DDRE-41. TREATMENT OF REFRACTORY PITUITARY NEOPLASMS WITH TEMOZOLOMIDE IN THREE PATIENTS

BACKGROUND There is relatively little information regarding the efficacy of temozolomide (TMZ) for pituitary adenomas; less than 100 cases treated with TMZ are reported, with a variable response rate of 50-75%, depending on response criteria. METHODS Retrospective review of patients with pituitary tumors treated with TMZ at University Hospitals Cleveland Medical Center. RESULTS Three patients were identified. Patient age at the time of TMZ treatment was 20, 51, and 70 years. Two were female, one male. Histology was prolactinoma in two and Cushing’s disease in one. Each patient had undergone multiple surgeries and medical treatments with insufficient response or relapse. Two had received radiosurgery; it was withheld in a 20 year old male due to concerns of optic nerve radiation injury. A 5d q 28d regimen was used in each, beginning at 150mg/M2 daily for initial dose then increased to 200mg/M2 daily. Diplopia and headache improved in one patient, whose serum prolactin significantly declined (222.8 to 81.9 ng/ml). Headache resolved in another patient and prolactin remained stable. In the patient with Cushing’s disease, headaches improved and ACTH remained elevated but stable. The tumor remained stable on MRI in each patient. There were no adverse effects from TMZ used over 5 to 29 months. CONCLUSIONS Our clinical experience adds to the limited published information regarding the effectiveness of TMZ for pituitary adenomas. In our case series, clinical improvement was noted in each of 3 patients with pituitary adenomas that had failed or recurred after other therapies. Serum prolactin significantly declined in one patient. This data suggests a beneficial role for TMZ in treating pituitary adenomas.

Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review

Background Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. Case presentation We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. Conclusion PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.

Evaluation of surgery and radiosurgery for acromegaly: A review of efficacy, complications, and follow-up

Background: Acromegaly is a rare disease caused by an over-increase in growth hormone (GH) and insulin-like growth factors. If left untreated, acromegaly is associated with many complications and increased mortality. The three modalities of treatment for this disease are surgery, pharmacotherapy, and radiotherapy. Another treatment option is stereotactic radiosurgery (SRS), which is used as an adjunct and alternative treatment in patients with acromegaly who are not suitable options for surgery. Methods: The present study is a review study conducted by searching the databases of Elsevier, PubMed, Springer, and Wiley, and using the keywords of acromegaly, treatment, transsphenoidal surgery, and radiosurgery. Fifteen studies, which had been performed between 2010 and 2021, were selected for review. Results: The results of these studies indicated that the use of SRS (LINAC SRS and GKRS) after surgery and medical treatment, before surgery and during radiotherapy improve biochemical and endocrine control and the quality of life of patients. However, due to some side effects of these treatments, it is necessary to conduct further studies in this field. Conclusion: All three modalities of treatment would be effective in acromegaly if used with appropriate indication in right sequence. Keywords: Pituitary Neoplasms, Pituitary Gland, Radiotherapy, Radiosurgery, Acromegaly

Identification of an optimal prolactin threshold to determine prolactinoma size using receiver operating characteristic analysis

Prolactinomas represent the most common type of secretory pituitary neoplasms, with a therapeutic management that varies considerably based on tumour size and degree of hyperprolactinemia. The aim of the current study was to evaluate the relationship between serum prolactin (PRL) concentrations and prolactinoma size, and to determine a cut-off PRL value that could differentiate micro- from macro-prolactinomas. A retrospective cohort study of 114 patients diagnosed with prolactinomas between 2007 and 2017 was conducted. All patients underwent gadolinium enhanced pituitary MRI and receiver operating characteristic (ROC) analyses were performed. 51.8% of patients in this study were men, with a mean age at the time of diagnosis of 42.32 ± 15.04 years. 48.2% of the total cohort were found to have microadenomas. Baseline serum PRL concentrations were strongly correlated to tumour dimension (r = 0.750, p = 0.001). When performing the ROC curve analysis, the area under the curve was 0.976, indicating an excellent accuracy of the diagnostic method. For a value of 204 μg/L (4338 mU/L), sensitivity and specificity were calculated at 0.932 and 0.891, respectively. When a cut off value of 204 μg/L (4338 mU/L) was used, specificity was 93.2%, and sensitivity 89.1%, acceptable to reliably differentiate between micro- and macro- adenomas.

Recent Understanding and Future Directions of Recurrent Corticotroph Tumors

Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing’s disease (CD), which has high morbidity and mortality due to hypercortisolemia. “Non-functioning” or silent CTs (SCT) and the Crooke’s cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Both tend toward more aggressive behavior, recurrence, and a higher rate of malignant transformation to pituitary carcinoma. Tumorigenesis involves genetic, epigenetic, and post-transcriptional disruption of cell-cycle regulators, which increase cell proliferation, POMC overexpression, ACTH transcription, and/or hypersecretion. Furthermore, functioning CTs develop resistance to glucocorticoid-mediated negative feedback on ACTH secretion, through increased expression of testicular orphan nuclear receptor 4 (TR4), heat-shock protein 90 (HSP90), and loss-of-function mutation of CDK5 and ABL enzyme substrate 1 (CABLES1) gene. Overt autonomous hypercortisolemia is difficult to control, and multiple diagnostic studies and therapeutic modalities are commonly required. Cell-cycle regulation depends mainly on p27, cyclin E, cyclin-dependent kinases (CDKs), and the retinoblastoma protein (Rb)/E2F1 transcription factor complex. Gain-of-function mutations of ubiquitin-specific protease (USP) 8, USP48, and BRAF genes may subsequently cause overexpression of epithelial growth factor receptor (EGFR), and enhance POMC transcription, cell proliferation, and tumor growth. Epigenetic changes through micro RNAs and decreased DNA deacetylation by histone deacetylase type 2 (HDAC2), may also affect tumor growth. All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation.

Delayed Craniospinal Metastasis of Aggressive Nonfunctioning Pituitary Adenomas as Pituitary Carcinomas

Background Clinical behavior of pituitary neoplasms is peculiar and notoriously difficult to predict. While aggressive tumors are common, metastasis is very rare, can be highly delayed, and there are no histological or clinical features to meaningfully predict this happening. Endocrinologically silent tumors are particularly difficult, as there is less opportunity to detect early metastasis. Together, this amounts to a situation of uncertainty over the appropriate management of such tumors before and after metastasis. Case Description The authors report two cases of nonfunctioning aggressive pituitary adenoma (APA) each requiring two transsphenoidal surgeries, a transcranial resection and radiotherapy. Both these tumors subsequently metastasized caudally along the neuraxis, years later, as a null cell carcinoma associated with a germline CHEK2 mutation and a silent Crooke's cell carcinoma. The former represents a novel oncogenetic association. Conclusion Delayed drop dural metastasis of pituitary carcinoma is becoming increasingly recognized. Surgical resection of the distant disease to confirm the diagnosis and relieve the mass effect, followed by temozolomide chemotherapy, is the current treatment of choice. The need for both long-term follow-up in patients with APA, and a high degree of suspicion toward dural-based radiographic findings is emphasized.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Adenoma hipofisário secretor de TSH: uma revisão sistemática / TSH-secreting pituitary adenoma: a systematic review

Introdução: Os adenomas hipofisários são tumores caracterizados pela proliferação de células adeno-hipofisárias produtoras de hormônios tróficos. Dentre eles, os adenomas hipofisários produtores de TSH (TSHomas), neoplasias benignas pouco frequentes, que correspondem a menos do que 3% dos adenomas hipofisários. Método: Pesquisamos os termos TSHomas, tireotropinomas e adenomas pituitários secretores de TSH nas bases Pubmed, Lilacs e Scielo. Incluímos artigos publicados entre 2010 e 2020, sendo excluídos relatos de casos, artigos indisponíveis e que não tratavam sobre o tema. Resultados e discussão: Os TSHomas são tumores fibrosos, monoclonais, com incidência entre 0,015 a 0,03 casos/100.000 habitantes, que se manifestam por hipertireoidismo e sintomas causados por efeito de massa. São diagnosticados diante da elevação de TSH juntamente a hormônios tireoidianos, na presença de alterações neurorradiológicas. O tratamento de primeira escolha consiste na neurocirurgia transesfenoidal, sendo os análogos de somatostatina e a radioterapia alternativas para o manejo de pacientes em que a intervenção cirúrgica é desaconselhada. Conclusão: Os TSHomas são raros, contudo, precisam ser investigados diante da secreção inadequada de TSH.Palavras chave: Adenoma, Hormônios tireoidianos, Neoplasias hipofisárias, Síndrome da secreção inadequada de TSH, Hipertireoidismo centralABSTRACTIntroduction: Pituitary adenomas are tumors characterized by the proliferation of adenohypophysis cells that produce trophic hormones. Among them, TSH-producing pituitary adenomas (TSHomas), uncommon benign neoplasms, whichcorrespond to less than 3% of pituitary adenomas. Method: We searched for the terms TSHomas, thyrotropinomas and pituitary adenomas secreting TSH in the Pubmed, Lilacs and Scielo databases. We included articles published between 2010 and 2020, excluding case reports, articles that were unavailable and did not deal with the topic. Results and discussion: TSHomas are fibrous, monoclonal tumors, with an incidence of 0.015 to 0.03 cases / 100,000 inhabitants, which are manifested by hyperthyroidism and symptoms caused by a mass effect. They are diagnosed with elevated TSH along with thyroid hormones, in the presence of neuroradiological changes. The first-choice treatment consists of transsphenoidal neurosurgery, with somatostatin analogs and radiotherapy being alternatives for the management of patients in whom surgical intervention is not recommended. Conclusion: TSHomas are rare, however, they need to be investigated due to inadequate TSH secretion.Keywords: Adenoma, Thyroid hormones, Pituitary neoplasms, Inappropriate TSH secretion syndrome, Central hypothyroidism

MON-918 Familial Paraganglioma: Familiar Case Report

Introduction: Pheochromocytomas and Paragangliomas (PGL) are rare tumors originating from chromaffin cells. They may be sporadic or associated with familial inherited genetic syndromes around 50-80%. There are several PGL syndromes, the most common being PGL 1 (SDHD mutations), PGL 2 (SDHAF), PGL 3 (SDHC), PGL 4 (SDHB), PGL 5 (SDHA), PGL 6 (SLC25A11) and PGL 7 (DLST). SDHB mutations generate a higher probability of malignant PGL, as well as risk of renal, GIST and pituitary neoplasms. We report the case of a patient with a positive family history for the autosomal dominant SDHB mutation.Clinical cases: FZR, male, 19 years old, history of headache, sweating, palpitations, and sudden onset tremors associated with hypertensive peaks. Physical examination: Blood Pressure 140x90mmHg lying down, 110x70 standing up. Performed examinations, of which altered, showed: Plasma metanephrines: 82 pg/mL (RV <65), Plasma normetanephrines: 1.488pg/mL (VR <196), Urinary Catecholamines: 1.784mcg/24h (RV: 80-500), Abdomen Resonance showed an expansive, solid, heterogeneous abdomen mass in posterior contact with the left psoas muscle, medial with the aorta, and lateral with jejunum loops, measuring 7x3.5 cm. MIBG scintigraphy: abnormal uptake in left kidney. Family history: uncle diagnosed with cervical paraganglioma with cervical lymph node metastasis, gastric GIST and PCR genetic sequencing identifying mutation in SDHB (Q.137 G > T in exon 2). Asymptomatic second cousin with positive genetic analysis for the same mutation and another deceased first cousin diagnosed with pheochromocytoma with bone metastasis. He underwent tumor resection that identified retroperitoneal paraganglioma with 10% KI67, Protein S-100, Chromogranin-A and Synaptophysin positive. Carried out PCR genetic analysis that identified the same Q.137 G > T mutation in exon 2 of the SDHB gene in heterozygosis.Twenty-six relatives were called for mutation research, of which 5 positive for the SDHB mutation, until now, including the patient’s mother and twin brother, both already investigating related diseases.We await new family members and, subsequently, the result of the mutation analysis to continue the clinical and laboratory follow-up of this family.Conclusion: Although rare, this condition should be remembered as a differential diagnosis of diseases with such clinical symptoms and, once characterized, investigate possible associations with genetic syndromes.

The Past, Present, and Future Statuses of Formerly Classified “Atypical Pituitary Adenomas”: A Clinicopathological Assessment of 101 Cases in a Cohort of More than 1,000 Pure Endoscopically Treated Patients in Single Center

Aim This study was aimed to assess the clinical aggressiveness of pituitary neoplasms that were previously defined as atypical adenomas. Methods A total of 1,042 pituitary adenomas were included in the study and 101 of them were diagnosed as atypical adenoma. Demographic characteristics, radiological evaluations, and clinical information were obtained from a computer-based patient database. Cases were categorized as atypical or typical using the criteria listed in 2004 Classification of Tumors of Endocrine Organs. Results The cure and reoperation rates did not show any statistically significant difference between the typical and atypical adenomas. However, a higher Ki-67 labeling index was found to be associated with a higher rate of reoperation (p = 0.008) in atypical adenomas. Of note, cavernous sinus invasion or parasellar extension was found to be associated with lower cure rates in patients with atypical pituitary adenomas (p < 0.001 and p = 0.001, respectively). Conclusion Although atypical pituitary adenomas are known to be more invasive, this study demonstrated that the reoperation and cure rates are the same for typical and atypical adenomas. Our findings advocate for omitting the use of atypical adenoma terminology based solely on pathological evaluation. As stated in the 4th edition of the World Health Organization (WHO) classification, accurate tumor subtyping, evaluation of proliferation by means of mitotic count and Ki-67 labeling index, and radiological and intraoperative assessments of tumor invasion should be taken into consideration in the management of such neoplasms.