The Role of Programmed Cell Death Ligand 1 Expression in Pituitary Tumours: Lessons from the Current Literature.

BACKGROUND: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. SUMMARY: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. KEY MESSAGES: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours.

Pituitary surgery and COVID.

An effect of the COVID-19 pandemic was the disruption of healthcare systems, especially surgical services provided to the community. Pituitary surgery was especially impacted, given the majority of cases were deemed non-urgent with very few exceptions, and the high risk of viral transmission conferred by the endoscopic endonasal transsphenoidal approach. Patients suffering from pituitary lesions with resultant endocrinopathy or visual symptoms saw their treatment delayed or altered, which had implications on their outcomes and care. This disruption extended to surgical training and the usual functioning of academic units, necessitating changes to curricula and implementation of novel methods of progressing surgical education. This review will explore the effect of the COVID pandemic on pituitary surgery, the experiences of various surgeons as well as the adaptations implemented on the frontlines. The lessons learned from the experience of the pandemic may assist specialists in gleaning insights regarding the care of patients in the future.

Diagnostic characteristics and management outcome in patients with acromegaly: A 15-year experience at a tertiary care hospital in Pakistan.

OBJECTIVE: To assess the diagnostic features of acromegaly, and analyse its management outcomes over a 15-year period in a tertiary care setting. METHODS: The descriptive, cohort, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of adult patients of either gender diagnosed with acromegaly based on biochemical and radiological evidence between January 2005 and December 2019. Data was retrieved from the medical records. Data was analysed using SPSS 19. RESULTS: Of the 84 subjects, 54(64.3%) were males and 30(35.7%) were female. The overall mean age was 38.69±13.52 years. The patients presented 5.43±4.3 years after the onset of symptoms, with somatic growth features, such as enlarged hands and feet which was the most common complaint 81(96.4%). Of all the patients, 73(86.9%) underwent trans-sphenoidal surgery for the removal of the pituitary adenoma, while 11(13.1%) opted out of the surgical option. Further, 9(12.3%) patients showed biochemical and radiological remission 6 months post-surgery. Out of the remaining 64(87.7%) patients, 38(59.4%) received radiosurgery or radiotherapy, 15(23.4%) underwent repeat trans-sphenoidal surgery, and 11(17.2%) chose medical treatment. CONCLUSIONS: Majority of patients failed to achieve remission after trans-sphenoidal surgery, which is the first line of treatment. Radiotherapy/repeat surgery was generally the options taken by those with persistent disease.

The Role of Optical Coherence Tomography Angiography in the Evaluation of Chiasmal and Retrochiasmal Compression.

The compression of the visual pathway is associated with structural retinal changes due to retrograde neurodegeneration. It was brought into question whether visual pathway compression is also associated with retinal vascular changes as assessed by optical coherence tomography angiography (OCT-A). The objective of this review is to discuss the role of OCT-A in the evaluation of patients with tumours of the sellar, parasellar, and retrochiasmal regions. The reported OCT-A parameters were the vessel densities of radial peripapillary capillary network, macular superficial vascular plexus and/or macular deep vascular complex. Optic nerve and macular OCT-A parameters were impaired in patients versus controls. These changes were associated with altered structural OCT parameters and visual field defects. OCT-A could be considered a marker of neurodegeneration in addition to structural OCT, and it has the potential to become a visual prognostic tool in patients with visual pathway compression.

UK practice on incidentally detected non-functioning pituitary microadenomas: analysis of two national surveys during a 12-year interval.

PURPOSE: The optimal management approach for presumed non-functioning pituitary microadenomas (microNFPAs) remains unclear. Our aim was to capture current UK practice and identify changes with time. METHODS: Two online surveys investigating clinicians' approaches were performed in 2009-2010 and 2021-2022 (advertised through Society for Endocrinology UK). RESULTS: 150 and 214 clinicians participated in the 2021 and 2009 survey, respectively (response rates 31.2% and 35.4%, respectively). At baseline, 2021 survey respondents were more likely to measure IGF-1 (96.0% vs 74.1%, p < 0.001) and morning cortisol (87.9% vs 62.6%, p < 0.001), and less likely GH (26.2% vs 42.6% p = 0.002), 24 h urine free cortisol (3.4% vs 23.2%, p < 0.0001) or dynamically assess adrenal reserve (11.4% vs 30.4%, p < 0.001). 47.2% of clinicians in 2021 would reassess pituitary function annually until discharge (in absence of tumour growth/symptoms). The 2021 survey respondents were more likely to stop imaging at or before 3 years (81.7% vs 44.3%, p < 0.001) and at or before 5 years (86.6.% vs 72.9%, p = 0.002), whilst 2009 survey respondents were more likely to continue imaging beyond 5 years (24% vs 7%, p < 0.001). Responses on imaging frequency/intervals showed notable variability in both surveys. CONCLUSIONS: Diagnostic and management approaches for microNFPAs have evolved in the UK. Biochemical investigations are performed in accord with consensus guidelines, though many clinicians perform annual biochemical surveillance without tumour growth/symptoms. A small number of clinicians request imaging beyond 5 years, but the frequency of imaging intervals until discharge remains variable. Robust evidence on the long-term natural history of microNFPAs is necessary to unify clinician approach.

Tumour microenvironment and pituitary tumour behaviour.

The pituitary tumour microenvironment encompasses a spectrum of non-tumoural cells, such as immune, stromal or endothelial cells, as well as enzymes and signalling peptides like cytokines, chemokines and growth factors, which surround the tumour cells and may influence pituitary tumour behaviour and tumourigenic mechanisms. Recently, there has been intensive research activity in this field describing various pituitary tumour-infiltrating immune and stromal cell subpopulations, and immune- and microenvironment-related pathways. Key changes in oncological therapeutic avenues resulted in the recognition of pituitary as a target of adverse events for patients treated with immune checkpoint regulators. However, these phenomena can be turned into therapeutic advantage in severe cases of pituitary tumours. Therefore, unravelling the pituitary tumour microenvironment will allow a better understanding of the biology and behaviour of pituitary tumours and may provide further developments in terms of diagnosis and management of patients with aggressively growing or recurrent pituitary tumours.

A comparison of macular ganglion cell and retinal nerve fibre layer optical coherence tomographic parameters as predictors of visual outcomes of surgery for pituitary tumours.

PURPOSE: The prognostic value of optical coherence tomography (OCT) of the macular ganglion cell layer (mGGL) versus peripapillary retinal nerve fibre layers (pRNFL) following chiasmal decompression is unclear. This study is the largest comparison of the two parameters to date and aims to clarify how their performance as covariates compare in predictive models of long-term visual outcomes following pituitary or parasellar tumour surgical resection. METHODS: This was a prospective, two-year, longitudinal cohort study in a single centre tertiary hospital setting. Participants with MRI evidence of pituitary or parasellar tumour compression of the optic chiasm who underwent surgical decompression, were enrolled. Associations between pre-operative OCT parameters and long-term visual outcomes were assessed using multivariable generalised linear mixed models and an age matched normative database. RESULTS: Final analysis included 216 eyes of 108 participants with a mean age (standard deviation) of 51.6 (17.04) years, of whom 58 (49%) were female. The superior inner mGCL was the best predictor of long-term visual field recovery, with an area under the curve of 0.90, a sensitivity of 80%, specificity of 88%, positive predictive value of 86%, and negative predictive value of 83%. CONCLUSION: mGCL performed better in predicting long-term visual field recovery post-pituitary or parasellar surgical resection. The superior inner mGCL was the best specific measure which may provide clinical utility in pre-operative counselling. In this study we clarify previously variable comparisons of mGCL and pRNFL parameters in post-operative predictive modelling.

Adamantinomatous craniopharyngioma as a model to understand paracrine and senescence-induced tumourigenesis.

Cellular senescence is a process that can prevent tumour development in a cell autonomous manner by imposing a stable cell cycle arrest after oncogene activation. Paradoxically, senescence can also promote tumour growth cell non-autonomously by creating a permissive tumour microenvironment that fuels tumour initiation, progression to malignancy and metastasis. In a pituitary tumour known as adamantinomatous craniopharyngioma (ACP), cells that carry oncogenic ß-catenin mutations and overactivate the WNT signalling pathway form cell clusters that become senescent and activate a senescence-associated secretory phenotype (SASP). Research in mouse models of ACP has provided insights into the function of the senescent cell clusters and revealed a critical role for SASP-mediated activities in paracrine tumour initiation. In this review, we first discuss this research on ACP and subsequently explore the theme of paracrine tumourigenesis in other tumour models available in the literature. Evidence is accumulating supporting the notion that paracrine signalling brought about by senescent cells may underlie tumourigenesis across different tumours and cancer models.

The 'muscle wonton' repair - A case series of internal carotid artery injuries at a single Centre during its 10-year experience in endoscopic transsphenoidal pituitary surgery.

INTRODUCTION: Although rare, injury to the internal carotid artery (ICA) during pituitary surgery may result in serious morbidity such as stroke or death. This case series explores a single centre's incidence and outcomes of ICA injury during endoscopic transsphenoidal pituitary surgery, discusses the current management options, and introduces the 'muscle wonton' (morcellised muscle wrapped in a single sheet of Surgicel®) as being a viable repair option. METHODS: All patients undergoing pituitary operations from January 2010 to December 2019 at the Queen Elizabeth Hospital, Birmingham, UK were included. Primary outcome was number of internal carotid artery injuries during pituitary surgery. Secondary outcome measures included pre-operative (demographic, risk factors such as previous radiotherapy, number of previous operations, imaging available), operative (intra-operative image guidance, intra-operative doppler ultrasound, which side ICA was damaged, repair technique) and post-operative result (death, cranial nerve VI palsy, or stroke). RESULTS: 7 out of 893 patients (0.8%) were identified as having an ICA injury. Four of the injuries were left sided. Average age was 54 years old, five were male. In four of the ICA injuries intra-operative navigation imaging was used, and a further two concurrently used ultrasound doppler. Three of the seven cases resulted in permanent morbidity (stroke). There were no other consistent demographic, pre-operative, operative, or post-operative similarities. The two patients with muscle wonton repair suffered no permanent serious complication of ICA injury (i.e. death, abducens nerve palsy, stroke). DISCUSSION: Our findings resemble the current literature, with left sided ICA injury being more common. Different methods for repairing ICA injury exist, however morcellised muscle patches have shown significant promise in animal models, and the perforated Surgicel® helps create an easy delivery method. The muscle wonton is a viable surgical option for repairing ICA injuries during pituitary surgery.

Paediatric patients with Cushing disease and negative pituitary MRI have a higher risk of nonremission after transsphenoidal surgery.

OBJECTIVE: Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD. PATIENTS: Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included. MEASUREMENTS: Clinical, imaging and biochemical data were analysed. RESULTS: One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1-6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7-5.8). CONCLUSIONS: Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings.

The electrophysiological tests in the early detection of the visual pathway dysfunction in patients with microadenoma.

PURPOSE: To evaluate the validity of electrophysiological tests in the early diagnosis of a ganglion cells and/or optic nerve dysfunction in patients with pituitary microadenoma. METHODS: 66 eyes, from 33 patients with microadenoma with no evidence of the optic chiasm compression in magnetic resonance imaging (MRI) and the visual impairment in the routine ophthalmological examination, standard static perimetry (24-2 white on white) and optical coherence tomography (HD-OCT), were analysed. The pattern electroretinogram (PERG), standard pattern visual evoked potentials (PVEPs) and multichannel visual evoked potentials (mVEPs) (ISCEV standards) were performed. The results obtained from the electrophysiological tests were compared to the same number of age-matched healthy controls. RESULTS: Statistically significant differences between the patients with microadenoma and healthy controls were detected in all electrophysiological tests (p < 0.001). The most frequent abnormalities were observed in mVEPs (25/33 patients, 75.8%; 43/66 eyes, 65.2%). The most frequent features registered in this test were: (1°4')-an increase in the P100wave latency from uncrossed fibres (13/33 patients, 39.39%; 21/66 eyes, 31.8%) and (0°16')-an amplitude reduction of this wave from the crossed fibres (11/33 patients, 33.33%; 19/66 eyes, 28.8%). The changes in PVEPs (15/33 patients, 45.5%; 25/66 eyes, 37.9%) and PERG (10/33 patients, 30.3%; 15/66 eyes, 22.7%) were also registered. Of all the tests and parameters analysed in the study, the greatest diagnostic value in detecting the visual pathway dysfunction in this group of patients was the amplitude of P100 wave from the crossed fibres of the mVEPs (1°4') with a sensitivity of 60.6% and a specificity of 93.8%. These parameters suggest that this type of dysfunction is downstream to the chiasm and can also indicate the visual pathway dysfunction severity. CONCLUSIONS: In patients with microadenoma, the abnormalities in the electrophysiological tests are registered even without clinical evidence of visual impairment from the routine ophthalmological examination, SAP, OCT and chiasmal compression in MRI. The mVEPs have the most significant role in the diagnosis of the visual pathway dysfunction in patients with microadenoma.

Predictive model of surgical remission in acromegaly: age, presurgical GH levels and Knosp grade as the best predictors of surgical remission.

PURPOSE: To identify presurgical clinical, hormonal and radiological variables associated with surgical remission in acromegaly and develop a predictive model for surgical remission. METHODS: Ambispective study of acromegaly surgical patients followed in two Spanish tertiary hospitals. Patients operated by the same neurosurgeon by endonasal endoscopic transsphenoidal approach (n = 49) were included to develop the predictive model, and patients operated by other neurosurgeons (n = 37) were used for external validation of the predictive model. The predictive model was developed with a multivariate logistic regression model based on the 2000 criteria. RESULTS: 86 acromegalic patients were included. 49 patients, 83.7% with macroadenomas and 32.7% with Knosp grade > 2, were included for the development of the predictive model. The overall rate of surgical remission with the 2000 criteria was 73.5% and 51.0% with the 2010 criteria. Using the 2000 criteria, variables associated with surgical remission were: older age (OR = 1.1, p = 0.001), lower basal presurgical GH levels (OR = 0.9, p = 0.003), Knosp 0-2 (OR = 34.1, p < 0.0001) and lower maximum pituitary adenoma diameter (OR = 0.9, p = 0.019). The model with the best diagnostic accuracy to predict surgical remission combined age, Knosp 0-2 and presurgical GH levels (AIC = 29.7, AUC = 0.95) with a sensitivity of 93.8% and a specificity of 75.0%. The estimated loss of prediction with the external validation (n = 37) was 4.2%. CONCLUSION: The predictive model with the best diagnosis accuracy for surgical remission combined age, Knosp 0-2 and presurgical GH levels, with a sensitivity of 93.8% and a specificity of 75.0%. This model could be very useful to select candidates to preoperative medical treatment and planning the follow-up.

Aggressive pituitary adenoma in the context of Lynch syndrome: a case report and literature review on this rare coincidence.

PURPOSE: Lynch Syndrome (LS) is a cancer-predisposing condition resulting from hereditary mutation of DNA mismatch repair genes. Gastrointestinal, urogenital, and endometrial carcinomas are well-known to predominantly occur in LS patients. In contrast, there are only few reports on brain tumours in the context of LS and to date intracranial tumour manifestation appear to be rather coincidental. METHODS: We present the case of a 56-year-old female developing aggressive lactotroph pituitary adenoma following a history of multiple Lynch-associated malignomas and having a confirmed MSH2 mutation. Furthermore, we performed a literature review via PubMed using the search terms 'Lynch Syndrome', 'HNPCC', 'MMR mutation' combined with 'intracranial tumour', 'sellar tumour', 'pituitary adenoma', or 'pituitary carcinoma', focusing on other reported cases and treatment regimens. RESULTS: A handful of studies have indicated an increased frequency of brain tumours in the context of LS, predominantly glioblastoma and less frequently low-grade glioma or other brain tumours. Based on our literature review, we summarized the known instances of pituitary adenoma in LS patients, including the present case. Furthermore, we reviewed the common recommendation of using temozolomide (TMZ) for treatment of aggressive pituitary adenoma or carcinoma and found strong indication that it might be insufficient in LS patients, while PD-1 blockade could be a promising treatment option. CONCLUSIONS: Combined with our case, there is a growing body of evidence that intracranial tumours and in particular those of the sellar region might be more prevalent in LS patients than previously assumed, due to their genetic profile substantially affecting viability and efficacy of treatment options. Clinical signs of aggressive tumour growth in combination with irresponsiveness to standard treatment in case of recurrence should lead to further diagnostic measures, because revelation of germline MMR mutations would call for an extended screening for other neoplastic manifestations and would markedly influence further treatment.

Meta-analysis on the effect of pituitary adenoma resection on pituitary function.

OBJECTIVE: A meta-analysis was conducted on the effect of pituitary adenoma resection on pituitary function. METHODS: The Cochrane Library, Ovid, PubMed, the Excerpta Medica Database (EMBASE), and the Chinese Biomedical Literature Databases (CBM) were searched to find trials about the evaluation of pituitary target glands before and after pituitary adenoma resection. The databases were searched from the earliest available trials until the end of September 2019. Based on the inclusion and exclusion criteria, two researchers independently selected literature, extracted data, and evaluated the quality of the studies, and then used Revman 5.2 software to conduct a meta-analysis. RESULTS: Eleven clinical trials were included, with a total of 3,237 subjects. Meta-analysis showed that the number of patients with hypofunction of the thyroid and gonadal axes substantially decreased after pituitary tumour resection, and that the difference was statistically significant: odds ratio (OR) = 1.72 [95% confidence interval (CI), 1.18-2.52; P = 0.005] and OR = 2.06 (95% CI, 1.42-3.00; P = 0.0002). The number of patients with a poor total suprarenal gland axis after pituitary tumour resection did not change significantly compared to the number found before the operation; the difference was not statistically significant: OR = 1.04 (95% CI, 0.72-1.48; P = 0.85). However, the number of patients who had adrenal axis dysfunction both before and after the operation was significantly reduced, and the difference was statistically significant: OR = 1.46 (95% CI, 1.21-1.78; P = 0.0001). CONCLUSION: The function of the thyroid and gonadal axes of pituitary gland tumour patients can be improved, to some extent, after pituitary tumour resection. Patients with pituitary tumours who have hypofunction of the adrenal axis can recover effectively after tumour resection.

A practical algorithm to predict postsurgical recurrence and progression of pituitary neuroendocrine tumours (PitNET)s.

OBJECTIVE: Pituitary neuroendocrine tumours (PitNET)s can be aggressive, thus presenting local invasion, postsurgical recurrence and/or resistance to treatment, responsible for significant morbidity. The study aimed at identifying prognostic factors of postsurgical outcome using data-driven classification of patients. DESIGN: Retrospective observational study. METHODS: Clinicopathological and radiological data of patients with PitNET treated via endoscopic endonasal surgery were collected. Tumour recurrence/progression and progression-free survival were assessed by classification tree analysis (CTA) and Kaplan-Meier curves, respectively. Histological subtype, cavernous/sphenoid sinus invasion, mitosis, Ki-67, p53, Trouillas' grading, degree of tumour exeresis and postsurgery disease activity were also evaluated. RESULTS: A total of 1066 (466 gonadotroph, 287 somatotroph, 148 lactotroph, 157 corticotroph and 8 thyrotroph) tumours were included; 21.7% invaded the cavernous/sphenoid sinus. Based on Trouillas' classification, 64.3% were grade 1a, 14.2% 1b, 16.1% 2a, and 5.4% 2b; 18.3% had >2/10 HPF mitoses, 24.9% had Ki-67 ≥3%; 15.8% were positive for p53. Exeresis was radical in 81.2% of the cases. Median follow-up was 59.2 months. At last evaluation, 79.4% of the patients were cured; 20.6% had disease persistence, controlled by medical treatment in 18.3% of them. Disease recurrence/progression was recorded in 10.9% of the cases. CTA identified 5 distinct patient subgroups with different risk of disease recurrence/progression. Grade 2 of the Trouillas' grading, >2/10 HPF mitoses, Ki-67 ≥3%, p53 protein expression (P < .001), tumour invasion (P = .002) and ACTH-subtype (P = .003) were identified as risk factors of disease recurrence/progression. CONCLUSIONS: The combined evaluation of Trouillas' grading, proliferation indexes and immunohistochemistry appears promising in the prediction of surgical outcome in PitNET.

Temozolomide therapy for aggressive pituitary tumours - current understanding and future perspectives.

The use of temozolomide (TMZ) for the management of aggressive pituitary tumours (APT) has revolutionised clinical practice in this field with significantly improved clinical outcomes and long-term survival. Its use is now well established however a large number of patients do not respond to treatment and recurrence after cessation of TMZ is common. A number of challenges remain for clinicians such as appropriate patient selection, treatment duration and the role of combination therapy. This review will examine the use of TMZ to treat APT including mechanism of action, treatment regimen and duration; biomarkers predicting response to treatment and patient selection; and current evidence for administration of TMZ in combination with other agents.

Perioperative nasal and paranasal sinus considerations in transsphenoidal surgery for pituitary disease.

Endoscopic endonasal skull base surgery has emerged as the treatment modality of choice for a range of skull base lesions, particularly pituitary adenomas. However, navigation and manipulation of the nasal corridor and paranasal sinuses requires that surgeons are aware of effective techniques to maximize patient outcomes and avoid sinonasal morbidity postoperatively. This paper is a narrative review aimed to provide an updated and consolidated report on the perioperative management of the nasal corridor and paranasal sinuses in the setting of endoscopic skull base surgery for pituitary disease. Anatomic variants and common surgical techniques are discussed. Post-operative complications are evaluated in detail. Understanding the structural implications of the endonasal approach to the sphenoid is crucial to optimization of the surgical outcomes. We propose guidelines for perioperative management of endoscopic endonasal skull base surgery for pituitary diseases. Standardized treatment algorithms can improve patient satisfaction, and increase the comparability and the quality of reported information across research studies.

E-cadherin expression is associated with somatostatin analogue response in acromegaly.

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E-cadherin expression by immunohistochemistry in fifty-five GH-producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E-cadherin levels exhibit a worse response to SSAs. E-cadherin levels are associated with GH-producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E-cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.

Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours.

The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age (<20 years), especially in boys, and the presence of genetic predisposition have a poorer prognosis. In addition, lactotroph tumours in men differ from those in women, being larger, more often invasive, and resistant to dopamine agonists. They are also more often high-grade with a high risk of recurrence and malignancy. The expression of estrogen receptor α is lower than in women and is closely correlated to aggressiveness. Proliferation markers (Ki-67 expression: ≥3%, mitotic count n > 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management.

Long-term follow-up of a large prospective cohort of patients with nonfunctioning pituitary adenomas: The outcome of a conservative management policy.

OBJECTIVE: To assess the clinical outcome of a strategy of conservative monitoring of patients with nonfunctioning pituitary adenomas (NFPA) after pituitary surgery and in patients without surgery. DESIGN: Retrospective study of outcomes, using a clinical information system. PATIENTS: An unselected, clinical series of patients seen in a single centre between 1989 and 2015. MEASUREMENTS: Review of clinical information system data to obtain details and dates of surgery, radiotherapy, pituitary imaging and outcomes. RESULTS: We identified 190 cases of NFPA. Trans-sphenoidal surgery (TSS) had been performed as primary therapy in 132 cases (all macro-adenomas). At a mean 7.6-years follow-up after TSS without immediate pituitary radiotherapy, recurrence occurred in 10.7% of cases with no visible postoperative residual adenoma, 38.8% with intrasellar and 66.7% with extrasellar residuum. Recurrence was defined as growth of residual tumour requiring intervention. On survival analysis, at 10 years, recurrence-free survival was 75% in patients with no residual tumour and 40% with intrasellar residuum. Recurrence occurred in 12.5% of 24 patients who had received postop radiotherapy. Patients were monitored conservatively without initial surgery in 65 patients. After a mean of 5-year monitoring, only 20% required intervention during follow-up (18.5% TSS) and 30.8% died of nonpituitary causes during follow-up. CONCLUSION: This study suggests that a conservative approach may be safe and appropriate in patients with NFPA if followed up with appropriate imaging surveillance, whether postoperative or without primary surgery.