority of FIPA families overall (15%) exhibit mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; AIP mutations are present in only half of IFS kindreds occurring as part of the FIPA cohort. In families with AIP mutations, pituitary adenomas have a penetrance of over 50%. AIP mutations are extremely rare in patients with sporadic pituitary adenomas. This review deals with pituitary adenomas that occur in a familial setting, describes in detail the clinical, pathological, and genetic features of FIPA, and addresses aspects of the clinical approach to FIPA families with and without AIP mutations.
T2-weighted MRI signal intensity of GH-secreting pituitary adenomas is gaining recognition as a marker of disease characteristics and may be a predictor of response to treatment of acromegaly. ...Adenomas that are T2-hypointense are more common, are smaller and are less likely to invade the cavernous sinus compared to the T2-iso and hyperintense tumors. T2-hypointense tumors are also accompanied by higher IGF1 values at baseline. When presurgical somatostatin receptor ligand (SRL) therapy is administered, T2-hypointense adenomas have better hormonal responses and have greater tumor shrinkage. Adjuvant SRL therapy of patients with T2-hypointense tumors that are uncured by surgery is also associated with a better hormonal response. We review the studies that have dealt with the T2-weighted signal intensity of GH-secreting pituitary tumors and elaborate on the details and nuances of this promising avenue of research.
Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a ...large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
Abstract Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and ...treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (> 1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed.
The epidemiology and genetics of pituitary adenomas Daly, Adrian F., MB BCh, PhD; Tichomirowa, Maria A., MD; Beckers, Albert, MD, PhD
Best Practice & Research Clinical Endocrinology & Metabolism,
10/2009, Letnik:
23, Številka:
5
Journal Article
Recenzirano
According to data derived from autopsy and radiological imaging series, pituitary tumours occur very commonly in the general population; however, most of these tumours are incidental findings with no ...obvious clinical impact. The historical data on the prevalence of pituitary adenomas in the clinical setting are scant and point to such tumours being relatively rare. Recent studies have shown that the prevalence of clinically relevant pituitary adenomas is 3–5 times higher than previously reported, which adds impetus to research into the aetiology of these tumours. Although the majority of pituitary adenomas are sporadic, approximately 5% of all cases occur in a familial setting and over half of these are due to Multiple Endocrine Neoplasia Type 1 (MEN-1) and Carney's Complex (CNC) disorders. Since the late 1990s, we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes as a condition termed Familial Isolated Pituitary Adenomas (FIPAs). The clinical characteristics of the FIPAs vary from those sporadic pituitary adenomas, as patients with FIPAs have a younger age at diagnosis and larger tumours. About 15% of the FIPA patients have mutations in the aryl hydrocarbon receptor-interacting protein gene ( AIP ), which indicates that the FIPA may have a diverse genetic pathophysiology.
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