The clinical, pathological, and genetic features of familial isolated pituitary adenomas

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.     

Clinical evaluations of pituitary apoplexy in incidental nonfunctional pituitary adenomas

Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each P < .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (P < .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each P < .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (P = .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each P < .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.     

垂体肿瘤239例临床特征分析

目的 探讨垂体瘤的临床特征及治疗方案.方法 回顾性分析福建省立医院自1994年1月至2007年6月间收住的239例垂体瘤患者的临床资料.结果 239例垂体腺瘤中,男性93例(38.9%),女性146例(61.1%).诊断时的平均年龄为(43.8±14.9)岁(范围为3.9～77岁).依据临床表现、影像学及内分泌检查、免疫组织化学染色所示,催乳素瘤为最常见的肿瘤(26.8%).手术治疗179例(74.9%),其中经蝶入路108例(60.3%),经额入路71例(39.7%),非手术治疗及随访者60例(25.1%).结论 垂体瘤可表现为内分泌异常、神经系统症状或其他原因行MRI意外发现;催乳素瘤为最常见的肿瘤.     

Clinical presentation and outcome of pituitary adenomas in teenagers

OBJECTIVE: Pituitary adenomas rarely occur in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. In this study we evaluated the symptoms at onset and the long-term consequences induced in teenagers by functioning or nonfunctioning pituitary adenomas. DESIGN AND PATIENTS: Clinical, biochemical and neuroradiological data of 44 young patients (12 males and 32 females, aged 16.3 +/- 1.9 years at diagnosis) with pituitary adenomas were evaluated retrospectively at baseline and after therapy. Patients underwent surgery, radiotherapy and/or medical treatment depending on clinical history and endocrine secretion of the tumour. Follow-up ranged from 8 to 252 months (median 55 months). MEASUREMENTS: Baseline and dynamic pituitary function were evaluated in all cases at diagnosis and after treatments. Magnetic resonance imaging (MRI) or computed tomography (CT) scan were performed before therapy and during follow-up. Hormone levels were measured using commercial radioimmunologic or immunoradiometric methods. RESULTS: Pituitary macroadenomas (group 1) or microadenomas (group 2) were found in 61% and 39% of cases, respectively. Overall, 68% were PRL-secreting, 7% GH-secreting, 5% ACTH-secreting and 20% nonfunctioning. The most frequent symptoms at onset were oligoamenorrhoea (62%) and galactorrhoea (59%) in the girls, and headache (58%) in the boys. Pubertal development was delayed in 12/27 (44%) cases with macroadenoma. Growth failure was observed in 4/44 (9%) patients (3 in group 1 and 1 in group 2). At diagnosis, hypopituitarism was detected in 10/27 (37%) patients with macroadenoma. Surgery alone cured 4/18 (22%) and 4/9 (44%) patients in group 1 and group 2, respectively. Adjuvant therapies (second surgery and/or radiotherapy and/or medical treatment) cured the disease in 2/13 (15%) patients with macroadenoma and allowed a persistent normalization in other 4/13 (31%) and 2/4 (50%) cases in group 1 and group 2, respectively. Medical treatment alone cured 2/9 (22%) patients with PRL-secreting macroadenoma and normalized PRL levels in another six (66%) with macroprolactinoma and in 2/7 (28%) patients with microprolactinoma. CONCLUSION: Delay of growth was rarely observed in teenagers with pituitary adenomas. At the onset of the disease, many girls complained of oligoamenorrhoea and galactorrhoea, while headache and delay of pubertal development were the symptoms more frequently referred by boys. Surgery alone was effective in a minority of patients and adjuvant therapies were helpful to obtain the remission of the disease in many cases. In patients with PRL-secreting pituitary adenoma, medical treatment, both as first choice or as adjuvant therapy, normalizes serum PRL levels in 14/27 (52%) cases.     

Familial pituitary adenomas

Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Mutations in the CDKN1B gene, encoding p27(Kip)1 were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas.     

Gonadotroph pituitary adenomas

Initially, the distinction between "functional" and "non-functional" adenomas was a purely clinical notion. A "non-secreting" adenoma was not considered to cause acromegaly nor Cushing's syndrome nor amenorrhea-galactorrhea syndrome. The term "chromophobe adenoma" has been used since the advent Herlant tetrachrome. More recently immunocytochemistry methods have demonstrated that most of the "clinically non functional" adenomas (chromophobe with classical histology) are actually gonadotrophin secreting adenomas or gonadotroph adenomas. Due to progress in immunocytochemistry applied to operated adenomas, it is now known that gonadotroph tumors account for 15 to 20% of all pituitary adenomas. Gonadotroph adenomas are monoclonal but their pathogenesis, unlike somatotroph adenomas causing acromegaly and despite numerous molecular studies, remains unknown. Gonadotroph adenomas are most always discovered in patients presenting a pituitary syndrome (half to three-quarters consult for a visual field disorder). Pituitary imaging almost always demonstrates a macroadenoma: two-thirds of the macroadenomas are enclosed. Anterior pituitary insufficiency is much more frequent than gonad hyperstimulation whether testicular (macro-orchidia) or ovarian (ovarian hyperstimulation similar to that observed in ovulation induction). A careful analysis of hormone assay results shows that baseline concentrations of gonadotrophin or their free sub-units is elevated in 30 to 50% of cases (especially FSH in men, and the free a sub-unit in premenopausal women). Dynamic tests contribute little to diagnosis: the GnRH test is positive in 75 to 100% of cases, the TRH test in 60 to 70% for FSH (or alpha) and when there is already a baseline hypersecretion of FSH (or a) in 20 to 30% of the cases for the LH when the baseline LH concentration is high. The immunocytochemistry of gonadotroph adenomas is slightly different from that of other adenomas: generally, only 5 to 10% of the cells, grouped in islets of variable size, dispersed in the tumoral parenchyma, bind anti-FH, anti-LH and/or anti-sub-unit a antisera. Surgery is the primary treatment for gonadotroph adenomas. Complementary radiotherapy may be discussed in case of a postoperative remnant. It is probably effective against recurrence. Medical treatment (dopaminergic agonists, somatostatin analogs, GnRH agonists and antagonists) have given disappointing results.     

Follicle-stimulating hormone-secreting pituitary adenomas

This retrospective study concerns 40 patients with an apparently nonsecretory pituitary adenoma who were operated on during an 11-yr period from 1971 to 1981. Among them, 6 men had elevated serum FSH levels. LH levels were normal in 5 and slightly elevated in 1. Testosterone levels were low in 2 patients and within normal limits in 2 others. Sexual impotency had developed from 6 months to 1 yr before surgery in all patients. Primary hypogonadism could be eliminated on clinical grounds (recent onset of hypogonadism, previous fertility of 5 of the 6, and postoperative improvement). After transsphenoidal adenomectomy, FSH levels returned to normal values in all, and clinical recovery occurred in most patients. Tumor tissue obtained at operation stained positively for the gonadotropins, but was negative for other pituitary hormones in all patients. The most probable explanation for these findings was that the tumors were responsible for the elevated FSH secretion. This explanation is supported by the immunocytochemical identification of gonadotropin-containing cells in the tumors. We conclude that these 6 men from a series of 40 patients who presented with pituitary tumor but no GH, PRL, or ACTH hypersecretion had primary gonadotropinomas.     

Gonadotroph cell pituitary adenomas

The frequency of gonadotroph cell adenomas among all unselected pituitary adenomas is likely much higher than previously suspected. The prevalence in one series of 139 men with pituitary macroadenomas was 17 per cent (24 per cent if adenomas secreting only alpha subunit are included). The clinical characteristics of patients with gonadotroph cell adenomas are similar. Most are middle-aged men who have a history of normal pubertal development and a normal fertility history and by examination are normally virilized and have testes of normal size. They are brought to medical attention because of visual impairment, which is the result of the enormous size of the adenoma. The most common hormonal characteristics of gonadotroph cell adenomas in vivo is hypersecretion of FSH, which is often accompanied by hypersecretion of FSH-beta and alpha subunits and less often by hypersecretion of LH-beta or intact LH. Another common characteristic is secretion of FSH and/or LH-beta in response to TRH. A few patients with gonadotroph cell adenomas hypersecrete intact LH and therefore have supranormal serum testosterone concentrations. A larger number have secondary hypogonadism, because the adenomas are not secreting intact LH but are compressing the normal gonadotroph cells and impairing LH secretion. These patients have concentrations of intact LH that are not elevated, despite subnormal testosterone concentrations. The testosterone increases markedly in response to human chorionic gonadotropin. Both the clinical and hormonal characteristics of gonadotroph cell adenomas usually make them readily distinguishable from pituitary enlargement due to long-standing primary hypogonadism. Most gonadotroph cell adenomas are now managed first by transsphenoidal surgery to attempt to restore vision as quickly as possible, and then by supervoltage radiation to prevent regrowth of the remaining adenomatous tissue. Surgery usually does improve vision, as well as the pretreatment hormonal abnormalities, and radiation reduces FSH hypersecretion further. Dopamine agonist therapy is experimental but warrants further trial. The hormonal abnormalities detected prior to treatment, such as supranormal basal concentrations of FSH, alpha, and FSH-beta and the FSH and LH-beta responses to TRH, can be used to monitor the response to therapy.     

内镜辅助下经鼻蝶入路手术治疗垂体瘤的临床效果观察

目的探讨内镜辅助下经鼻蝶入路手术治疗垂体瘤的临床效果。方法将该院2017-05～2018-05收治的92例垂体瘤患者,根据手术方法不同分为对照组和研究组,对照组行经鼻蝶显微镜垂体瘤切除术治疗,研究组行内镜辅助下经鼻蝶入路手术治疗。对比两组患者的临床疗效及两组患者内分泌激素水平及术后并发症发生情况。结果研究组的临床疗效优于对照组(P0.01),同时研究组的术后并发症总发生率显著低于对照组(P0.01);治疗后研究组血管紧张素、肾素、去甲肾上腺素等内分泌激素水平低于对照组(P0.01)。结论内镜辅助下经鼻蝶入路手术治疗垂体瘤患者的效果更佳,患者内分泌激素水平的影响相对较低,治疗有效率高,不良反应少,值得进一步推广。     

Radiosurgery for pituitary adenomas

Pituitary adenomas represent nearly 15% of all intracranial tumors. Multimodal treatment includes microsurgery, medical management and radiotherapy. Microsurgery is the primary recommendation for nonfunctioning and most of functioning adenomas, except for prolactinomas that are usually managed with dopamine agonist drugs. However, about 30% of patients require additional treatment after microsurgery for recurrent or residual tumors. In these cases, fractionated radiation therapy has been the traditional treatment. More recently, radiosurgery has been established as a treatment option. Radiosurgery allows the delivery of prescribed dose with high precision strictly to the target and spares the surrounding tissues. Therefore, the risks of hypopituitarism, visual damage and vasculopathy are significantly lower. Furthermore, the latency of the radiation response after radiosurgery is substantially shorter than that of fractionated radiotherapy. The goal of this review is to define the efficacy, safety and role of radiosurgery for treatment of pituitary adenomas and to present the preliminary results of our institution.     

The radiology of pituitary adenomas

The radiologic management of pituitary adenomas has changed considerably over the last decade. With the development of sophisticated new technologies, diagnostic testing has evolved from pneumoencephalography to pluridirectional tomography, computed tomography, and currently magnetic resonance imaging. This article discusses these dramatic changes and demonstrates the present state-of-the-art and utility of radiologic methods in diagnosing microadenomas and macroadenomas and in differentiating these lesions from parasella lesions.