BACKGROUND. Pituitary adenomas display an array of hormonal and proliferative activity. Once primarily classified according to size (microadenomas, < 1 cm; macroadenomas, greater than or equal to 1 cm), these tumors are now further classified according to immunohistochemistry and functional status. With these additional classifications in mind, the goals of the current study were to determine the prevalence of pituitary adenomas and to explore the clinical relevance of the findings. METHODS. The authors conducted a metaanalysis of all existing English-language articles in MEDLINE. They used the search string (pituitary adenoma or pituitary tumor) and prevalence and selected relevant autopsy and imaging evaluation studies for inclusion. RESULTS. The authors found an overall estimated prevalence of pituitary adenomas of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies). CONCLUSIONS. Given the high frequency of pituitary adenomas and their potential for causing clinical pathologies, the findings of the current study suggest that early diagnosis and treatment of pituitary adenomas should have far-reaching benefits. (C) 2004 American Cancer Society.
The WHO categorizes pituitary tumours as typical adenomas, atypical adenomas and pituitary carcinomas, with typical adenomas constituting the major class. However, the WHO classification does not provide an accurate correlation between histopathological findings and clinical behaviour. Tumours lacking typical histological features are classified as atypical, but not all are clinically atypical or exhibit aggressive behaviour. Pituitary carcinomas, by definition, have craniospinal or systemic metastases, although not all display classical cytological features of malignancy. Aggressive pituitary adenomas, defined from a clinical perspective, have earlier and more frequent recurrences and can be resistant to conventional treatments. Specific biomarkers have not yet been identified that can distinguish between clinically aggressive and nonaggressive pituitary adenomas, although the antigen Ki-67 proliferation index might be of value. This Review highlights the need to develop new biomarkers to facilitate the early detection of clinically aggressive pituitary adenomas and discusses emerging markers that hold promise for their identification. Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. New drugs, such as temozolomide, have potential use in the management of these patients; anti-VEGF therapy, mTOR and tyrosine kinase inhibitors are also potentially useful in managing selected patients.
Summary Background Pituitary adenomas (PAs) are associated with increased morbidity and mortality. The optimal delivery of services and the provision of care for patients with PAs require distribution of the resources proportionate to the impact of these conditions on the community. Currently, the resource allocation for PAs in the health care system is lacking a reliable and an up-to-date epidemiological background that would reflect the recent advances in the diagnostic technologies, leading to the earlier recognition of these tumours. Objectives To determine the prevalence, the diagnostic delay and the characteristics of patients with PA in a well-defined geographical area of the UK (Banbury, Oxfordshire). Patients and methods Sixteen general practitioner (GP) surgeries covering the area of Banbury and a total population of 89 334 inhabitants were asked to participate in the study (data confirmed on 31 July 2006). Fourteen surgeries with a total of 81,449 inhabitants (91% of the study population) agreed to take part. All cases of PAs were found following an exhaustive computer database search of agreed terms by the staff of each Practice and data on age, gender, presenting manifestations and their duration, imaging features at diagnosis, history of multiple endocrine neoplasia type 1 and family history of PA were collected. Results A total of 63 patients with PA were identified amongst the study population of 81,149, with a prevalence of 77·6 PA cases/100,000 inhabitants (prolactinomas; PRLoma: 44·4, nonfunctioning PAs: 22·2, acromegaly; ACRO: 8·6, corticotroph adenoma: 1·2 and unknown functional status; UFS: 1·2/100,000 inhabitants). The distribution of each PA subtype was for PRLoma 57%, nonfunctioning PAs 28%, ACRO 11%, corticotroph adenoma 2% and UFS 2%. The median age at diagnosis and the duration of symptoms until diagnosis (in years) were for PRLoma 32·0 and 1·5, nonfunctioning PAs 51·5 and 0·8, ACRO 47 and 4·5 and corticotroph adenoma 57 and 7, respectively. PRLoma was the most frequent PA diagnosed up to the age of 60 years (0-20 years: 75% and 20-60 years: 61% of PAs) and nonfunctioning PA after the age of 60 years (60% of PAs). Nonfunctioning PAs dominated in men (57% of all men with PA) and PRLoma in women (76% of all women with PA). Five patients (7·9%) presented with classical pituitary apoplexy, with a prevalence of 6·2 cases/100,000 inhabitants. Conclusions Based on a well-defined population in Banbury (Oxfordshire, UK), we have shown that PAs have a fourfold increased prevalence than previously thought; our data confirm that PAs have a higher burden on the Health Care System and optimal resource distribution for both clinical care and research activities aiming to improve the outcome of these patients are needed.
Pituitary adenomas are benign intracranial neoplasms that can result in morbidity owing to local invasion and/or excessive or deficient hormone production. The prevalence of symptomatic pituitary adenomas is approximately 1:1,000 in the general population. The vast majority of these tumours occur sporadically and are not part of syndromic disorders. However, germline mutations in genes known to predispose individuals to familial pituitary adenomas are found in a few patients with sporadic pituitary adenomas. Mutations in AIP (encoding aryl-hydrocarbon receptor-interacting protein) are the most frequently observed germline mutations. The prevalence of these mutations in patients with sporadic pituitary adenomas is similar to 4%, but can increase to 8-20% in young adults with macroadenomas or gigantism, and also in children. Germline mutations in MEN1 (encoding menin) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas, which highlights the importance of the chromosome 11q13 locus in pituitary tumorigenesis. In this Review, we describe the clinical features of patients with sporadic pituitary adenomas that are associated with AIP or MEN1 mutations, and discuss the molecular mechanisms that might be involved in pituitary adenoma tumorigenesis. We also discuss genetic screening of patients with sporadic pituitary adenomas and investigations of relatives of these patients who also have the same genetic mutations.
Introduction: The term atypical pituitary adenoma (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., "extensive" nuclear staining for p53; "elevated" mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes. Methods: Of the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis. Results: We determined significant threshold values for p53 (>= 2 %; AUC: 0.94) and the mitotic index (>= 2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index >= 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (p < 0.001); OR 5.2// p53 (p < 0.001); OR 3.1// mitotic index (p < 0.001); OR 2.1// invasiveness (p < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (p = 0.008; OR: 0.4; CI95 %: 0.18; 0.77). Conclusions: Here we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.
Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.
Rationale: Pituitary adenomas and paragangliomas are both rare endocrine diseases. Paragangliomas (PGL)/pheochromocytomas (PHEO) are part of an inherited syndrome in about 30% to 40% of cases. Among familial cases, mutations of the succinate dehydrogenase (SDH) subunit genes (succinate dehydrogenase subunit [SDH] B, SDHC, SDHD, succinate dehydrogenase subunit AF2 [SDHAF2], and SDHA) are the most common cause.() Patient concerns: We here report a 31-year-old patient with a known SDHD mutation whose disease has been revealed by a left PHEO during childhood and who presented at age 29 years a large paraganglioma of the right jugular foramen, a concomitant PHEO of the left adrenal and 2 retroperitoneal paragangliomas. A pituitary incidentaloma was found during investigations on a fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET). Diagnosis: A pituitary magnetic resonance imaging (MRI) confirmed the presence of a 14 mm pituitary macroadenoma. The pituitary function was normal except for hypogonadotropic hypogonadism. On examination of the fundus, a diagnosis of Pseudo Foster-Kennedy syndrome was made due to a venous compression of the right jugular vein caused by the paraganglioma (PGL). The pituitary adenoma was not compressive to the optic chiasm. Interventions: A treatment with acetazolamide was started in order to improve intracranial hypertension. The patient couldn't benefit of a surgical approach for the paraganglioma of the right jugular foramen; the patient has been treated with stereotactic radiosurgery (Gamma Knife). Outcomes: The most recent MRI revealed that the right jugular foramen PGL is stable and the latest visual assessment demonstrated stability despite a recent reduction in acetazolamide dosage. A surveillance by MRI of the pituitary adenoma has been planned. Lessons: The association of a pituitary adenoma to paragangliomas within a same patient is very uncommon and raises the question of related physiopathological mechanisms.
Non-functioning pituitary carcinomas (NFPC) are defined as tumours of adenophyseal origin with craniospinal or systemic dissemination, with the absence of a hormonal hypersecretion syndrome. These are a histologically heterogenous group of tumours, comprising gonadotroph, null cell, “silent” tumours of corticotroph, somatotroph or lactotroph cell lineages as well as plurihormonal Pit-1 tumours. NFPC are exceedingly rare, and hence few cases have been described. This review has identified 38 patients with NFPC reported in the literature. Recurrent invasive non-functioning pituitary adenomas (NFPA) were observed in a majority of patients. Various factors have been identified as markers of the potential for aggressive behaviour, including rapid tumour growth, growth after radiotherapy, gain or shift of hormone secretion and raised proliferative markers. Typically, there is a latency of several years from the original presentation with an NFPA to identification of metastases and only 5 cases reported with rapidly progressive malignant disease within 1 month of presentation. Therapeutic options include debulking surgery, radiation therapy and chemotherapy with temozolomide recommended as first line systemic treatment. Although long-term survivors are described, prognosis remains generally very poor (median survival 8 months). Improvements in molecular tumour profiling may assist in predicting tumour behaviour, guide therapeutic choices and identify novel therapies.
•We analyzed the relationship between NF-κB, MMP-9, and MICA expression in pituitary adenomas.•The expression levels of NF-κB, MMP-9, and MICA were positively related in patients with pituitary adenomas.•The interactions of NF-κB, MMP-9, and MICA play an important role in the development of pituitary adenomas. The aim of this study was to examine the expression levels of NF-κB, MMP-9, and MICA and their relationship between each other in pituitary adenomas as a histological basis for the study of the expression and shedding mechanism of MICA and mechanism of immune escape of pituitary adenomas. Our study indicated that MICA, MMP-9 and NF-κB mRNA and protein levels were more highly expressed in pituitary adenomas than healthy tissues. The expression levels of NF-κB, MMP-9, and MICA were positively related in patients with pituitary adenomas. In conclusion, the activation of NF-κB can up-regulate the expression of MICA and induce the expression of MMP-9, which hydrolyzes MICA into sMICA to promote tumor immune escape. The interactions of NF-κB, MMP-9, and MICA play an important role in the development of pituitary adenomas, and MMP-9 could be used as a new target for inhibiting tumor cell immune escape.