Nonfunctioning Pituitary Adenomas Research Articles

DDDR-47. TARGETING HTR2B SUPPRESSES NON-FUNCTIONING PITUITARY ADENOMA GROWTH AND SENSITIZES CABERGOLINE TREATMENT VIAINHIBITING GΑQ/PLC/PKCΓ/STAT3 AXIS

Abstract BACKGROUND Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline’s (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. METHODS We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. RESULTS Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.

PATH-01. SELLAR SOLITARY FIBROUS TUMORS WHO GRADE II AND III: MIMICS OF NON-FUNCTIONING PITUITARY ADENOMAS

Abstract Solitary fibrous tumors WHO grade II and III (SFTs II/III) are rare mesenchymal neoplasia accounting for 0.4% of primary central nervous system tumors. SFTs II/III located in the sella turcica region are even rarer and, since the first case described in 1983, only 21 case reports of sellar/suprasellar SFTs II/III (ssSFTs II/III) have been described to this day. We aim to analyze ssSFTs II/III and to demonstrate that can be differentiated from non-functioning pituitary adenomas through pathological examination alone. We analyzed 20 case reports of ssSFTs II/III identified through PubMed and Google searches and a new unpublished case presented at Emory University. ssSFTs II/III are equally represented in both sexes, with 11 cases over 21 occurring in females and the mean age of onset at 46 years old. Clinically, ssSFTs II/III present with compression symptoms related to the tumor location. Headache, visual field defects, and anterior hypopituitarism-related symptoms are frequent chief complaints. As such, almost all cases of ssSFTs II/III had a pre-biopsy working diagnosis of non-functioning pituitary adenomas. The differentiation between SFTs II/III and pituitary adenomas based on imaging findings remains challenging, and surgical biopsies are necessary for a definitive diagnosis. ssSFTs II/III surgical reports describe a unifying trait of a highly vascular tumor adherent to the dura that bleeds profusely after resection. These characteristics are less consistent with a pituitary adenoma. The genetic hallmark of SFTs at all anatomical sites is paracentric inversions at 12q13, fusing the NAB2 and STAT6 genes, with consequent overexpression of STAT6. Pituitary adenomas lack this genetic signature. ssSFTs II/III have an overlapping presentation and similar imaging findings of pituitary adenomas, but different management and prognosis. Hence, it is crucial to include ssSFTs II/III among the pre-biopsy differential of sellar/suprasellar masses identified on imaging. Pathology confirmation is required to guide therapy.

Outcomes Associated With Stereotactic Radiosurgery After Multiple Resections of Nonfunctioning Pituitary Macroadenomas: An International, Multicenter Case Series.

Stereotactic radiosurgery (SRS) represents an effective treatment for nonfunctioning pituitary adenomas (NFPAs). However, no data have yet been published regarding results of SRS on NFPAs after multiple previous resections. Retrospective multicentric data of patients diagnosed with NFPA and who underwent multiple resections (≥2) before SRS were reviewed and analyzed. The treatment interval spanned the period of 1992 to 2022. Cox regression and Kaplan-Meier curves were used to assess predictive factors and the probability of tumor control and hypopituitarism. Among the 311 patients (median age: 50.2 [IQR: 18.0] years), 226 (72.7%) had undergone ≥2 previous resections. The median margin dose was 14 Gy (IQR: 4.0 Gy), and the median tumor volume 3.6 cm3 (IQR: 4.8). Overall, the probability of tumor control after SRS was 93.3% (CI 95%: 89.9-96.9) and 86.7% (CI 95%: 81.1-92.6) at 5 and 10 years, respectively. A margin dose >14 Gy was associated with a decreased risk of tumor progression (hazard ratio = 0.33, CI 95% = 0.15-0.75, P = .008). At a last clinical follow-up of 4.1 (IQR 6.1) years, 10.1% (30/296) developed at least 1 new hormone deficiency after SRS. The cumulative probability of new hormone deficiency was 6.1% (95% CI: 3.0-9.1), 10.3% (95% CI: 5.8-14.6), and 18.9% (95% CI: 11.5-25.8) at 3, 5, and 10 years after SRS, respectively. The average latency between SRS and development of new hormone deficiencies was 3.3 years (IQR 4.1). A maximum point dose to the pituitary stalk >10 Gy was associated with a new deficiency (hazard ratio = 4.06, CI 95% = 1.57-10.5, P-value = .004). For patients with NFPA with multiple previous resections, SRS offers effective local tumor control and a low risk of delayed hypopituitarism for managing these challenging adenomas. SRS should be strongly considered in patients with NFPA with 2 previous resections compared with considering a third resection.

Cognitive decline in Cushing's syndrome: A systematic review.

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non-functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full-text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer-reviewed journal. The full-text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case-control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre-operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings.

Improving the radiological prediction of surgical resection of nonfunctioning pituitary adenomas.

Nonfunctioning pituitary adenomas (NFPAs) are benign tumors growing in the sellar region. Total surgical excision of the lesion is recommended as the preferred treatment choice with preservation of adjacent structures. The objective is to establish a radiological score to predict the feasibility of NFPA total surgical excision. Patients with treatment-naïve NFPA who underwent a transsphenoidal approach and sellar magnetic resonance imaging (MRI) in the preoperative period and 3 months after surgery were included. Data on age, sex, tumor diameter, extrasellar extension, postoperative cure rates, and hormone and transcription factor expression were collected. A combined score was proposed based on Knosp and SIPAP classifications. We proposed 3 classification groups depending on the tumoral extension to the suprasellar, infrasellar, anterior and posterior directions of the sellar region. A total of 164 patients were included in the study, and 85 (52%) were female. Total excision was obtained in 46% (n = 75) of the patients. The majority of tumors were of gonadotrophic lineage (59%), followed by corticotrophic (17%) and other less common types. Largest tumor diameter was 6.8cm [mean 3.8cm (± 1.1cm)]. From the established groups, 10 patients were classified in Group I, of whom 8 (80%) patients underwent total excision, 115 patients were classified in Group II, of whom 58 (50%) underwent complete excision and 39 patients in Group III, of whom 9 (23%) underwent complete excision (p value < 0.001). The newly proposed score helps to determine the feasibility of total NFPA excision, allowing for better surgical planning and predictions of postoperative outcomes.

B2R-D2R Interaction in Prolactinomas and Nonfunctional Adenomas: Impact on Dopamine Resistance.

Prolactinomas, the most common pituitary-secreting adenomas, can be effectively treated with dopamine D2 receptor (D2R) agonists. However, a subset of them (∼20%) are resistant to dopamine-based therapies and require extirpation. The molecular mechanisms underlying their escape from dopaminergic regulation are not fully elucidated and may include alterations in D2R signaling. D2R can heteromerize with other G protein-coupled receptors, resulting in modulation of dopaminergic signaling. Because the bradykinin receptor type 2 (B2R) is overexpressed in prolactinomas, we interrogated whether this dopaminergic dysregulation observed in some prolactinomas may depend on a physical and functional interaction between D2R and B2R. The formation of B2R-D2R complexes in cultured cells transiently expressing both receptors was validated using NanoBiT technology. Interestingly, although D2R stimulation did not alter B2R-induced intracellular calcium mobilization, B2R stimulation abolished D2R signaling through modulation of cAMP. The existence of B2R-D2R complexes in pituitary adenomas biopsies was evaluated using an ALPHALisa approach. Importantly, B2R-D2R complexes were detected in human prolactinomas and nonfunctioning pituitary adenomas, but not in mixed (prolactin + growth hormone)-secreting adenomas. These results suggest that overexpression of B2R in resistant prolactinomas may promote the formation of B2R-D2R complexes, with B2R precluding D2R signaling, thus generating resistance to D2R agonists.

6400 An Unusual Presentation of Silent Corticotroph Pituitary Macroadenoma

Abstract Disclosure: N. Mon: None. V. Lohano: None. B. Williams: None. N. Lehman: None. R. Kulkarni: None. S.L. Mokshagundam: None. Silent Corticotroph Pituitary Adenomas (SCA) are a rare group of nonfunctioning pituitary adenomas (NFA) comprising 3-6% of all pituitary adenomas and up to 20% of corticotroph adenomas. SCA are biologically and clinically distinct from Cushing disease and NFA. SCA present with headache, visual field impairment, hypopituitarism, and pituitary apoplexy. We present a case of SCA with the initial presentation of syncope with undetectable ACTH and very low AM cortisol level.A 67 year-old-female was incidentally found to have a pituitary macroadenoma in MRI brain for syncope work up in 2017. MRI reported 1.4 x 1.2 x 1.3 cm sellar mass with suprasellar extension, minimal mass effect on the optic chiasm and no cavernous sinus invasion. Initial labs showed ACTH &amp;lt;5 (7.2-63.3 pg/mL), AM cortisol 0.8 (6-28ug/dl), Prolactin 101.1 (3.3-27 ng/mL), TSH 0.08 (0.34-5.60 uIU/mL), Free T4 0.6 (0.58-1.64 ng/dL), FSH 1.7 (2-5 mIU/mL), LH &amp;lt;0.2 (1-13 mIU/mL), IGF-1 33 ( 41-279 ng/mL). ACTH stimulation test: cortisol 0.5 ug/dl at baseline, 5.8 ug/dl at 60min. She was diagnosed with panhypopituitarism and hyperprolactinemia due to stalk effect. Hydrocortisone and Levothyroxine (LT4) were started. She underwent pituitary macroadenoma resection for optic chiasm decompression in 2017. Pathology reported pituitary neuroendocrine tumor (pitNET), but no immunostaining was done at that time. Follow up MRI in 2019 showed residual pituitary tumor. In 2023, she endorsed headaches, mood changes, fatigue and weight gain. Physical exam was unremarkable except BMI 34.75. Prolactin, Free T4, IGF-1 were normal. MRI in 2023 revealed recurrent and enlarging pituitary adenoma (1.9 x 1.4 x 1.6 cm) with suprasellar extension, abutting the optic chiasm, and left cavernous sinus invasion with internal carotid artery encasement. She underwent revision transsphenoidal resection of pituitary tumor to decompress the optic chiasm with plan for subsequent focused radiation to the cavernous sinus portion. Postoperative period was uneventful and hydrocortisone and LT4 were continued on discharge. Final pathology reported silent corticotroph lineage pitNET with low Ki67, immunostaining positive for TPIT, CAM5.2, and negative for ACTH. ACTH-negative SCA are a rare subtype and more likely to have lower ACTH levels, and multiple microcysts on MRI than ACTH-positive SCA. New WHO classification of pitNET highlights the histological typing and subtyping based on immunostaining of pituitary lineage transcription factors as the cornerstone for accurate classification. SCA are more biologically aggressive tumors with a high propensity of recurrence and resistance to conventional treatment. TPIT and ACTH immunostaining significantly improved the diagnosis of SCA and thereby close clinical follow up for early recognition and management of SCA recurrence. Absence of serum markers of recurrence makes this challenging. Presentation: 6/1/2024

6977 Unraveling Secondary Adrenal Insufficiency and an Invasive Pituitary Macroadenoma in a COVID-19 Positive Patient

Abstract Disclosure: F. El Sayed: None. A.A. Banka: None. Invasive pituitary macroadenomas extend into the extrasellar region and invade surrounding dural, periosteal, or mucosal tissues, often exceeding 1 centimeter and potentially compressing adjacent structures. Nonfunctioning pituitary adenomas (NFPAs), as they enlarge, can cause visual field impairment and ophthalmoplegia, with the decision for surgical intervention influenced by the degree of optic chiasm compression. NFPAs are sometimes associated with impaired endocrine function, particularly secondary adrenal insufficiency (sAI), which, warrants specific clinical attention. Management involves a combination of surgical interventions, such as transsphenoidal surgery, and medical approaches, including tailored hormone therapy or radiation therapy based on the tumor's characteristics. Clinical case: A 51-year-old female with a history of Sjogren's disease presented with a one-week duration of nausea, vomiting, diarrhea, and fatigue. Upon admission, she tested positive for COVID-19. Her vital signs indicated hypotension with a blood pressure in the 80s/40s range, a heart rate in the 90s, and she was afebrile on room air. Laboratory findings revealed significant hyponatremia (Na+ 118), K+ 4.3, HCO3- 19, and glucose 80. Workup for hyponatremia included a cortisol stimulation test, revealing secondary adrenal insufficiency with baseline cortisol of 3.5 ug/dl, 10.7ug/dl after 30 minutes, and 12.7ug/dl after 60 minutes. The patient denied exogenous steroid use, hypothyroid symptoms, polyuria, or polydipsia, and reported no headaches or visual symptoms. Endocrine evaluation showed hypogonadism despite post-menopausal status, with low estrone, estradiol, LH, and FSH levels. She was initiated on Cortef (hydrocortisone) with symptomatic improvement. Further investigation through an MRI revealed a large lobulated sellar mass measuring 3.2 x 2.8 x 3.5 cm compressing the optic chiasm and partially encasing the right internal carotid artery, leading to peripheral visual defects confirmed on perimetry. Following endoscopic endonasal pituitary macroadenoma resection, there was no evidence of interval growth on a one-year follow-up MRI scan. Discussion: The presented case highlights the importance of considering invasive pituitary macroadenomas in the differential diagnosis of patients with hyponatremia, particularly when accompanied by suggestive symptoms and an atypical cortisol response. The coexistence of COVID-19 adds a layer of complexity to the clinical scenario, necessitating a comprehensive approach to both infectious and endocrine management. Timely recognition, appropriate endocrine assessment, and targeted interventions, such as hydrocortisone replacement and surgical resection, are crucial for optimizing outcomes in patients with this intricate interplay of pituitary pathology and infectious states Presentation: 6/1/2024

8263 Long-term Imaging Follow-up of Non-functioning Pituitary Adenomas

Abstract Disclosure: N. Mehrotra: None. M.M. Ross: None. A.S. Chilukuri: None. S. Eljamri: None. C. Ewing: None. S. Patel: None. V. Patel: None. L.B. Siegel: None. D. Sistla: None. R.K. Shariff: None. P.K. Fazeli: None. Pituitary adenomas are common, affecting ∼15% of the population. Once a pituitary adenoma has been identified on imaging, an evaluation is undertaken for pituitary hormone excess and for pituitary hormone deficiency in the setting of larger adenomas (typically 1cm in size or greater). Hormone-producing or functioning pituitary adenomas are typically treated with medical or surgical therapy, but non-functioning pituitary adenomas can be followed conservatively if they are not contributing to morbidity. The natural history of non-functioning pituitary adenomas has not been well characterized and therefore although guidelines recommend follow-up pituitary imaging, there are no specific guidelines addressing how frequently or for how long these lesions should be followed. Our aim was to describe the clinical history of non-functioning pituitary adenomas using long-term clinical data from a large academic health system. We identified 791 patients who met our inclusion criteria of having more than one brain/pituitary MRI performed at least 3 months apart with a suspected non-functioning adenoma identified on the initial MRI. Each medical record was individually reviewed to confirm whether the adenoma was non-functioning based on clinical/biochemical evaluation. Patients were a median [interquartile range] of 48.3 [34.4, 63.6] years of age at the time of first MRI and 65% (n=517) were women. At presentation, 66% (n=523) of the pituitary adenomas were microadenomas (&amp;lt; 1 cm in size) and 34% were macroadenomas (&amp;gt; 1 cm). All patients had an MRI repeated at least 3 months after the initial MRI with median time of total imaging follow-up of 39.8 [17.0, 75.6] months. During follow-up, 658 patients were noted to have a stable lesion or a decrease in size of the adenoma. Patients whose lesion was noted to grow on MRI were slightly older than those who did not have growth (growth: 57.1 [41.9, 70.3] years versus no growth: 46.8 [33.7, 62.3] years, p&amp;lt; 0.0001). There were no differences with respect to BMI, hypopituitarism, smoking history or alcohol use between those with growth versus those without growth. Seventy-eight patients (9.9%) had surgical resection of their adenoma during follow-up. The most common indication for surgery was growth of the lesion (n=27), followed by visual changes (n=22). In the patients with a microadenoma at presentation, 90.8% remained stable in size or decreased in size during a median follow-up of 43.2 [20.5, 78.6] months. Only 2.3% of patients with a microadenoma at presentation underwent surgical resection during follow-up. In conclusion, the majority of non-functioning pituitary adenomas remain stable during prolonged imaging follow-up. Further study is needed to determine predictors of growth of non-functioning pituitary adenomas. Presentation: 6/2/2024

6672 Pituicytomas and Spindle Cell Oncocytomas: Rare Posterior Pituitary Tumors

Abstract Disclosure: Y. Park: None. A. Shen: None. M. Christie: None. J. Wentworth: None. C.J. Yates: None. J. King: None. Background: Pituicytomas and spindle cell oncocytomas (SCO) are rare non-functioning benign posterior pituitary tumors that can present as suprasellar or sellar-suprasellar masses.[1] Pituicytomas originate from the pituicytes in the neurohypophysis and infundibulum of the pituitary gland.2 SCO were previously thought to derive from the adenohypophysis,3 however, are now classified as a tumor of the neurohypophysis characterized by immunohistochemical reactivity to thyroid transcription factor 1 (TTF1).4 According to the World Health Organization 2021 classifications, pituicytomas, granular cell tumors and SCO may represent morphologic variations of the same tumor expressing TTF1.5 Due to their rarity, their clinical characteristics are not yet well-defined and can be mistaken as non-functioning pituitary adenomas. Methods: We retrospectively reviewed the clinical data of two patients with pituicytomas and two patients with SCO confirmed on histopathology at our institution, evaluating their clinical characteristics and management outcomes. Results: Two male patients, aged 59 and 79, were diagnosed with pituicytoma, and two male patients, aged 33 and 55 were diagnosed with SCO. Three presented with visual impairment from mass effects and three patients had hypogonadotropic hypogonadism. None had pre-operative arginine vasopressin (AVP) deficiency. All lesions were isointense on T1-weighted, and most were hyperintense on T2-weighted magnetic resonance imaging. Three cases had non-gross total resection due to hypervascularity. Postoperatively, two patients developed AVP deficiency and three developed persistent anterior pituitary insufficiency (Table 1). Pituicytomas had a Ki67 of 1-3%, and SCO had a Topoisomerase labelling index of &amp;lt;1%. In one case of pituicytoma, due to tumor recurrence 2 years after initial surgery, adjuvant radiotherapy was considered. However, the patient developed a severe peri-tumoral subarachnoid hemorrhage and died prior to receiving radiotherapy. In contrast, the progression of the residual SCO occurred at a slower rate. Discussions: Posterior pituitary tumor differentials are broad, including pituicytoma, SCO, granular cell tumor, craniopharyngioma, meningioma and germinoma;6 hence, histopathological diagnosis is crucial. Although benign, pituicytomas and SCO can result in increased morbidity and postoperative complications, such as AVP deficiency and hypopituitarism. Recurrence and progression are common.7, 8 Gross total resection is optimal, but this is difficult due to hypervascularity.9 Our case of peri-tumoral subarachnoid hemorrhage resulting in death emphasizes the hypervascular nature of pituicytomas. Patients with pituicytomas and SCO should be monitored for tumor progression or recurrence and hemorrhagic complications. Adjuvant radiotherapy may be considered for the management of tumor recurrence. Presentation: 6/3/2024

8574 Single cell multiomics suggests tumor cell energy metabolism heterogeneity in non-functioning gonadotroph pituitary adenomas

Abstract Disclosure: F.M. Ruf-Zamojski: None. Z. Zhang: None. W. Cheng: None. G.R. Smith: None. M. Zamojski: None. N. Mendelev: None. Y. Ge: None. D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. C.L. Andoniadou: None. E. Zaslavsky: None. X. Chen: None. O.G. Troyanskaya: None. M. Mercado: None. S.C. Sealfon: None. Pituitary adenomas cause hormonal dysregulation and severe morbidity. The absence of clear biomarkers for prognosis/treatment and the high risk of recurrence make management challenging. Non-functioning gonadotroph pituitary adenomas (NFPAs) represent proliferation of gonadotroph lineage cells without an increase in secretion of gonadotropins. Detection is often delayed until mass effects cause visual defects. Higher resolution molecular study may improve classification, diagnosis, treatment, and provide insight into adenoma biology. We analyzed four NFPAs using unbiased genome-wide same-cell single nucleus 10X Genomics multiome assay (transcriptome and chromatin accessibility) to define individual cell identity/states in comparison with normal gonadotrope cell references from twelve age/sex-matched human post-mortem pituitaries. In total, we generated high quality multiomics single-cell data for 33,832 adenoma cells and 5,451 normal gonadotropes. We identified tumor, immune, vascular, and proliferative cells confirming cellular heterogeneity. Multidimensional scaling analysis using Manhattan distances between cell types showed that NFPA gonadotropes were closer in gene expression to healthy gonadotropes among all pituitary cell types. In addition, we observed differences in the macrophage and endothelial cell populations between tumors and healthy pituitaries. Next, we studied gene regulatory circuitry (regulated gene, modulating transcription factor and its chromatin interaction site) using the new Control of Regulation Extracted from Multiomics Assays (CREMA, [1]) multiome analysis method which showed high variation between normal and tumor gonadotropes. Within each adenoma, the NFPA tumor cells encompassed two main subgroups of cells, one group (GT+ marker tumor cells) expressing established gonadotrope markers and another group not (GT- marker tumor cells). GT+ and GT- tumor cells formed a cluster distinct from healthy gonadotropes. GT+ and GT- tumor cells differed by their level of expression of mitochondrial genes, suggesting decreased aerobic capacity associated with the GT- tumor subgroup. Interestingly, differential analyses between the healthy and the NFPA gonadotropes from same-cell multiome data highlighted dissimilar gene expression and chromatin accessibility patterns.Our newly collected single cell data characterize the difference between NFPA tumor cells and normal gonadotrope cells. Our results suggest a Warburg-effect like difference in aerobic respiratory capacity among tumor cells within the same pituitary adenoma. Overall, this study brings new insights into the molecular characteristics of NFPAs, including tumor cell heterogeneity, and represents a new resource for the field. [1] PMID: 38084892. Presentation: 6/1/2024

6823 A Puzzling Case: Complete Regression of Pituitary Macroadenoma

Abstract Disclosure: N.T. Mazengia: None. D.R. Vangipuram: None. S.K. Majumdar: None. Introduction: The natural course of nonfunctioning pituitary macroadenomas remains poorly understood, largely because the majority are surgically treated [1]. There are a few case reports describing the spontaneous regression of nonfunctioning pituitary macroadenomas. Here we describe a case of pituitary macroadenoma which completely regressed following childbirth and two months of cabergoline therapy. Case Presentation: A 25-year-old female presented with bilateral nipple discharge and persistently elevated prolactin levels ranging from 31µg/liter to 45.9 µg/liter (NV &amp;lt;25 µg/L). She did not have any signs and symptoms of hypo or hypersecretion of the pituitary hormones. All her pituitary hormone levels were within normal range. Initial MRI revealed a pituitary mass measuring 9x13x9mm (AP, TR, CC). Given her lack of symptoms, the decision was made to follow up without any intervention. A repeat MRI after one year showed the size of the mass to be 11x13x11mm. Two years after her initial diagnosis, the patient had a spontaneous pregnancy, during which she remained asymptomatic with normal pituitary hormone levels. She had Cesarean delivery at term with no complication. She was lost to follow-up for about two years after childbirth then presented with breast discomfort and galactorrhea at which time, she was started on cabergoline. A subsequent MRI done two months after the start of cabergoline showed asymmetric fullness of the pituitary gland on the right with no discrete measurable lesion. Conclusion: We currently lack a comprehensive explanation for the regression observed in our patient. Silent ischemia may have played a role, particularly considering the natural increase in pituitary gland size during pregnancy. We are not sure if the regression can be solely attributed to the two months of cabergoline treatment. In asymptomatic patients diagnosed with nonfunctioning pituitary macroadenoma, tumor regression can potentially occur through either a "wait and watch" strategy or medical management using dopamine agonists, specifically cabergoline. However, the use of cabergoline as a primary treatment for asymptomatic nonfunctioning pituitary adenoma warrants further investigation. This is especially crucial given that, in most cases, nonfunctioning pituitary macroadenomas tend to increase in size during follow-up without any intervention.

Stereotactic radiosurgery for recurrent/residual nonfunctioning pituitary adenoma: a single-arm systematic review and meta-analysis.

Nonfunctioning pituitary adenomas (NFPAs) are a significant subtype of pituitary tumors, accounting for 30% of all pituitary tumors and 10-20% of intracranial tumors. The primary treatment for NFPAs is resection, but complete resection is often challenging due to the tumor's proximity to critical structures, leading to frequent recurrences. Stereotactic radiosurgery (SRS) has emerged as a viable treatment option for recurrent or residual NFPAs, but its long-term efficacy and safety profile require further investigation. This systematic review followed PRISMA guidelines and included studies published up to February 2024. We searched MEDLINE, Embase, and Cochrane databases for studies evaluating SRS for recurrent/residual NFPAs. Inclusion criteria focused on studies reporting outcomes and complications of SRS, while exclusion criteria omitted case reports, case series, and non-English studies. Data extracted included demographic details, dosimetry parameters, and follow-up durations. The risk of bias was assessed using the ROBINS-I tool, and statistical analyses were performed using single-arm meta-analyses. A total of 24 studies involving 3,781 patients were included. The mean follow-up duration was 60months. Tumor control was achieved in approximately 92.3% of patients. The risk of developing hypopituitarism post-SRS was 13.62%, while the risk for panhypopituitarism was 2.55%. New visual field deficits occurred in 3.94% of patients. Cranial nerve deficits were rare, with event rates below 1% for CN III, CN V, and CN VI. SRS is effective in managing recurrent or residual NFPAs, achieving high tumor control rates. However, the risk of hypopituitarism remains a significant concern, necessitating regular endocrinological monitoring. While generally safe, the potential for new visual field deficits and other cranial nerve deficits must be considered. SRS remains a valuable treatment option, but clinicians should be aware of its potential complications.

Expression assays of selected lncRNAs in non-functioning pituitary adenomas

PurposeNon-functioning pituitary adenomas (NFPAs) are a group of these neoplasms originated from the adenohypophyse and do not show evidence of hormonal oversecretion. However, different genes and lncRNAs have been found to be dysregulated in these samples.Material and methodsIn this study, in order to identify novel biomarkers, a set of regulatory lncRNAs for the two important hub genes, i.e. STAT3 and EGFR were selected and subjected to experimental investigation. These lncRNAs were EGFR-AS1 for the EGFR gene, and LINC00240, FALEC and SNHG12 for the STAT3 gene.ResultsAll studied genes were down-regulated in NFPA samples compared with normal tissues adjacent to the tumors (NTATs), except for FALEC whose expression was not different between these two sets of samples. EGFR was the most significantly down-regulated gene in NFPAs (Expression ratio (95% CI) = 0.009 (0.002–0.04), P value < 0.0001). ROC curve analyses proposed that the expression levels of SNHG12, EGFR, EGFR-AS1 and LINC00240 can be used to distinguish NFPAs from NTATs with AUC values of 0.88, 0.83, 0.7 and 0.66, respectively. Spearman's correlation analyses showed significant correlations between FALEC and EGFR-AS1 in both types of tissues, and between FALEC and EGFR in NFPAs. Moreover, expression of LINC00240 was correlated with EGFR-AS1, FALEC and SNHG12 in NFPAs.ConclusionTaken together, EGFR and STAT3-related lncRNAs may be involved in the pathogenesis of NFPA.

Pituitary Apoplexy: Comorbidities, Management and Outcomes. A Spanish Observational Multicenter Study

Abstract Background Pituitary apoplexy (PA) is the paradigm of endocrine and neurosurgical emergency. Objective To evaluate the comorbidities, risk factors, clinical presentation, pituitary apoplexy score (PAS) and the outcomes of surgical vs. conservative management of PA in Spain. Methods Spanish multicenter, observational study of 301 patients with acute PA. Statistical analyses compared risk factors, clinical presentation and outcomes between the surgical and conservative treatment groups, adjusting for potential confounders. The prevalence of cardiovascular risk factors in patients with pituitary apoplexy was compared with the Spanish population and with patients with non-functioning pituitary adenomas. Results Median age was 59.3 years, 201 (66.8%) were men and non-functioning adenomas (77.9%) were the most common tumor type. The prevalence of diabetes (20.3% vs 13.9%, p&amp;lt;0.01), hypertension (48.8% vs 33.4%, p&amp;lt;0.01) and dyslipidemia (44.2% vs 23.3%, p&amp;lt;0.01), exceeded the Spanish age-adjusted population prevalence. Overall, 209 (69.4%) underwent surgery and 92 (30.6%) received conservative treatment. Surgical patients had larger tumors (26.2 vs 21.0 mm, p&amp;lt;0.01), chiasmal compression more frequently (77.2% vs 53.4%, p&amp;lt;0.01) and higher values of PAS. In the follow-up, while there were no statistically significant differences in anterior pituitary hormonal deficits between treatments, permanent vasopressin deficiency was more frequent after surgery (14.8% vs 3.3%, p&amp;lt;0.01). Conclusion There is a high burden of cardiovascular risk factors among patients with PA suggesting that metabolic factors may play a potential role in the development of PA. This underscores the need for comprehensive management of these conditions in addition to treating the apoplexy itself in this population. Surgical management has a relevant place in PA approach mainly in patients with higher PAS. However, it leads permanent vasopressin deficit more frequently than conservative approach.

Risk factor analysis and prediction model to establish recurrence or progression of non-functioning pituitary adenomas in men after transnasal sphenoidal surgery

This paper aims to analyze the risk factors for the recurrence or progression of non-functioning pituitary adenomas (NFPAs) in male patients after transnasal sphenoidal surgery and to develop a predictive model for prognosis. Clinical and follow-up data of 126 male patients with NFPAs treated by transnasal sphenoidal surgery from January 2011 to January 2021 in Fuzhou 900th Hospital were retrospectively analyzed. Lasso regression analysis was used to screen the best predictors, and the predictors were further screened by multivariate logistic regression analysis, and the nomogram prediction model was constructed. The performance of the model was verified by three aspects: discrimination, calibration and clinical utility by using the consistency index (C-index), receiver operating characteristic curve (ROC), calibration curve, clinical decision curve (DCA) and Clinical impact curve (CIC). Out of 126 cases, 7 (5.56%) showed postoperative tumor recurrence, and 18 (14.29%) exhibited postoperative residual regrowth (progression). Age (P = 0.024), maximum tumor diameter (P < 0.001), modified Knosp grade (P < 0.001), resection extent (P < 0.001), Ki67 (P < 0.001), pressure symptom (P < 0.001), Pre-op hypopituitarism (P = 0.048), Post-op new hypopituitarism (P = 0.017) showed significant differences among the recurrence group, the progression group, and the alleviation group. Three independent risk factors (Ki67, modified Knosp grade, and resection extent) affecting postoperative remission were used to construct a predictive model for long-term postoperative failure to remit. The C-index of the nomogram model was 0.823, suggesting that the model had a high discriminatory power, and the AUC of the area under the ROC curve was 0.9[95% CI (0.843, 0.958)]. A nomogram prediction model based on modified Knosp grading (grades 3B-4), resection extent (partial resection), and Ki-67 (≥ 3%) predicts the recurrence or progression of NFPAs in men after transnasal sphenoidal surgery.

Clinical case of plurihormonal pituitary adenoma (STH/ACTH/TSH/FSH/LH-secreting), diagnostic pitfalls

According to numerous studies, the most common pituitary tumors are prolactinomas, reaching 60% of all clinically significant adenomas, the next in order are non-functional pituitary adenomas, somatotropinomas, corticotropinomas and thyrotropinomas. Plurigormonal tumors occur in less than 1% of all pituitary adenomas. The most common form of mixed secretion adenoma in this patient population, derived from the Pit-1 cell line, produces various combinations of hormones: growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH). This article presents a patient with a plurihormonal two-component pituitary macroadenoma with a rare and exceptional combination of secreted hormones - GH / adrenocorticotropic hormone (ACTH) / TSH / follicle-stimulating hormone (FSH) / luteinizing hormone (LH) with minimal nonspecific clinical manifestations such as diabetes mellitus and poorly controlled arterial hypertension.

Pituitary apoplexy: a comprehensive analysis of 93 cases across functioning and non-functioning pituitary adenomas from a single-center.

Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce. A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center. 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5cm, with larger tumors in FPA (3.2cm vs. 2.3cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches. PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery.

Long-Term Outcomes After Cyberknife Radiosurgery for Nonfunctioning Pituitary Adenomas.

Stereotactic radiosurgery (SRS) has been widely adopted as an important adjunctive treatment modality for managing nonfunctioning pituitary adenomas (NFPAs). However, current studies on the long-term effects of SRS on pituitary adenomas have been largely limited by small sample sizes and short follow-up periods. The aim of this study was to evaluate the long-term outcomes of SRS for NFPAs. We conducted a retrospective review of 178 patients with NFPAs who received Cyberknife radiosurgery at a single institution between February 2008 and July 2021. Long-term outcomes of tumor control, new-onset hypopituitarism, and new visual disorders were assessed. During a median radiological follow-up of 49.7 months (range, 2.5-158.1 months), only 11 (7.0%) patients experienced tumor progression. The progression-free survival at 3, 5, and 10 years was 97.47%, 95.57%, and 93.04%, respectively. New-onset hypopituitarism was diagnosed in 27 (16.9%) patients with a median clinical follow-up duration of 71.2 months (range, 11.5-175.4 months). The median time from SRS to new-onset hypopituitarism was 28.3 months (range, 2.8-101.7 months). The cumulative incidence of new-onset hypopituitarism at 3, 5, and 10 years was 8.47%, 12.43%, and 15.25%, respectively. Biological effective dose >140 Gy and single fraction equivalent dose >16.0 Gy were significant risk factors for new-onset hypopituitarism (P = .046). Other adverse events were experienced by 15 (8.4%) patients, 9 (5.1%) of whom presented with new visual disorders. Development of new visual disorders was associated with a pretreatment tumor volume of >2.5 mL (P = .044). SRS is an effective and relatively safe means of managing both primary and residual/recurrent NFPAs.

Combined Endonasal and Transseptal Approach to Achieve Binostril Access in Endoscopic Skull Base Approaches to Minimize Nasal Morbidity: A Technical Note

IntroductionOver the years, feasibility & safety of EEAs has become well established & the focus has now shifted to minimising the nasal morbidity. To this end, several modifications in nasal stage have been described that have focussed primarily on preservation of nasal mucosa on right side of nasal cavity (NC). However, the issue of nasal mucosal preservation on left side of NC has largely been ignored. In this paper, the author describes a modified technique that can eliminate mucosal damage in left NC. MethodIn modified technique, trans-septal approach is utilised on left & endonasal on right side. A hemitransfixion incision is used to raise left submucosal tunnel. The mucosa of tunnel lies laterally in apposition with lateral nasal wall, thereby protecting it from injury by repeated passage of instruments. When tunnel mucosa is pushed back medially, left NC appears absolutely normal without any evidence of mucosal damage. ResultsCombined endonasal & trans-septal technique for nasal stage was performed in 51 patients with sellar/suprasellar lesions. Nonfunctional pituitary adenomas were the most common pathology (macroadenomas-n=14; Giant adenomas-n=10) followed by functional adenomas (acromegaly-n=10; prolactinomas- n=3; Cushings’s disease- n=1), craniopharyngiomas (n=6), clival tumours (n=5), & tuberculum sella meningiomas (n=2). ConclusionsA combination of endonasal and trans-septal approaches utilises the advantages of both endoscopic & microscopic approaches sans the disadvantage of restricted space seen in microscopic approaches. It makes binostril approach least disruptive to left nasal mucosa & thus can reduce overall morbidity of EEAs.