PRL-secreting Adenomas Research Articles

Comparative study on clinicopathological characteristics of functional and non-functional subtypes in pituitary adenomas

BackgroundPituitary adenomas comprise clinical and pathological characteristics of functional and non-functional subtypes. To enhance our understanding of diagnostic presentations, our study aimed to know the clinicopathological characteristics of pituitary adenomas of both functional and non-functional subtypes. The purpose of our study was to investigate the clinicopathological characteristics of pituitary adenomas, including demographic characteristics, clinical presentations, hormone secretion patterns, invasiveness, and cellular characteristics.MethodsA total of 41 cases of pituitary adenomas were analyzed, with 63.4% classified as non-functional adenomas (NFPA) and 36.6% as functional adenomas (FPA). Clinical presentations vary, with vision loss and headaches commonly occurring in both NFPA and FPA. In FPAs, serum hormone levels varied and were categorized into growth hormone-secreting (53.3%), ACTH-secreting (26.7%), PRL-secreting (13.3%), and FSH-secreting (6.7%) subtypes. Moreover, clinical presentations in FPA included diplopia, giddiness, vomiting, ptosis, and limb weakness. Clinical features varied across subtypes, with acromegaly in growth hormone-secreting adenomas, moon facies and weight gain in ACTH-secreting adenomas, poor facial growth in PRL-secreting adenomas, and vision loss in FSH-secreting adenomas. Meanwhile, NFPA were predominantly macroadenomas (88.5%) and exhibited various morphological patterns.ResultsThe proliferation index is higher in functional adenomas (mean 1.32) as compared to non-functional (mean 0.91). Clinical presentations varied across functional and non-functional adenomas. Growth hormone-secreting adenomas were the most common functional subtype, while LH and null cell adenomas were common non-functional subtypes. Two cases were invasive adenomas with a low Ki67 index. Sheets were the most common morphological pattern. PCA analysis revealed significant differences between the two groups, with PC 1 explaining 92.111% of the variance.ConclusionsOur study elucidates the clinicopathological characteristics of pituitary adenomas, highlighting significant differences between functional and non-functional subtypes. These findings underscore the importance of tailored diagnostic and management strategies to optimize outcomes for patients with pituitary adenomas.

Italian Guidelines for the Management of Prolactinomas.

This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Immunohistochemical Patterns of Pituitary Adenomas in Southeastern Nigeria, a 10-year Histopathologic Review

ABSTRACT Introduction: Pituitary adenomas [PAs] constitute the third most common primary intracranial tumours, with a wide prevalence rate of 1% to 40%. Histologic (H & E) classification into acidophilic, basophilic and chromophobic adenomas have little clinical relevance but WHO recommended immunohistochemical subclassification has both therapeutic and prognostic significance. This immunohistochemical subclassification has not been done in our environment, making it imperative for us to evaluate the patterns in our environment. Aim: To determine the immunohistochemical patterns of PAs in Southeastern Nigeria. Materials and Methods: This was a 10-year retrospective review of all PA biopsies received at University of Nigeria Teaching Hospital Enugu, Memphys Hospital for Neurosurgery Enugu and Grace Pathology Consults Enugu, Nigeria. The age, sex, histologic, immunohistochemical subtypes and biopsy size of all diagnosed PAs were analyzed using Statistical Package for Social Sciences (SPSS) version 20 (New York: IBM Inc.) and the results were expressed in descriptive statistics. Results: One hundred cases of PAs were identified in this study constituting 19.6% of all primary intracranial tumors received at our study centers during the period under review. There were 45 (45.0%) females and 55 (55.0%) males giving a female to male ratio of 1:1.2, and a mean age of 45.3 years. The commonest histologic type was acidophilic adenoma (49.0%), followed by basophilic (40.0%) and chromophobic (11.0%) adenomas. Null cell adenomas were the most common immunohistochemical subtype (44.0%), followed by PRL-secreting adenomas (27.0%). Others were Luteinizing hormone (LH) − 13 (13.0%), follicle stimulating hormone (FSH) − 7 (7.0%), growth hormone (GH) − 3(3.0%), TSH − 2(2.0%) and ACTH − 1(1.0%) adenomas. Conclusion: PAs predominate amongst males, occurring mostly in the middle age groups in Southeastern Nigeria. Null cell adenoma is the commonest immunohistochemical subtype followed by PRL-secreting adenomas. Routine immunohistochemical characterization is required for accurate diagnosis and optimal patient care.

Coexistence of PRL-secreting adenoma and germ cell tumor in 14-year-old adolescent

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Early Left Ventricular Diastolic Dysfunction in Females with Chronic Hyperprolactinemia: A Doppler Echocardiographic Study.

Despite the myocardial prolactin (PRL) binding activity and the known effect of enhancing contractility in the isolated rat heart, little information is available concerning the cardiovascular consequences of hyperprolactinemia in humans. To elucidate the effects of chronic hyperprolactinemia on cardiac structure and function, twenty-four patients with isolated PRL-secreting adenoma and twenty-four controls underwent a complete mono- and two-dimensional Doppler-echocardiography. Blood pressure and heart rate were similar in the two groups, and no significant differences were observed as to left ventricular (LV) geometry between patients and controls. Resting LV systolic function was normal in patients with hyperprolactinemia, as shown by similar values of fractional shortening and cardiac output. Conversely, hyperprolactinemic patients exhibited a slight impairment of LV diastolic filling, as demonstrated by the prolongation of the isovolumetric relaxation time and the increase of the atrial filling wave of mitral Doppler velocimetry (58 ± 13 vs. 47 ± 8 cm/s, p < 0.05) with a subgroup of females (16%) having a clear diastolic dysfunction, and a worse exercise capacity (6 min walking test 452 ± 70 vs. 524 ± 56; p < 0.05). In conclusion, hyperprolactinemia in humans may be associated with a slight impairment of diastolic function, with an overt diastolic dysfunction in a subgroup of females which correlated with poorer exercise performance, in the absence of significant abnormalities of LV structure and systolic function.

Gamma Knife Radiosurgery for Pituitary Tumors: A Systematic Review and Meta-Analysis.

Simple SummaryPituitary tumors represent approximately 10–15% of all brain neoplasms. Gamma Knife, the most commonly used stereotactic radiosurgery technique worldwide, plays an important role in the treatment of several pituitary neoplasm. It is currently used in cases of residual or recurrent tumors after surgery or as primary treatment when surgery is contraindicated. Its goals are long-term tumor control, preservation of visual function, and, for secreting pituitary adenomas, endocrine remission. Several retrospective case-series (level of evidence IV) on Gamma Knife for pituitary tumors have been published describing encouraging outcomes; only one systematic review and meta-analysis on non-functioning pituitary adenoma has been recently reported. We provide a systematic review of the literature and meta-analysis from the last two decades on Gamma Knife radiosurgery for several pituitary tumors with the aim of describing and confirming safety and effectiveness of this technique.To describe and evaluate outcomes of Gamma Knife radiosurgery (GK) for the treatment of pituitary tumors over the past twenty years, a systematic review and meta-analysis according to PRISMA statement was performed. Articles counting more than 30 patients were included. A weighted random effects models was used to calculate pooled outcome estimates. From 459 abstract reviews, 52 retrospective studies were included. Among them, 18 reported on non-functioning pituitary adenomas (NFPA), 13 on growth hormone (GH)-secreting adenomas, six on adrenocorticotropic hormone (ACTH)-secreting adenomas, four on prolactin hormone (PRL)-secreting adenomas, and 11 on craniopharyngiomas. Overall tumor control and five-year progression free survival (PFS) estimate after one GK procedure for NFPA was 93% (95% CI 89–97%) and 95% (95% CI 91–99%), respectively. In case of secreting pituitary adenomas, overall remission (cure without need for medication) estimates were 45% (95% CI 35–54%) for GH-secreting adenomas, 64% (95% CI 0.52–0.75%) for ACTH-secreting adenomas and 34% (95% CI: 19–48%) for PRL-secreting adenomas. The pooled analysis for overall tumor control and five-year PFS estimate after GK for craniopharyngioma was 74% (95% CI 67–81%) and 70% (95% CI: 64–76%), respectively. This meta-analysis confirms and quantifies safety and effectiveness of GK for pituitary tumors.

The Expression of Stem Cell Markers (CD133, NESTIN, OCT4, SOX2) in Invasive Pituitary Adenomas

The pituitary gland serves as the center of the endocrine system. Stem cells are typically found in a specialized microenvironment of the tissue, called the niche, which regulates their maintenance, self-renewal, fate determination, and reaction to external influences. The aim of this study is to elucidate the role of stem cells in the initiation, invasion, and progression of pituitary adenomas. All specimens were collected between January 2007 and April 2015. Radiological classification (invasiveness) for all cases was performed according to the Wilson-Hardy classification system. Immunohistochemical staining was performed to all specimens for CD133, Oct4, Sox2 and nestin. The study included 48 patients. Of 48 patients, 17 (35.4%) were male and 31 (64.6%) were female. Mean age is 47.10±14.14 (17-86 yrs.). According to the Wilson-Hardy classification system, 27 (56.3%) were non-invasive adenomas. There was no statistical significance between the expression of pituitary stem cell markers (CD133, OCT4, SOX2, nestin) and invasiveness. All stem cell markers are stained extensively in pituitary adenomas, except for SOX2 which was stained weakly. However, there is no effect of stem cells on invasiveness of pituitary adenomas because we cannot find a difference of the staining level between invasive and non-invasive adenomas. Nestin was stained extensively in functional adenomas, especially for GH, PRL, and gonadotropin secreting adenomas. SOX2 was stained extensively for ACTH-secreting adenomas.

Giant Prolactinoma Complicated by Cerebrospinal Fluid Rhinorrhea, Behavioral and Neurological Changes Following Dopamine Agonist Therapy: A Case Report

Introduction: Giant prolactinomas, defined as pituitary PRL-secreting adenomas whose size exceeds 40 mm and with a PRL level of >1000 ng/ml, are very rare. Their treatment and outcome can be unpredictable and challenging for clinicians. Case Report: A 47-year-old male was referred to the Neuroendocrine Department due to a large pituitary tumor invading the suprasellar region, both cavernous and sphenoidal sinuses, and pharyngeal space. He had been suffering from intensive headaches and visual deterioration for two years; he had also experienced sexual dysfunction. Discussion: We detected extremely high serum PRL levels (Eƒ700000 mU/l) and hypopituitarism. Bromocriptine therapy (BRC) was started with a gradual dose increase. Ten days after the commencement of medical treatment, cerebrospinal fluid (CSF) rhinorrhea appeared. He underwent neurosurgery two months later; the bone erosion was localized and repaired. Tumor biopsy revealed a PRL-secreting tumor with a low proliferative index (Ki67<0.5). After surgery, he continued with BRC and shortly after experienced behavior changes, such as mood oscillations, anxiety, impulsivity, irritability, impaired concentration, and tremor. To control his tumor, pramipexol and levodopa treatment were introduced but with a moderate effect. However, only after the reduction of the BRC dose, his mental and neurological complaints abated significantly. A close follow-up for the next three years detected a low prolactin level and significant tumor shrinkage (MRI), with visual field improvement and reversion of pituitary function. Conclusion: Giant prolactinomas are invasive but respond well to dopamine agonists. However, CSF rhinorrhea, behavioral and neurological changes can occur during medical treatment, suggesting a need for vigilance throughout the dopamine agonist therapy.

Early recognition of aggressive pituitary adenomas: a single-centre experience.

Pituitary adenomas are usually considered benign tumours, although some of them can exhibit an aggressive behaviour. Patients with clinically aggressive pituitary adenomas are frequently diagnosed with larger masses, and may present an earlier recurrence (or persistence) after surgery. Our aim was to characterise the clinical, histopathological and radiological features of patients with aggressive pituitary adenoma, in order to correlate their clinical behaviour with the response to treatment plan. We considered an aggressive pituitary adenoma on the basis of radiological features (size, local invasion), pathological reports (atypical adenoma: MIB-1 >3%, p53 immunoreactivity, increased mitotic activity) and clinical aspects (response to surgery, radiotherapy and medical treatment). Among our cohort of 582 patients, we considered 102 subjects with aggressive pituitary adenomas (18%, 56 male and 46 female): 14 adrenocorticotrophic hormone (ACTH)-secreting, 18 growth hormone (GH)-secreting, 23 prolactin (PRL)-secreting and 47 non-secreting, with a median follow-up of 5years. In the whole cohort, 75% of patients with aggressive pituitary adenomas presented invasion of surrounding structure, especially GH-secreting, PRL-secreting and non-secreting. Besides invasion, their remission rate after surgery, radiotherapy or medical treatment was similar, irrespective of hormonal secretion. Surgery was the most performed treatment (overall remission rate of 24%), especially in those patients with ACTH- or GH-secreting adenoma, and 22% of patients were submitted to radiotherapy, with a remission rate of 45% after a median of 3years. Two consecutive years of medical treatment, in patients with secreting pituitary adenoma, achieved disease control in 41% of them. Considering pathological reports, 24% of cases were defined as atypical adenomas; radiological characteristics, responses to medical treatment and remission rates were similar among patients with typical and atypical adenoma. We proposed a new and comprehensive definition of aggressive pituitary adenoma, based upon radiological, clinical and pathological features. In a selected cohort of patients, radiological invasion resulted in the most common marker to describe the aggressive behaviour of pituitary adenoma. Surgery, radiotherapy and medical treatment (the latter only in secreting adenoma) achieved disease control in half of the patients with aggressive adenoma, especially surgery in those with ACTH-oma and medical treatment in those with GH- and PRL-secreting adenoma. Nevertheless, radiological, clinical or atypical features did not affect the outcome.

Microsurgical therapy of pituitary adenomas.

We report the efficacy and safety of transsphenoidal microsurgery in a large and homogeneous cohort of patients with pituitary adenomas (PAs) treated at a single Institute by a single neurosurgeon. A total of 2145 consecutive patients undergoing first surgery for a PA were included: 795 (37.1%) had a nonfunctioning pituitary adenoma (NFPA), 595 (27.7%) acromegaly, 496 (23.1%) Cushing's disease, 208 (9.7%) a PRL-secreting adenoma, and 51 patients (2.4%) a TSH-secreting adenoma. Remission was achieved when strict hormonal and radiological criteria were met. Early surgical remission was achieved in 66% of acromegalic patients, 79.6% of patients with Cushing's disease, 64.4% of prolactinomas, 74.5% of patients with a TSH-secreting adenoma, and 66.9% of NFPAs. The mean (±SE) follow-up was 60.1 ± 1.3 months. The recurrence-free survival at 10 years was 78.2% in acromegalic patients, 68.1% in prolactinomas, 74.3% in Cushing's disease, 70.3% in TSH-secreting adenomas, and 75.3% in NFPAs. Preoperative hypoadrenalism recovered in 35.3%, hypogonadism in 43.3% and hypothyroidism in 37.4% of patients with impaired function before surgery. The mortality rate was 0.2% and major morbidity 2.1%. New onset hypoadrenalism occurred after surgery in 2.5% of patients at risk, hypogonadism in 4.1%, and hypothyroidism in 1.8%. Permanent diabetes insipidus (DI) occurred in 0.9% of patients. In experienced hands, transsphenoidal microsurgery for PAs achieves remission in most patients with a low complication rate. Pituitary function is preserved in most cases and can recover in more than one-third of patients with preoperative hypopituitarism.

High Ki-67 expression is associated with prolactin secreting pituitary adenomas.

Pituitary adenomas represent the third most common primary intracranial tumor in neurosurgical practice. To understand the biological behaviour of the pituitary adenomas previous studies have determined the tumor proliferation rate using monoclonal antibodies targeted against the Ki-67 antigen. The aim of this study was to correlate the Ki-67 index with hormonal profiles of pituitary adenomas. The study included 50 pituitary adenomas. For histopathologic evaluation, the sections were stained with routine hematoxylin and eosin method. Additional paraffin sections from each tumor were immunostained using primary antibodies against the following pituitary hormones: somatotropin (STH), prolactin (PRL), adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). To detect the expression of Ki-67 we used a mouse anti-human monoclonal antibody (clone K2). The percentage of Ki-67 positive nuclei (Ki-67 labeling index) was assessed by counting approximately 1000 nuclei of the tumor cells at ×400 magnification. Out of the 50 tumor samples, 31 (62%) pituitary adenomas showed proliferative activity, and the proliferation rate was variable in this group. The overall mean Ki-67 labeling index was 1.59 ± 1.47, ranging from 0.3% to 6.6%. In 5 cases, the Ki-67 index was >3%, all of them being prolactinomas. The Ki-67 index was higher in PRL-secreting adenomas (mean ± SD was 3.37 ± 1.80, range 0.9 - 6.6%). Our study provides the evidence that a higher Ki-67 value is associated with pituitary adenomas that secrete PRL (prolactinomas and mixed STH/PRL-secreting adenomas).

Ectopic Functional Adenoma in the Cavernous Sinus: A Diagnostic and Surgical Challenge

Object: Ectopic pituitary adenomas are extremely rare and mostly arise in the proximity of the pituitary gland, e.g., the cavernous sinus (CS), the pituitary stalk or the suprasellar space. Their location may be a common cause of failed diagnosis and unsuccessful transsphenoidal surgery. We present a case of mixed ACTH- and PRL-secreting adenoma located in the left CS.

Does elevated morning prolactin concentration in children always mean the diagnosis of hyperprolactinemia?

It has recently been suggested that prolactin (Prl) level above the upper limit of normal range, recorded in a single measurement in serum is enough to diagnose hyperprolactinemia (HPrl). The aim of the study was the analysis of the circadian rhythm of Prl secretion in children with an increased morning Prl concentration in order to establish whether it is a real hyperprolactinemic state or not. The analysis comprised a group of 44 children (32 boys and 12 girls, aged from 4.2 to 14.1 years, mean±SD: 10.4±3.5 years) with either short stature or precocious puberty, with an elevated Prl concentration at 8:00 a.m., suggesting hyperprolactinemic state. In all patients the circadian Prl secretion profile was assessed on the basis of Prl concentrations in 9 blood samples, collected in 3-h intervals. An analysis of the circadian Prl rhythm was performed. Depending on the medical history and the magnetic resonance imaging result, the children were divided into the following groups: A - congenital disorders of hypothalamic-pituitary region (n=10); B - acquired disorders of hypothalamic-pituitary region (other than pituitary adenomas) (n=15), C - pituitary adenomas (n=19). The control group consisted of 14 healthy children (9 boys and 5 girls), aged from 5.2 to 14.3 years, mean±SD: 10.8±3.2 years. In only 18 children (41%), apart from a higher morning Prl concentration, an elevated Prl concentration at other time points was observed and the circadian rhythm was disturbed, implying hyperprolactinemic state (2 children from Group A, 8 from Group B and 8 form Group C). In the remaining 26 children (59%), higher morning Prl concentrations were not accompanied by elevated Prl concentrations at other time points of the circadian profile. In children with elevated Prl concentrations in the morning, a circadian Prl secretion profile should be performed in order to avoid overdiagnosing of continuous HPrl. In children with the presence of pituitary adenoma and increased morning Prl concentrations, the diagnosis of Prl-secreting adenoma is not completely obvious.

Acromegaly and the thyroid gland

Acromegaly is a chronic disease caused by hypersecretion of growth hormone (GH), most frequently from a pituitary somatotropic adenoma. Its prevalence was estimated at 60–70 cases per million people, but in recent years it seems to be higher (even 86 cases per million). Approximately 3-4 new cases of acromegaly are annually diagnosed per million people. In acromegalic patients, the mortality rate is 2-4 times higher than in the general population. The most common causes of death in patients in question are cardiovascular and/or respiratory complications, or neoplastic diseases. Data indicating the increased risk of the development of benign and malignant tumors of various organs, particularly of the colon, thyroid gland, breast, and prostate, are reported in numerous studies. An elevated level of IGF-I seems to be responsible for the increased risk of cancers. It is to be recalled that IGF-I is a mitogenic, anti-apoptotic and angiogenesis-promoting factor. Prevalence of cancers in acromegalic patients remains controversial: some authors describe the increased prevalence, in contrast, others do not. The difference among studies may be due to a low incidence of acromegaly per se, retrospective nature of studies or to differences in study designs. In most studies, patients with cancers diagnosed prior to acromegaly were excluded [1]. The presence of IGF-I receptors was shown in both normal and neoplastic thyroid tissue in humans, a long time ago. There are numerous scientific evidence that IGF-I reveals an important, TSH–independent effect in growth processes in humans thyroid [2,3]. Moreover, there are a lot of studies describing the increased prevalence of goitre (both diffuse and nodular) in acromegalic patients, and many authors have demonstrated a positive correlation between the thyroid volume and serum IGF-I concentration. Large meta-analysis published recently by Wolinski et al. [4] has confirmed that both thyroid nodular disease and thyroid carcinoma are significantly more frequent in acromegalic patients than in general population (Table ​(Table11). Table 1 Studies with control group included in meta-analysis – the table taken from the study by Wolinski et al. [4], modified. Asterisk (*) - persons with non-functioning or Prl secreting adenomas. Accordingly, these results demonstrate that the repeated thyroid ultrasound (US) examination and careful evaluation of possible lesions (together with cytological assessment) should be important part of follow-up in patients with acromegaly. Wolinski et al. [4] documented that in newer studies on acromegalic subjects, thyroid disorders were reported more frequently - in studies published after year 2008, thyroid nodular disease occurred in about 65% of patients whereas in older studies approx. in 54%. Similar phenomenon could be recorded in case of thyroid carcinomas – 6% patients in newer reports published after 2008 vs. 3% in older studies, published before 2008. These results speak for the hypothesis that the improvement in diagnostic methods and therapy of acromegaly extends the survival time of patients, what - in turn - increases the prevalence of benign and malignant neoplasms possible to detect. Result of selected studies on acromegaly and thyroid disorders, published in recent years, are presented in Tables ​Tables22 and ​and33. Table 2 Results of the retrospective study by Turkish authors [1], including 64 acromegalic patients who were subjected to thyroid US examination and thyroid function tests (distribution of thyroid diagnoses). Table 3 Results of study from Brasil, including 106 acromegalic patients, who were subjected to thyroid US examination [5]. In 4 patients (3.8%) thyroid carcinoma was diagnosed in cytological examination (2 cases - multifocal papillary thyroid carcinoma, 1 - ...

Endoscopic endonasal transsphenoidal approach for pituitary adenomas invading cavernous sinus

Objective To investigate the effects of endoscopic endonasal transphenoidal approach in the treatment of pituitary adenomas invading the cavernous sinus (CS).Methods A retrospective analysis was performed in 135 pituitary adenomas extending to CS treated via endoscopic endonasal transphenoidal approach between April 2008 and April 2013.The most common adenoma type was non-functioning pituitary adenomas (NFPAs) (86 cases,63.7％),followed by PRL-secreting adenomas (28 cases,20.7％),growth hormone (GH)-secreting adenomas (18 cases,13.3％),ACTH-secreting adenomas (2 cases,1.5％),and TSH-secreting adenomas(1 cases,0.7％).The average diameter of the tumors was (30.0 ± 1.1)mm(10-69 mm).The shapes of the tumors were as the following:round (97 cases,72.6％),dumb bell (8 cases,5.9％),and multi-lobe (30 cases,21.5％).The patients were divided into two groups according to the Knosp classification:third grade (57 cases,42.2％) and fourth grade (78 cases,57.8％).Results Gross total resection was achieved in 40 patients (29.6％),subtotal (＞90％) in 45 (33.3％),partial (＞70％) in 42 (31.1％),and decompression (＜70％) in 8 (5.9％).There were 4 patients (3.0％) accompanied with postoperative cerebraospinal fluid leak,2 with visual decrease,and 5 with transient diabetes insipidus.One paient died due to postoperative intracranial hematoma.In 18 patients with GH-secreting adenomas,4 achieved endocrinological remission after surgery,and 9 significant GH decrease.In 28 patients with PRL-secreting adenomas,6 had a normal serum PRL level within one week postoperatively,and 21 remarkable PRL decrease.Conclusions The endoscopic endonasal transphenoidal approach was a safe and effective option for the resection of pituitary adenomas invading the CS. Key words: Pitutiary adenomas; Invasive; Caverous sinus ; Neuroendoscope ; Endonasal transsphenoidal approach

Increased serum interleukin-22 levels in patients with PRL-secreting and non-functioning pituitary macroadenomas

Cytokines' involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8±14.4years) and 30 healthy controls (19 males, mean age 50.4±8.4years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29-70.12) vs. 5.58 (0.19-21.46)pg/mL, p<0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82-70.12) vs. 21.29 (11.29-56)pg/mL, p=0.039]. IHC revealed a strong IL-22R staining in 100% of PRL-omas and 60% of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60% of NFPAs.

Familial isolated pituitary adenomas: An emerging clinical entity

Familial pituitary tumors are increasingly recognized. While some of these cases are related to wellknown syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex soma- totroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.

Germline AIP Mutations in Apparently Sporadic Pituitary Adenomas: Prevalence in a Prospective Single-Center Cohort of 443 Patients

Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete. We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas. A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study. The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification. AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case. This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.

Plurihormonality and Pluripotentiality of GH-Secreting Adenoma Based on Pathological Analysis of 242 patients with Acromegaly

Aim: To disclose the nature of plurihormonality and pluripotentiality of growth hormone (GH)-secreting adenomas. Methods: A total of 242 patients with GH-secreting adenomas were studied by immunohistochemistry, electron microscopy and clonal analysis (X-linked human androgen receptor gene assay). Results: GH-secreting adenoma showed a greater variety and number of hormones produced compared with those of PRL-secreting adenomas (p<0.01, Welch’s t-test). The number of cases with GH-secreting adenoma that simultaneously produced ACTH were 50 (21%) out of 242. There were two different types of co-localization of ACTH- and GH-secreting cells within adenoma; (1) adenoma with co-localized ACTH- and GH-immunoreactive cells in a random pattern, and (2) adenoma with a small cell cluster of ACTH-immunoreactive cells within GH-secreting adenomas. There were three different tissue phenotypes in GH-secreting adenomas; (a) mixed tumors composed of adenoma and neuronal cells, (b) co-localization of GHsecreting adenoma and mature bone tissue, and (c) co-localization of GH-secreting adenoma and nerve bundles. In this study, immunoreactivity for nestin was observed in these three different phenotypes of GH-secreting adenomas, not only in perivascular spaces of pituitary tumor vessels but also in parenchymal cells of the pituitary adenoma. Conclusion: Various kinds of cells can differentiate from the stem cells in GH-secreting adenomas, which may result in plurihormonality and pluripotentiality of adenomas.

Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

DLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly down-regulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.