Pituitary Carcinoma Research Articles

9375 Acth-Producing Pituitary Carcinoma in the Falx Cerebri and Other Unusual Locations

Abstract Disclosure: J.E. Esquivel Vargas: None. A. Cob Guillén: None. A.B. Santos Rojo: None. A. Hong Lo: None. ACTH-producing Pituitary Carcinoma in the Falx Cerebri and other unusual locations Background: Pituitary carcinoma is a condition defined by metastasis of a pituitary tumor to a distant location. Pituitary carcinomas are very rare and account for approximately 0.12% of adenohypophyseal tumors (1). Clinical case: We present a case of a 29-year-old female who was followed up in our Endocrinology Department. Past medical history included the diagnosis of Cushing Disease and transsphenoidal tumor resection at 12 years of age, followed by transcranial resection two years later because of persistently elevated adrenocorticotropic hormone (ACTH). Despite the surgical management, the patient persisted with increased ACTH and hypercortisolism, so bilateral adrenalectomy was performed a year later. Two years after the procedure, the patient presented with a newly diagnosed pituitary macroadenoma, so the diagnosis of Nelson Syndrome was made. Linear accelerator radiotherapy was given, which reduced the size of the tumor. Later, multiple imaging studies showed multiple lesions on the falx cerebri, posterior clinoid process, retroclival region, cerebellopontine angle, pterygopalatine fossa, infratentorial region, and posterior ethmoidal cells. Biopsy and immunohistochemistry of the falx cerebri lesions described ACTH-producing pituitary adenocarcinoma. Treatment was given with intramuscular octreotide, dabrafenib, and trametinib. Despite persistently elevated ACTH levels, the patient has since remained clinically stable, without new development or worsening of symptoms. Conclusion: There are 3 unique aspects of our case. First, we reported an unusual presentation of this disease, because the patient in our case was a female with an early age of onset, in contrast with the reported literature. Second, this is the first reported case demonstrating pituitary carcinoma in the falx cerebri. Third, the prognosis of pituitary carcinoma is very poor, and mortality is extremely high, however, the patient in our case has been followed up for 7 years since the diagnosis of the metastatic lesions and has remained clinically stable.

7166 EFFECT OF ANTI-NEOPLASTIC THERAPIES ON CARCINOMA AND AGGRESSIVE PITUITARY TUMORS : A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Disclosure: V.D. Nunes-Nogueira: None. A.R. Cardoso: None. A.C. Zimmermann: None. Introduction: Approximately 10% of the pituitary adenomas can have an aggressive behavior and 0.2% can present metastasis, being classified as pituitary carcinomas. Objective: Evaluate the tumor control obtained by anti-neoplastic therapies that are still little explored in the context of carcinoma and aggressive pituitary tumors. Methods: A systematic review according to the Joanna Briggs Institute has been conducted. We have included studies that evaluated patients with carcinoma or aggressive pituitary tumors who underwent treatment with at least one of the following therapies: Temozolomide, VEGF Inhibitors, Peptide Receptor Radionuclide Therapy (PRRT), Everolimus, Immune Checkpoint Inhibitors, EGFR Inhibitors, Capecitabine and temozolomide (CAPTEM). The main outcome assessed by the study was the frequency of tumor response according to the RECIST protocol classification. Embase, Medline, LILACS, and CENTRAL were our source databases. Proportional meta-analyses were performed to calculate the overall frequencies of complete remission (CR), partial remission (PR; minimum shrinkage of 30%), stable disease (SD) and progression disease (PD). We used Stata Software 18, the updated command “metaprop_one” and fit the logistic normal random effect model. Results: None clinical trial was found, and sixty case report/case series were included. The most frequent therapy used was temozolomide (101 patients), followed by PRRT, pembrolizumab, lapatinib, CAPTEM, bevacizumab, ipilimumab/ nivolumab and everolimus, with respectively 9, 6 ,6, 6, 4, 3 and 1 individuals. The majority of patient in temozolomide studies had prolactinomas (40/101), followed by Cushing’s disease (25/101), the overall frequency of CR with this drug was 1% (ch^2=2.7; p=0.049, Predictive Interval (PI) 1% to 93%, 7 events), PR was 45% ( ch^2=1.8, p=0.091, PI= 8-89%, 46 events), SD 14% (CI 95%=5 a 33%, 20 events), and PD was 25% (95%CI: 14-40%, 28 events). Two patients receiving CAPTEM presented CR, no other studies presented this outcome. In the PRRT studies, the overall frequency of PR was 22% (95%CI 6 to 58%) and PD was 44% (95%CI 18 to 75).Conclusion: Temozolomide has been the therapy most frequent used in the management of carcinoma and aggressive pituitary tumor, being PR the most frequent outcome, followed by PD and SD, with low percentage of CR. The other drugs approached by this review showed similar poor response although they were less tested in the context of this neoplasms. Presentation: 6/2/2024

Endoscopic endonasal approach for resection of sellar leiomyosarcoma metastasis: illustrative case.

Leiomyosarcoma (LMS) is a rare neoplasm that arises from tissues of embryonic mesodermal origin. Primary tissues of origin can include smooth muscle cells of the abdominopelvic viscera, blood vessels, or arrector pili muscles. LMS is known to metastasize to the lungs, with few reported cases of spread to the central nervous system. A 66-year-old male with cutaneous LMS of the left forearm with metastases to the lungs and kidney that had been treated with chemoradiation presented with worsening headaches. Magnetic resonance imaging revealed a sellar lesion. An endocrine workup was unremarkable. Imaging over 6 months revealed rapid interval growth. Positron emission tomography demonstrated moderate uptake. Given the rapid growth, the patient was offered an endoscopic endonasal approach for resection. Pathology confirmed LMS. To the authors' knowledge, this is the first documented case of LMS metastasis to the sella. Pituitary carcinoma or metastases to the sellar region should be in the differential among patients with sellar region tumors with a rapid growth rate, bony erosion, or findings of lesions in the upper cervical lymph nodes or soft tissue. Tumors that show significant interval growth should raise suspicion for nonadenomatous lesions, and surgical intervention should be considered even in the absence of endocrinological dysfunction or cranial neuropathies. https://thejns.org/doi/10.3171/CASE2435.

Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation- negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.

Aggressive Prolactinoma with Progression to Pituitary Carcinoma: A Case Report.

Adenomas of the pituitary gland, predominantly prolactinomas, can exhibit aggressive behavior. Aggressive prolactinomas are characterized by radiographic invasion, rapid growth, clinically significant progression despite standard therapies, and recurrence after surgery or radiotherapy. Pituitary carcinoma is rare (0.1-0.2% of pituitary tumors) [1, 2]. Case Presentation: In 2005, a 50-year-old man presented with bitemporal hemianopsia and severe asthenia due to a large pituitary tumor. Hormonal tests revealed hyperprolactinemia and panhypopituitarism; he received hormonal replacement and dopamine agonists (DA) therapy with a reduction in prolactin levels. Ten years later, he experienced tumor regrowth consistent with pituitary apoplexy and VI cranial nerve palsy. MRI showed a macroadenoma with suprasellar extension and compression of the optic structures. The patient underwent transsphenoidal surgery in view of the partially resistant disease. Histopathology showed a pituitary macroadenoma, and immunohistochemistry showed a high mitotic index (Ki-67 80%). In 2016, the patient developed a partial deficit of the left sixth cranial nerve. He underwent a new surgery but with incomplete resection. In view of the aggressive and resistant nature of the disease, he received radiotherapy. In 2020, prolactin levels began to increase again. MRI showed an occipital- temporal lesion. Subsequently, he underwent radiotherapy and started chemotherapy with temozolomide, resulting in the normalization of prolactin levels in the absence of DA therapy. The patient is currently in remission, with no evidence of tumor recurrence. Conclusion: It was found that 15% of prolactinomas are resistant to DAs, and resistance to DA may signal malignant transformation. Therefore, multimodality therapy and molecular analysis are critical for aggressive prolactinomas and pituitary carcinoma.

Clinically active pituitary tumors

The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary microadenomas. The most common clinically relevant pituitary adenomas are prolactin-secreting, followed by HI, and far less common are growth hormone (GH)-, adrenocorticotropic hormone (ACTH)- and thyroid-stimulating hormone (TSH)-secreting adenomas. Pituitary adenomas are usually benign, although aggressive growth and invasion occurs in individual cases. Very rarely, they give rise to metastases and are then termed pituitary carcinomas. All pituitary tumors require endocrine testing for pituitary hormone excess. In addition to the medical history and clinical examination, laboratory diagnostics are very important. Symptoms such as irregular menstruation, loss of libido or galactorrhea often lead to the timely diagnosis of prolactinomas, and hyperprolactinemia can easily confirm the diagnosis (considering the differential diagnoses). Diagnosis is more difficult for all other hormone-secreting pituitary adenomas (acromegaly, Cushing's disease, TSHoma), as the symptoms are often non-specific (i.e., headaches, weight gain, fatigue, joint pain). Furthermore, comorbidities such as hypertension, diabetes, and depression are such widespread diseases that pituitary adenomas are rarely considered as the underlying cause. Timely diagnosis and appropriate treatment have asignificant impact on morbidity, mortality, and quality of life. Therefore, the role of primary care physicians is very important for achieving an early diagnosis. In addition, patients with pituitary adenomas should always be referred to endocrinologists to ensure optimal diagnosis as well as treatment.

Thyroid and neurobehavioral effects of DiNP on GH3 cells and larval zebrafish (Danio rerio)

Diisononyl phthalate (DiNP) has been used to replace bis(2-ethylhexyl) phthalate (DEHP) and is frequently found in the environment and humans. DiNP is reported for its anti-androgenic activity; however, little is known about its effects on thyroid function and neurodevelopment. In the present study, the thyroid disruption and neurobehavioral alteration potential of DiNP and its major metabolites were assessed in a rat pituitary carcinoma cell line (GH3) and embryo-larval zebrafish (Danio rerio). In GH3 cells, exposure to DiNP and its metabolites not only increased proliferation but also induced transcriptional changes in several target genes, which were different from those observed with DEHP exposure. In larval fish, a 5-day exposure to DiNP caused significant increases in thyroid hormone levels, following a similar pattern to that reported for DEHP exposure. Following exposure to DiNP, the activity of the larval fish decreased, and neurodevelopment-related genes, such as c-fos, elavl3, and mbp, were down-regulated. These changes are generally similar to those observed for DEHP. Up-regulation of gap43 and down-regulation of elavl3 gene, which are important for both thyroid hormone production and neurodevelopment, respectively, support the potential for both thyroid and behavioral disruption of DiNP. Overall, these results emphasize the need to consider the adverse thyroid and neurodevelopmental effects in developing regulations for DEHP-replacing phthalates.

Immunotherapy for endocrine tumours: a clinician's perspective.

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

P-57 A case of pituitary carcinoma treated with osilodrostat for severe Cushing's syndrome

Abstract Introduction Pituitary carcinoma is a rare disorder accounting for 0.1–0.2% of pituitary tumors. We present a case of a male subject with ACTH-secreting pituitary carcinoma with metastasis to the spine, achieving eucortisolism on osilodrostat treatment. Clinical Case A 31-year-old male presented with complaints of pain in the rear-left thigh, numbness in the left-hand fingers and shoulder. MRI revealed an invasive pituitary tumor which had spread to the left frontal and temporal lobes with infiltration of the dura mater and compression of the left part of the optic chiasm, multiple formations in the large hemispheres, hemispheres of the cerebellum, in the right internal auditory meatus and at the level of the C1 vertebra compatible with metastasis. Spinal MRI showed a mass at Th6, L1-S2 level compatible with metastasis (Fig.1). The patient was diagnosed with Cushing's disease (CD) at 23 (late-night serum cortisol 1450 nmol/L (64–327), late-night salivary cortisol (LNSC) 66.4 nmol/L (0.5–9.65), 24hUFC 608 nmol/L (100–379), ACTH 107.3 pg/mL (7.2–63.3)) and underwent transsphenoidal pituitary surgery for pituitary macroadenoma 26×18×29 mm with biochemical remission. Two years later his symptoms of CD relapsed and he had a second transsphenoidal surgery. Histological examination showed an atypical corticotroph tumor with Ki67 – 11.6%. Two months after surgery, Kiber knife surgery was performed. However, 2 years later he had gradual deterioration of vision due to loss of lateral margins. A third transcranial adenomectomy was performed with following panhypopituitarism and diabetes insipidus. The tumor was positively stained for ACTH and also contained some atypical features including nuclear pleomorphism. Postoperative chemotherapy adjuvant treatment with Temozolomide and Carboplatin was prescribed. After 6 cycles, proton radiotherapy was done. In order to control hypercortisolism the patient received ketoconazole 800 mg per day, cabergoline 1 mg twice weekly and pasireotide 1.8 mg per day. However, it was not possible to achieve remission of hypercortisolism. As an adverse event of pasireotide, diabetes mellitus developed, which required insulin therapy and finally lead to pasireotide cessation. Ketoconazole and cabergoline were discontinued and osilodrostat treatment was initiated with a final dose of 5 mg daily over 2 years. He also received another course of radiation therapy at the age of 31 years. Over the past 2 years of observation, his ACTH level ranged from 37 pg/mL to 325.1 pg/ml. In spite of tumor progression and raised ACTH, the patient remains in eucortisolism (late-night serum cortisol 163.3 nmol/L, LNSC 5.21 nmol/L, 24hUFC 70.14 nmol/L) on osilodrostat 10 mg daily. Conclusion In this case osilodrostat was effective at controlling hypercortisolism, but its effects on the tumor are unknown. As this patient is the first described case of corticotroph carcinoma tumor treated with Osilodrostat, the results should be taken with caution.Figure 1.Pituitary and spinal MRI of the patientT1-weighted MRI demonstrating (A) chiasmal-sellar region formation, (B) formation in the rigt internal auditory meatus, (C) a highly invasive sacral L1–S2 metastasis

O-01 Case report: Temozolomide treatment of refractory prolactinoma

Abstract Introduction Treatment of refractory prolactinoma is challenging. Temozolomide (TMZ), an oral chemotherapeutic agent, has been recommended as an effective drug for refractory pituitary adenomas or carcinomas. Clinical Case We report a 53-year-old male who presented with diplopia, left eye proptosis, conjunctival congestion, and headache. Magnetic resonance imaging (MRI) showed a macroadenoma 20×17 mm in diameter with compression of the optic chiasm and invasion of both cavernous sinuses. Hormonal evaluation revealed hyperprolactinemia of 2382 ug/L, 120x above the upper limit of normal (ULN), with central hypothyroidism and hypogonadism. Cabergoline was recommended as an initial treatment. Despite the maximum cabergoline dose of 1.5 g daily, tumor volume increased with visual disturbances and headaches. Prolactin (PRL) remained 60x above ULN so the patient underwent transsphenoidal surgery. Tumor histology was consistent with an atypical pituitary adenoma, positively stained for prolactin and sporadically for growth hormone, Ki-67 of 6.4%, no mitosis and negative p53. Postoperatively, the PRL level was still high (25x above ULN) with tumor remnants in both cavernous sinuses. Due to the tumor resistance to dopamine agonist treatment and uncomplete surgical resection, patient underwent stereotactic gamma knife radiosurgery (GK prescription dose 22 Gy, isodose 49%) simultaneously with TMZ treatment. After 2 cycles of TMZ (1. cycle TMZ 300mg/5days, 2. cycle TMZ 400 mg/5days), the PRL level decreased significantly (126 ug/L). The plan is to apply a total of 6 cycles of temozolomide. Conclusion Clinical evidence for the efficacy of TMZ in refractory prolactinoma remains limited, but early use of this agent may be helpful in some cases.

Aggressive pituitary tumors and carcinomas: modern classification, advances and prospects in treatment

Despite slow growth of most pituitary tumors and high rates of total resection and/or effective therapy, pituitary neoplasms are characterized by aggressive behavior with high growth rate, frequent relapses and resistance to standard treatments in 10% of cases. In modern WHO classifications of tumors of the central nervous system, endocrine and neuroendocrine tumors, the authors propose the definition «pituitary neuroendocrine tumor» instead of previous «pituitary adenoma» and «metastasizing pituitary neuroendocrine tumor» instead of «pituitary carcinoma». Currently, there are no effective prognostic markers of aggressive tumors. This complicates early diagnosis. It is proposed to apply a five-stage prognostic classification based on proliferation rate (including mitotic count, Ki-67 index and p53 immunoexpression) and morphometric markers of invasiveness for all resected pituitary neoplasms. This approach would be valuable for earlier detection of aggressive tumors and pituitary carcinomas. Compression of visual pathways, third ventricle and brain stem due to rapid growth of aggressive tumors usually requires redo surgeries with subsequent radiotherapy. Hormonally active tumors require therapy with somatostatin analogues and dopamine agonists in maximum possible doses. Chemotherapy with temozolomide as first-line option is recommended if standard treatment is ineffective. Alternative treatment includes peptide receptor radionuclide therapy (PRRT), molecular targeted therapy (bevacizumab, tyrosine kinase inhibitors, everolimus and cyclin-dependent kinase inhibitors) and immunotherapy (checkpoint inhibitors). Considering the need for combined treatment, these cases should always be discussed by a multidisciplinary team (neurosurgeon, endocrinologist, radiotherapist, oncologist, pathologist) with necessary qualifications and experience in treating these patients. Treatment of aggressive tumors and pituitary carcinomas is becoming an active and rapidly developing direction in neurosurgery, endocrinology and oncology.

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

Diagnosis and Management of Aggressive/Refractory Growth Hormone‐Secreting Pituitary Neuroendocrine Tumors

The majority of acromegaly and gigantism are caused by growth hormone‐secreting pituitary neuroendocrine tumors (PitNETs). Most cases can be cured or controlled by surgery, medical therapy, and/or radiotherapy. However, a few of these tumors are resistant to traditional therapy and always have a poor prognosis. The title aggressive/refractory is used to differentiate them from pituitary carcinomas. To date, there is no definitive conclusion on how to diagnose aggressive/refractory growth hormone‐secreting PitNETs, which may have slowed the process of exploring new therapeutical strategies. We summarized the literature described diagnosis and treatment of the disease. Potential disease markers and prospective therapies were also included.

Aggressive and Metastatic Pituitary Neuroendocrine Tumors: Therapeutic Management and Off-Label Drug Use.

Pituitary neuroendocrine tumors (PitNETs) are the most common pituitary tumors and the second most common brain tumors. Although the vast majority (>90%) are benign, a small percentage (<2%) are aggressive. These aggressive PitNETs (AgPitNETs) are defined by the presence of radiological invasion, a high rate of cell proliferation, resistance to conventional treatments, and/or a high propensity for recurrence. Lastly, there are the rare pituitary carcinomas, also known as metastatic PitNETs (MetPitNETs), which account for only 0.2% of cases and are defined by the presence of craniospinal or distant metastases. At present, there are no definitive factors that allow us to predict with certainty the aggressive behavior of PitNETs, making the therapeutic management of AgPitNETs a real challenge. Surgery is considered the first-line treatment for AgPitNETs and MetPitNETs. Radiation therapy can be effective in controlling tumor growth and regulating hormone hypersecretion. Currently, there are no approved non-endocrine medical therapies for the management of AgPitNETs/MetPitNETs, mainly due to the lack of randomized controlled clinical trials. As a result, many of the medical therapies used are off-label drugs, and several are under investigation. Temozolomide (TMZ) is now recognized as the primary medical treatment following the failure of standard therapy (medical treatment, surgery, and radiotherapy) in AgPitNETs/MetPitNETs due to its ability to improve overall and progression-free survival rates in responding patients over 5 years. Other therapeutic options include pituitary-targeted therapies (dopamine agonists and somatostatin analogs), hormonal antisecretory drugs, non-hormonal targeted therapies, radionuclide treatments, and immunotherapy. However, the number of patients who have undergone these treatments is limited, and the results obtained to date have been inconsistent. As a result, it is imperative to expand the cohort of patients undergoing treatment to better determine the therapeutic efficacy and safety of these drugs for individuals with AgPitNETs/MetPitNETs.

ED-1 PITUITARY TUMORS IN 5TH WHO CLASSIFICATION 2022: WHAT DO YOU MEAN BY PITNET?

Abstract It has been well known that the terminology has been changed from pituitary adenoma(4th WHO) which means benign epithelial tumors to pituitary neuroendocrine tumor(5th WHO 2022). It is apparent that the anterior pituitary cells and derived tumors contain intracytoplasmic neurosecretory granules and belong to neuroendocrine cells, and naturally neuroendocrine tumors. The pancreatic and gastrointestinal neuroendocrine neoplasms(NEN) are composed of well differentiated neuroendocrine tumors(NET) and poorly differentiated neuroendocrine carcinoma(NEC). NETs are potentially malignant(metastatic) tumors and are further graded to G1,G2,G3 by proliferative activities(mitoses or Ki-67 indices) showing correlation with prognosis . PitNET which means pituitary NET is now classified by transcription factors(PIT1,TPIT,SF1) and some tumors show clinical symptoms,(hormone production) invasive growth and rarely metastasize indicating potential malignant behavior. From this broad biological spectrum of PitNET, ICD-O coding /3(primary malignancy) has been proposed(5th WHO CNS, Pediatrics and Endocrine volumes). It has been known that some histological patterns (Sparsely granulated somatotroph PitNET, Crooke cell PitNET and others) are related more aggressive growth of PitNETs, but metastatic behavior is very hard to predict histologically. So in WHO 4th edition, the term pituitary carcinoma was used only after confirming metastasis or remote spread. The metastatic tumors are now called metastatic PitNETs. Five tiered grading by proliferation and invasion has been also proposed(Trouillas). Now we need more updated genomic studies such as single cell RNA sequencing to clarify biologic behavior of the individual PitNET cells to further clarify the their nature. . In my talk, several points of interests regarding PitNETs will be discussed by demonstrating histology and biology of representative cases.

Survival determinants of patients with uncertain behavior pituitary tumors: A Surveillance, Epidemiology, and End Results (SEER) database study

IntroductionThe “borderline” pituitary tumor category between typical benign adenomas and pituitary carcinomas is a subject of ongoing controversy. Surveillance, Epidemiology, and End Results (SEER) database classifies uncertain behavior pituitary tumors (UPTs) under the “borderline” category including atypical adenomas with presumed propensity for aggressive behavior. Very little is known about UPT patient survival prognostic factors. We aimed to characterize survival risk factors of patients with UPT according to the SEER database. MethodsSEER 17 database was queried for pituitary tumors and further separated by SEER classification of “Borderline” under the category “ICD-O-3 Hist/behav, malignant”. Patient demographics, tumor characteristic, extent of disease and treatment data were extracted and analyzed. A nomogram was built assessing survival. ResultsThree hundred and thirty-two patients diagnosed between 2004 and 2019 were included. The survival rates at 1, 5 and 10 years were 86.8 %, 78.6 % and 65.1 %, respectively. Female sex and age <65 years correlated with a better prognosis (HR 2.41, 95 % CI [1.57–3.68], p = 4.00E-05 and HR 5.47; 95 % CI [3.53–8.45], p = 3.00E-15). Patients undergoing surgery had a better prognosis than those pursuing non-surgical management (HR 0.43, 95 % CI [0.19–0.97], p = 0.02). A nomogram incorporating sex, age and surgical versus non-surgical treatment status was created. The nomogram demonstrated acceptable accuracy in estimating the survival probability at 1- and 2-years, with a C-index of 0.751 (95 % CI: 0.641–0.861). ConclusionFemale sex, age <65 years and surgical resection are significant factors determining UPT patient survival based on SEER data. The proposed nomogram achieved good potential for predicting UPT patient survival.

THU018 Remarkable Response Of ACTH-secreting Pituitary Carcinoma To Immune Checkpoint Inhibitors: A Case Report

Abstract Disclosure: J. Park: None. W. Choi: None. A. Hong: None. J. Yoon: None. H. Kim: None. H. Kang: None. Background: ACTH-secreting pituitary carcinoma transformed from Cushing’s disease is very rare and has aggressive characteristics with limited treatment options. We report a case of ACTH-secreting pituitary carcinoma patient who showed a excellent response to immune checkpoint inhibitors (ICIs). Clinical Case: A 70-year-old female presented with a rapidly growing pituitary carcinoma transformed from Cushing’s disease after bilateral adrenalectomy. Her tumor initially responded to 6 cycles of temozolomide and 7 cycles of temozolomide plus capecitabine. However, multiple brain and pulmonary metastases were newly seen on following imaging studies and the patient had worsening generalized pigmentation on her whole body with newly developed headache, diplopia, and ptosis of the left eye. After introduction of three cycles of ipilimumab plus nivolumab therapy, her plasma ACTH level decreased dramatically from 58,000 pg/ml to 198 pg/ml with improving skin pigmentation and headache episodes. We maintained nivolumab and observed that the plasma ACTH level be normalized to 44 pg/ml (normal range: 6 – 60 pg/ml). Her follow-up brain MRI and chest CT scan also showed marked response, some of the chest lesions even showed nearly complete response (figure 1). On the last follow-up visit, we confirmed that she was in good general condition and tolerable to nivolumab maintenance therapy with glucocorticoid replacement. Conclusion: Immune checkpoint inhibitors (ICIs) may be effective therapeutic options in aggressive pituitary carcinoma and can be considered in temozolomide resistant cases. Moreover, because of the excessively high cost, we emphasize the necessity of clinical trials of ICIs for rare diseases like pituitary carcinomas to expand insurance coverage and reduce the unmet needs of medical care.

THU108 Pituitary Carcinoma Diagnosed After Ten Years Of Smoldering Ectopic Nasopharyngeal Cushing’s

Abstract Disclosure: L. Carafone: None. E. Vates: None. M. Johnson: None. I. Shafiq: None. Introduction: Pituitary carcinomas are rare and typically carry a poor prognosis. Diagnosis of pituitary carcinoma is made when there is metastasis to one or more sites distant from the pituitary, including craniospinal or systemic metastases. Clinical Case: A 54-year-old man presented to the endocrine clinic in 2011 with recurrent urinary tract infections, thoracic compression fractures, uncontrolled hypertension with hypokalemia, and weight gain. Examination revealed facial plethora, supraclavicular fat pad, central obesity, multiple ecchymoses, proximal muscle weakness and muscle atrophy of the upper and lower extremities. Workup demonstrated abnormal 1 mg overnight dexamethasone suppression test (cortisol after 1 mg dexamethasone 25.7 mcg/dL, n≤1.8 mcg/dL), elevated salivary cortisol (4340 and 2950 ng/dL, n≤99 ng/dL), elevated 24 hr urinary-free cortisol (271.7 mcg/24hr, n≤60 mcg/24 hr), and elevated ACTH (240 pg/mL, n≤46 pg/mL). MRI brain showed a large, lobulated mass in the sphenoid sinus adjacent to the inferior left lateral aspect of the pituitary fossa. He underwent surgical resection of the mass and pathology was consistent with pituitary adenoma, corticotroph cell type. Following surgery, laboratory studies showed normal salivary cortisol (&amp;lt;50 ng/dL, n≤99 ng/dL) and 24 hr urinary-free cortisol (22.4 mcg/24hr, n≤60 mcg/24 hr). After two years of sustained remission, he experienced local recurrence for which he underwent repeat surgery with subsequent remission. One year later, this was again followed by recurrence for which he was treated with intensity-modulated radiation therapy and medical therapies including cabergoline, ketoconazole and eventually metyrapone. Six years after the second surgery, MRI showed increasing heterogeneous enhancement at the postoperative site, and he underwent a third surgery with tumor resection and the same pathology results as the initial resection. He was subsequently treated with fractionated proton therapy. He continued to require metyrapone to manage hypercortisolism despite reassuring serial MRI scans. A right neck mass was palpated in 2022 and CT demonstrated a right level 2b lymph node measuring 2.3 x 1.8 x 2.3 cm. FNA revealed neoplastic cells and he underwent right neck dissection with excision of the lymph node. Pathology was consistent with pituitary tumor, corticotroph cell type. Given metastasis of the pituitary tumor to a cervical lymph node, a diagnosis of pituitary carcinoma was made. Conclusion: The time course in pituitary carcinoma is highly variable from the initial diagnosis of the pituitary tumor to the diagnosis of metastatic disease. In this case, the diagnosis of pituitary carcinoma was made nearly one decade after the initial identification of a pituitary tumor. Metastatic disease should be considered in aggressive pituitary tumors when biochemical and radiologic findings are discordant. Presentation: Thursday, June 15, 2023

FRI324 Pituitary Macroadenoma With Carcinomatous Transformation And Multiple Cranial Masses And Spinal Leptomeningeal Carcinomatosis: A Case Report

Abstract Disclosure: C. Cristancho: None. G. Szabo: None. Background: Aggressive pituitary tumors are invasive tumors not responding to standard therapies and presenting with multiple local recurrences; if metastases occur, the tumors are defined as pituitary carcinoma (PC) Clinical Case: 51- year-old Hispanic woman with history of pituitary macroadenoma diagnosed at the age of 41, when presented with weight gain and decrease in visual acuity. Per records initial Brain MRI reported hyperintense sellar lesion of 2.1x2.3x2.6 cm with supra-sella extension and shift of optic chiasm. Patient had 4 pituitary surgeries between 2014-2018 due to growth and had radiation and Temozolomide between 2018-2020. Pathology was diffusely positive for ACTH, PRL, and Ki-67 was 10-20%, P 55 positive staining was 25-30%. As a result from pituitary surgeries patient developed central hypothyroidism, and central AI. Subsequent mornings cortisol were nl between 16-18. No UFC or LNSC were available. MEN1 negative. Brain MRIs done between 2019 and 2020 showed stable 13x8 mm residual pituitary mass with postoperative changes. Patient denied history of diabetes, fragility fractures, HTN, DVTs. She had regular menstrual periods until age of 42. Had left adrenal mass resection in 2019 with benign pathology results. During her initial endocrinology visit her ROS was positive for lower back pain and mild proximal muscle weakness. Patient denied visual changes, headaches, skin changes, polydipsia or polyuria. Physical exam was remarkable for small buffalo hump, and 5-/5 proximal muscle weakness. Negative for moon face, purple striae, acanthosis nigricans, hirsutism, acne. Initial tests were consistent with ACTH-dependent CS: elevated cortisol PM: 18.2 (n &amp;lt;10ug/dL) and LNSC 0.58 and 0.64 mcg/dl (n &amp;lt;0.09), 24-hr UFC 264 (n &amp;lt;50 mcg/dl), abnormal ACTH 150 (n &amp;lt;50 pg/ml).Brain MRI revealing extra-axial mass of 1.6 x1.1 cm overlying posterior aspect of right cerebellar hemisphere and focal lesion in left prepontine cistern of 0.8 cm. Leptomeningeal Enhancement. No sellar mass. Spine MRI showed scattered nodules lining the cord throughout the cervical and upper thoracic spine concerning for metastatic disease. Right cerebellar mass biopsy positive for metastatic pituitary neuroendocrine tumor corticotroph cell subtype, ACTH, chromogranin A, synaptophysin positive; PRL, TSH, GnRH, alpha subunit staining was negative; Ki-67 of 2%. Temozolomide, Capecitabin, and Ketoconazole 200 mg TID were started. Subsequent LNSC &amp;lt;0.03 and &amp;lt;0.03 mcg/dl, UFC at 3 different times were 12.8, 11.2 and 8.1 mcg/dl showing rapid decrease of cortisol levels in a 4-week period. A block-replace approach was decided with Dexamethasone 1 mg daily and a lower dose of Ketoconazole 200 mg BID. Patient reports no side effects. Presentation: Friday, June 16, 2023

Regulation of long noncoding RNAs in the pathogenesis and clinical implications of pituitary adenomas.

Pituitary adenoma (PA) is a type of tumor that develops in the sella turcica and is one of the most frequent intracranial tumors. It belongs to a type of adenoma derived from a single clone of cells in the pituitary gland. PA ranks third among all intracranial tumors, following only gliomas and meningioma. The average prevalence rate is approximately 15% at autopsy and 22.5% at radiological examinations. Most PAs are benign and non-invasive adenomas that can be removed surgically or controlled with medication. However, approximately 35% of them show invasion into nearby anatomical structures and cannot be completely resected. 0.1%~0.2% of PA cases eventually develop into pituitary carcinomas. Additionally, PA may cause severe morbidity due to mass effects and the disorder of pituitary hormone secretion. Therefore, there is an urgent need to clarify the pathological mechanism of PA, improve the accuracy of diagnosis, and develop targeted therapies. Although current knowledge about the pathogenesis of PA remains limited, epigenetic modulation of PA has been increasingly implicated. Long non-coding RNAs (lncRNAs) are known to regulate gene expression post-transcriptionally and exert substantial roles in the initiation, progression, or suppression of various tumors. Accumulating evidence has shown close relationships between lncRNA dysregulation and PA development. This review highlights recent progress in the study of lncRNAs in PA pathogenesis and their potential as diagnostic/prognostic biomarkers or therapeutic targets for PA patients.