Machine Learning May Be An Alternative To BIPSS In The Differential Diagnosis Of ACTH-Dependent Cushing's Syndrome.

OBJECTIVE: This study aimed to develop machine learning (ML) algorithms for the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) based on biochemical and radiological features. METHODS: Logistic regression algorithms were used for ML, and the area under the receiver operating characteristics curve (AUROC) was used to measure performance. We used Shapley Contributed Comments (SHAP) values, which help explain the results of the ML models to identify the meaning of each feature and facilitate interpretation. RESULTS: A total of 106 patients, 80 with Cushing's disease (CD) and 26 with ectopic ACTH syndrome (EAS), were enrolled in the study. The ML task was created to classify patients with ACTH-dependent CS into CD and EAS. The average AUROC value obtained in the cross-validation of the logistic regression model created for the classification task was 0.850. The diagnostic accuracy of the algorithm was 86%. The SHAP values indicated that the most important determinants for the model were the 2-day 2-mg dexamethasone suppression test, the > 50% suppression in the 8-mg high-dose dexamethasone test, late-night salivary cortisol, and the diameter of the pituitary adenoma. We have also made our algorithm available to all clinicians via a user-friendly interface. CONCLUSION: ML algorithms have the potential to serve as an alternative decision support tool to invasive procedures in the differential diagnosis of ACTH-dependent CS.

European Medical Students' Views on Neurosurgery, with Emphasis on South-East Europe (Albania, Greece, Serbia, and Turkey).

BACKGROUND: Neurosurgery, an intricate and dynamic surgical specialty, faces challenges in attracting medical graduates. Despite its potential appeal, a decreasing trend in medical students opting for surgical specialties, including neurosurgery, is noted. This study aims to assess European medical students' perceptions of neurosurgery, focusing on South-East Europe, and address concerns about the declining interest in this field. METHODS: A comprehensive digital survey, comprising 33 questions, was distributed to 1115 medical students across 17 European countries. The survey, conducted over 9 months, gathered responses through European neurosurgical societies, the European Association of Neurosurgical Societies (EANS), and university channels. Statistical analysis utilized IBM Statistical Package for the Social Sciences, presenting data through counts, proportions, and χ2 tests. RESULTS: The study reveals that, over the survey period, 834 medical students completed the questionnaire, with a predominant representation from South-East Europe. While 43.2% of participants were considering a surgical career, neurosurgery emerged as the most preferred specialty (26.37%). Despite this interest, 80.2% reported insufficient knowledge about pursuing a neurosurgical career, with limited exposure during medical education. Concerns about work-life balance, heavy workload, and hierarchical structures were prominent among respondents. CONCLUSIONS: The findings underscore the need for targeted interventions to address concerns influencing medical students' decisions regarding neurosurgery. Improving neurosurgical education, dispelling misconceptions, and creating a supportive work environment are crucial steps to attract and retain diverse talented individuals in neurosurgery. These efforts will be vital in narrowing the gap between the demand for neurosurgeons and the number of medical graduates entering the field, ensuring a sustainable future for this essential surgical specialty.

Changing presentation of acromegaly in half a century: a single-center experience.

OBJECTIVE: Investigate the changes in the characteristics of presentation, in patients with acromegaly over a period of approximately half a century. METHODS: The medical records of patients diagnosed with acromegaly between 1980 and 2023 were retrospectively reviewed. The collected data were examined to assess any changes observed over the years and a comparison was made between the characteristics of patients diagnosed in the last decade and those diagnosed in previous years. RESULTS: A total of 570 patients were included in the study, 210 (37%) patients were diagnosed in the last decade. Patients diagnosed before 2014 had longer symptom duration before diagnosis, advanced age, larger pituitary adenomas, higher incidence of cavernous sinus invasion, and higher GH and IGF-1 levels than those diagnosed last decade (p < 0.05, for all). Furthermore, the patients diagnosed before 2014 had a lower rate of surgical remission (p < 0.001), and a higher prevalence of comorbidities such as diabetes, hypertension, colon polyps, and thyroid cancer at the time of diagnosis (p < 0.05, for all). CONCLUSION: There may be a trend for earlier detection of patients with acromegaly.

The Combination of Dopamine Agonist Treatment and Surgery May Be the Best Option in Challenging Prolactinoma Cases: A Single-Centre Experience.

OBJECTIVE: To investigate the initial and long-term remission rates, factors related to remission, secondary treatments, and outcomes for patients with prolactinoma who underwent endoscopic transsphenoidal surgery (ETSS). METHODS: The medical files of the 45 prolactinoma patients who underwent ETSS between 2015 and 2022 were retrospectively reviewed. Relevant demographic and clinical data were obtained. RESULTS: Twenty-one (46.7%) patients were female. The median age of patients at ETSS was 35 (interquartile range, 22.5-50) years. The median clinical follow-up of patients was 28 (interquartile range 12-44) months. The initial surgical remission rate was 60%. Recurrence was detected in 7 patients (25.9%). Postoperative dopamine agonists were used in 25 patients, radiosurgery in 2, and second ETSS in 4 patients. After these secondary treatments, the long-term biochemical remission rate was 91.1%. The factors associated with failure in surgical remission are: male gender, older age, higher tumor size, advanced Knosp and Hardy stage, and elevated prolactin level at diagnosis. A prolactin level of <19 ng/mL in the first postoperative week predicted surgical remission with a sensitivity of 77.8% and a specificity of 70.6% in patients who received preoperative dopamine agonist treatment. CONCLUSIONS: In macro adenomas and/or giant adenomas with cavernous sinus invasion, and significant suprasellar extension, which constitutes the difficult part of prolactinoma treatment, neither surgery nor medical treatment alone may be effective enough. Both treatment modalities should be carried out together by a team of neurosurgery and endocrinology in the management of these patients.

Gender differences in work-life balance of European neurosurgeons.

Introduction: Neurosurgery is one of the most demanding medical specialties. For neurosurgeons, balancing professional activity with personal life can be challenging. Research question: To evaluate gender differences in contribution of neurosurgeons in the household and child-rearing, as well as their impact on personal life and career. Material and methods: An anonymous, electronic, 59-item web-based survey was administered to National Neurosurgical Societies of Europe, and European Member Societies of the European Association of Neurosurgical Societies (June-October 2021). Results: A total of 205 European neurosurgeons (87 females and 118 males, mean age 40.7) are included in our survey. In neurosurgery, females are significantly more likely to be alone (37.9%), while males are significantly more likely to have children (66.9%). In terms of household efforts, females spend more time than males on the same tasks. Most participants (71.2%) view gender issues as a disadvantage in career pursuing. Women feel less accepted (54.3%) and having fewer opportunities (58.6%), while men believe that pregnancy/child-rearing (65.8%) and having many roles (51.3%) are the main obstacles. Both genders (77.6%) favor more convenient working conditions for young parents.Discussion and Conclusion. In our study we found that, women neurosurgeons take more responsibilities at home, especially in the child-rearing years. Female neurosurgeons are more likely to live alone or stay childless more often compared to their male colleagues. Supportive facilities, flexible programs, universal life policies and presumably curbing of the social stereotypes are of importance to overcome gender inequities that women are still facing in neurosurgery.

Machine learning as a clinical decision support tool for patients with acromegaly.

OBJECTIVE: To develop machine learning (ML) models that predict postoperative remission, remission at last visit, and resistance to somatostatin receptor ligands (SRL) in patients with acromegaly and to determine the clinical features associated with the prognosis. METHODS: We studied outcomes using the area under the receiver operating characteristics (AUROC) values, which were reported as the performance metric. To determine the importance of each feature and easy interpretation, Shapley Additive explanations (SHAP) values, which help explain the outputs of ML models, are used. RESULTS: One-hundred fifty-two patients with acromegaly were included in the final analysis. The mean AUROC values resulting from 100 independent replications were 0.728 for postoperative 3 months remission status classification, 0.879 for remission at last visit classification, and 0.753 for SRL resistance status classification. Extreme gradient boosting model demonstrated that preoperative growth hormone (GH) level, age at operation, and preoperative tumor size were the most important predictors for early remission; resistance to SRL and preoperative tumor size represented the most important predictors of remission at last visit, and postoperative 3-month insulin-like growth factor 1 (IGF1) and GH levels (random and nadir) together with the sparsely granulated somatotroph adenoma subtype served as the most important predictors of SRL resistance. CONCLUSIONS: ML models may serve as valuable tools in the prediction of remission and SRL resistance.

Should we take precautions to avoid respiratory compromise while delaying CPAP resumption following transsfenoidal surgery? An alternative approach in a patient with severe obstructive sleep apnea: case report.

BACKGROUND: We describe a patient with severe obstructive sleep apnea scheduled for transsfenoidal surgery. Early postoperative use of continuous positive airway pressure (CPAP) was considered unsafe because increased risk of intracranial complications. METHODS: Aiming to bypass the upper airway obstruction and thus avoid CPAP, a 6-mm nasopharyngeal airway was introduced by the surgical team under endoscopic vision. In the postoperative period and during follow-up, patient and his family did not complain about apnea/hypopnea episodes and nasopharyngeal airway was tolerated comfortably. CONCLUSION: We recommend this technique as an alternative in obstructive sleep apnea patients undergoing transsfenoidal surgery.

Fibroblast Growth Factor Receptor-4 Expression in Pituitary Adenomas is Associated with Aggressive Tumor Features.

PURPOSE: To investigate the relationship of Fibroblast Growth Factor Receptor-4 (FGFR-4) expression with radiologic, pathologic, and clinical parameters in pituitary adenomas. METHODS: Among 307 patients who underwent pituitary surgery for a pituitary adenoma between 2000 and 2015, we included 161 patients (53 gonadotroph, 26 corticotroph, 25 null cell, 22 lactotroph, 13 somatotroph, 8 adenomas with unusual combination, 7 Pit-1 positive adenomas, and 7 lactosomatotroph) based on availability of pathology specimens. Patients' radiologic, pathologic, and clinical parameters were determined. FGFR-4 immunostaining was evaluated using a semi-quantitative histologic score (H-score). RESULTS: The mean follow-up period was 61 (IQR=32-84) months. The median H-scores for FGFR-4 were higher in patients without remission, those with residual lesion, and T2-hyperintense adenoma (p<0.05). Ki-67 level was higher in patients without remission compared to those in remission (p<0.05). The mean Ki-67 levels did not differ between patients with and without residual lesion or T2-hyperintense tumor (p>0.05). There was no significant difference (p>0.05) when the H-score and Ki-67 levels were assessed in terms of sex, sellar-dural invasion, Knosp and a grading system for superior, inferior, parasellar, anterior and posterior tumor extension Classification, tumor function or presence of poor subtype. Adenomas with Ki-67 expression ≥3% had higher FGFR4 expression levels than those with <3% expression (p=0.002). There was a weak positive correlation between H-score and Ki-67 (p=0.011; r=0.201). CONCLUSIONS: Higher levels of FGFR-4 in pituitary adenomas could be use a marker for more aggressive tumor behavior.

Association between ß arrestin 2 and filamin A gene variations with medical treatment response in acromegaly patients.

BACKGROUND: Acromegaly is a disease that occurs as a result of excessive growth hormone caused by pituitary adenomas. Some acromegaly patients show resistance to somatostatin analog (SSA) treatment. Filamin-A (FLNA) and ß-arrestins are thought to play a role in the response to SSAs. We aimed to investigate the relationship between FLNA-rs782079491 and ß-arrestin-2-rs34230287 single-nucleotide polymorphisms and disease risk, as well as treatment response in patients with acromegaly in the Turkish population. METHODS: The genotypes of 110 acromegaly patients and 99 controls were determined by realtime PCR. The genotype distributions were compared with clinical data on the disease. RESULTS: There was no association between the ß-arrestin-2 gene polymorphism and the response to SSA treatment in acromegaly patients. For responder patients to SSAs, the ß-arrestin-2-rs34230287 CT+TT genotype was associated with higher microadenoma as compared with the CC genotype (p = 0.017). The FLNA polymorphism was not observed in the study group. CONCLUSIONS: We showed that there was no association between the polymorphic genotypes of FLNA and ß-arrestin-2 genes with acromegaly disease and SSAs response in the Turkish population. However, there was a relationship between ß-arrestin-2 and some of the clinical characteristics. Furthermore, the CC genotype and the C allele are risk factors associated with tumor growth rate in acromegaly patients.

T2-weighted magnetic resonance imaging as a novel predictor of surgical remission in newly diagnosed pituitary macroadenomas presenting as acromegaly.

BACKGROUND: Any preoperative diagnostic assessment that can predict the success of the operation in acromegaly will provide a positive impact on overall remission rates. The aim of this study is to reveal whether the signal intensity in T2-weighted Magnetic Resonance Imaging can predict postoperative results in acromegaly patients with macroadenoma. METHODS: We analyzed our surgical results in regard to T2-weighted images in newly diagnosed consecutive 124 patients with acromegaly, operated between 2014 and 2019. The T2-intensity of the pure somatotroph macroadenomas was correlated with the clinical, radiological, surgical and histopathological characteristics of the acromegaly patients. RESULTS: We found a predominance of T2-hyperintensity in our series (45%) and the T2-hypointense pure somatotroph adenomas were detected in only 34% of our patients. Total resection was performed in 72% of newly diagnosed acromegaly patients in this series. Accordingly, total resection was achieved in 69% of the T2-hyperintense group, 77% of the T2-hypointense group and 69% of the T2-isointense group. The surgical remission rates for the T2-hyper-, hypo- and isointense groups were 54.5%, 80.7%, and 68.7%, respectively. The surgical remission rate in the T2-hyperintense group was significantly lower than those of hypo- and isointense groups in newly diagnosed acromegaly patients. CONCLUSIONS: This study demonstrates a close relationship between the T2 signal intensity and the surgical remission rates in acromegaly patients with macroadenoma. Preoperative T2-intensity images may predict the probability of post-surgical remission in patients with newly diagnosed acromegaly. Further support fort this idea comes from recent guidelines for acromegaly management in which the potential utility of using T2 intensity to optimize patient management has been emphasized.

Long term predictive ability of preoperative retinal nerve fiber layer thickness in visual prognosis after chiasmal decompression surgery.

OBJECTIVE: To investigate the relationship between preoperative retinal nerve fiber layer (RNFL) thickness and the recovery of visual field (VF) and visual acuity (VA) 1 year after surgery in chiasmal compression patients presenting with visual impairment. PATIENTS AND METHODS: Twenty-nine eyes of 16 patients with chiasmal compression and 14 eyes of 14 control subjects were enrolled. All patients undergoing chiasmal decompression surgery via a transsphenoidal approach were prospectively evaluated before and 1 year after surgery with best corrected visual acuity (BCVA, logMAR), mean deviation (MD) value with standard automated perimetry (SAP) and RNFL thickness with optical coherence tomography. Eyes with chiasmal compression were divided into two groups according to the mean preoperative RNFL thickness: ≥ 100 µm (Group 1) and < 100 µm (Group 2). The relationship between the mean preoperative RNFL thickness and visual prognosis parameters (VF, VA) was analyzed. RESULTS: The mean preoperative RNFL thickness was 115.92 ± 8.97 µm, 84.0 ± 8.85 µm, and 114.21 ± 7.75 µm in Group 1 (n = 15 eyes), Group 2 (n = 14 eyes) and the control group (n = 14 eyes), respectively. The mean preoperative BCVA was 0.15 ± 0.3 in Group 1, and 0.41 ± 0.39 in Group 2. The mean BCVA increased to 0.03 ± 0.1 in Group 1 in the postoperative period but did not change in Group 2. MD value was - 6.10 ± 5.54 in the preoperative period and - 2.59 ± 2.23 in the postoperative period for Group 1 (p = 0.014), while it was - 18.97 ± 4.14 in the preoperative period and - 18.57 ± 4.51 in the postoperative period in Group 2 (p = 0.24). CONCLUSIONS: This study suggests that lower mean preoperative RNFL thickness was associated with poorer long-term visual prognosis. Preoperative RNFL thickness measurements may be helpful in predicting the recovery of VF and VA after decompression surgery in patients with chiasmal lesion presenting with visual impairment.

European women in neurosurgery: I - A chronology of trailblazers.

Neurosurgery as a distinct speciality has been around for 100 years. Some of the earliest women neurosurgeons were European, emerging from the 1920's onwards. Here we detail the rise of women in neurosurgery across Europe with a decade by decade account of big events and firsts across the continent. The emerging themes are seen in stories of pioneers with enormous resilience, camaraderie, trailblazing and triumphing in a system with great obstacles and challenges. Our journey through this chronology brings us to the modern day, where most European countries have or have had a woman neurosurgeon and the future for women in neurosurgery in the continent is very bright.

European women in neurosurgery: II - Historical characters and living legends.

A collaborative global working group of women neurosurgeons in multiple countries at different stages of their neurosurgical careers undertook the task of researching the history of European women in neurosurgery. While doing so, we happened upon many remarkable female neurosurgeons who overcame great adversity, made tremendous contributions to society and institutional neurosurgery, and displayed numerous talents beyond the operating room. In the first part of this paper, we recounted a chronology of female neurosurgeons in Europe, highlighting the most remarkable achievements of women in every decade, from the 1920's to 2020. In this paper, we honor fascinating women in European neurosurgery, both historical characters and living legends. These women have overcome great adversity and have also excelled in a huge variety of pursuits. While some were themselves refugees, we also have uncovered noteworthy examples of women who immersed themselves in humanitarian missions and who tried to better the world through political action. There are stories of women beating the odds, taking on biased institutions and proving their worth, in spite of the prevailing system. Most inspirational, we have discovered through our comprehensive research on the history of women in European neurosurgery that the future is increasingly female.

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients.

INTRODUCTION: Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. MATERIAL AND METHODS: Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. RESULTS: In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. CONCLUSION: The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas.

PURPOSE: To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor ß (ERß), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA). METHODS: Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry. RESULTS: There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERß gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERß protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERß, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04). CONCLUSIONS: GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERß, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

A follow-up study on outcomes of endoscopic transsphenoidal approach for acromegaly.

OBJECTIVE: A thorough follow-up study in which the same clinic presents the change in the surgical outcomes of acromegaly over the years, is still lacking in the endoscopic era. In this study, we intended to evaluate the clinical characteristics, radiological features, surgical and late remission rates of newly diagnosed acromegaly patients treated in our clinic between 2014 and 2019 in order to delineate the surgical remission status according to radiological, microscopic, and hormonal features. As a follow-up to our initial report, we also aimed to display the change of surgical remission rates over time in a tertiary center. METHODS: A total of newly diagnosed 106 patients with acromegaly, who underwent endoscopic endonasal trans-sphenoidal approach (EETSA) in the last five years were retrospectively analyzed and presented in this study. Medical records were reviewed in clinical, biochemical, pathological, and radiological aspects to assess the relationship of preoperative patient characteristics with surgical remissions. RESULTS: The percentages of the giant pituitary adenomas (≥4 cm), adenomas with suprasellar extension and adenomas with surgically proven invasion of the cavernous sinus in the present series were 13%, 34%, and 20%, respectively. Gross total resection was achieved in 80% of the patients. Surgical remission and late remission rates were 66% and 86%, respectively. Nine (9.4%) patients in our current report had postoperative transient diabetes insipidus. The mean follow-up period in this series was 36.1 ±â€¯18.1 (range 12-59) months. CONCLUSION: The presented surgical results are considerably better than our published initial series of acromegaly patients operated in the same clinic between 2007 and 2014. The improvement in surgical remission rate support a positive surgical volume - remission rate relationship for acromegaly in the era of endoscopic endonasal skull base approaches. One possible factor for better results may be the increasing surgical experience in EETSA, which follows a trend toward gradual improvement of long-term late remissions via a multidisciplinary approach.

A Novel Expression Profile of Cell Cycle and DNA Repair Proteins in Nonfunctioning Pituitary Adenomas.

The molecular mechanisms underlying the formation of nonfunctioning pituitary adenomas (NFAs) are largely unknown. In this study, we aimed to understand the relationship between NFAs and functional pituitary adenomas and the possible role of proteins involved in cell cycle, senescence, and DNA damage control mechanisms in the etiology of NFA. We analyzed pATM-S1981, pRb-S608, Rb, pE2F1-S364, p16, E2F1, p73, cyclin D1, and CHEK2 protein expression (in a group of 20 patients with acromegaly, 18 patients with Cushing's disease (CD), and 29 NFA patients) by immunohistochemistry and their relevant mRNA expression by qRT-PCR (in a group of 7 patients with acromegaly, 7 patients with CD, and 7 NFA patients). The clinical and histopathological results on the patients were statistically evaluated. pE2F1-S364 protein expression in the CD group was significantly lower than that in the NFA and acromegaly groups (p = 0.025, p = 0.034, respectively). However, the expression of the p16 protein was lower than in the NFA group than in the CD and acromegaly groups (p = 0.030, p = 0.033, respectively), and E2F1 protein expression was significantly higher in the NFA group than in the CD group (p = 0.025). p73 protein expression in patients with acromegaly was significantly higher (p = 0.031) than that in the CD group. CHEK2 mRNA expression in the CD group was significantly higher than that in the acromegaly group (p = 0.012). The selective and tumor-specific associations between E2F1, pE2F1-S364, CHEK2, and p73 mRNA and protein levels indicate their involvement in pituitary adenoma formation in NFA, CD, and acromegaly patients.

Clinicopathologic Characteristics and Surgical Treatment of Plurihormonal Pituitary Adenomas.

OBJECTIVE: Plurihormonal pituitary adenomas (PPAs) have recently been divided into 2 subtypes: pituitary specific transcription factor 1-positive plurihormonal pituitary adenomas (PIT-1+ PPAs) and plurihormonal adenomas with unusual immunohistochemical combinations (PAwUIC). The purpose of this study was to review patients with PPAs, elucidate their clinicopathologic characteristics, and present the surgical results. METHODS: Records were analyzed for 665 patients who underwent endoscopic endonasal transsphenoidal surgery for pituitary adenomas between 2007 and 2018. Data were reviewed for 27 patients who met the definition of PPAs and delineated regarding clinical, radiologic, pathologic features, and surgical outcomes. RESULTS: Of the 27 patients, 18 had PAwUIC, and 9 patients were diagnosed with PIT-1+ PPAs. Twenty-four patients (88.8%) had macroadenomas, including 6 giant adenomas (≥4 cm) (22.2%). Cavernous sinus invasion was found in 12 patients (44.4%). Pathologic examinations showed high aggressivity in nearly half of the patients. Most patients with PAwUIC (77.8%) had features of nonfunctioning pituitary adenomas, and only 4 had features of hormone-secreting pituitary adenomas. Gross total resection rates were 57.1% for PAwUIC and 77.8% for PIT-1+ PPAs. The remission rate for hormone-secreting pituitary adenomas was 100% in this case series. Mean follow-up was 74.4 ± 33 months (range, 6-121 months) for overall groups. CONCLUSIONS: To our knowledge, this is the first study to describe the clinicopathologic features of newly classified PPAs, which are characterized by aggressive behavior with higher values of percentage of cavernous sinus invasion. Relevant pathologic diagnosis of PPAs is crucial for appropriate management and follow-up.