OBJECTIVE: This study investigates the rare occurrence of tumor-to-tumor metastasis in Pituitary Neuroendocrine Tumors (PitNETs), also known as pituitary adenomas, aiming to enhance understanding of its diagnostic and therapeutic challenges. We report two cases from our institution of tumor-to-tumor metastasis involving PitNETs, followed by a systematic literature review.
METHODS: We conducted a comprehensive literature review using PubMed and Google Scholar databases. This review provides insights into patient demographics, clinical presentations, primary tumor origin, management approaches and outcomes.
RESULTS: We identified 38 documented cases of tumor-to-tumor metastasis involving the pituitary gland in the literature. This revealed a diverse range of primary tumor origins, with lung, breast, and renal carcinomas being the most prevalent. Clinical presentations varied, with visual disturbances emerging as the most frequently reported symptom. Surgical interventions predominantly resulted in subtotal resection. Kaplan-Meier survival analysis demonstrated that endoscopic endonasal approaches (EEA) are associated with longer median survival times compared to other surgical methods.
CONCLUSIONS: Tumor-to-tumor metastasis to PitNETs must be considered in differential diagnoses of sellar masses. Prompt and accurate diagnosis, coupled with a multidisciplinary treatment strategy, is essential. Our study contributes to the scarce literature on such metastases, providing a foundation for further understanding of this complex pathological entity.

OBJECTIVE: In surgical practice during endoscopic endonasal approach (EEA), Growth Hormone-secreting Pituitary Neuroendocrine Tumors (GH-secreting PitNET) patients show morphologic differences in the nasal cavities and sinuses, leading to a narrower surgical field and a carotid prominence and potentially increasing the complexity of the surgical and the risk of complications. The aim of the study is to evaluate the anatomical differences of the sphenoid sinus between patients with GH-secreting PitNETs and patients with non-functioning Pituitary Neuroendocrine Tumors (NF-PitNET) underwent EEA.
METHODS: This is a monocentric retrospective study conducted at author\'s institution. The minimum intercarotid distance (ICS), the largest diameter of the sphenoid sinus (DSS) and the distance between vomer and clivus (VCD) were collected and compared. Presence, localization and course of intersphenoid sinus septum (ISS) were also evaluated.
RESULTS: 100 consecutive patients were identified: 57 males (57%) and 43 females (43%), with a mean age of 55 years. 60 patients had NF-PitNET (60%) and 40 had GH-secreting PitNET (40%). GH-secreting PitNET group presented inferior values of ICD (16.8±3.94 mm vs. 20.4±3.94 mm, p<0.001), DSS (32.5±9.81 mm vs. 38.6±11.03 mm, p=0.006) and VCD (25.5±6.96 mm vs. 29.6±8.47 mm, p=0.012) compared to NF-PitNET group. ISS showed no differences between the two groups.
CONCLUSIONS: ICD, DSS and VCD resulted smaller in acromegalic patients, confirming that patients with GH-secreting PitNETs have a narrower surgical field. A meticulous anatomical preoperative planning and neuronavigation are important to recognize the sphenoid anatomical landmarks in order to reduce the risk of complications, especially in acromegalic patients.

Aggressive pituitary neuroendocrine tumors (PitNETs) present significant morbidity, and multimodal therapies including surgery, radiotherapy, and medications are frequently required. Chemotherapy, particularly temozolomide, is often pursued for tumors that progress despite these treatments. Although peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs is approved for the treatment of well-differentiated gastrointestinal neuroendocrine tumors, its use in aggressive PitNETs is limited. We describe the case of a 65-year-old man who presented with vision changes and hypopituitarism at age 33 secondary to a nonfunctioning gonadotroph PitNET. His initial treatment included a craniotomy followed by radiation therapy. With tumor regrowth, he required transsphenoidal surgeries at age 44 and age 52. At age 56, further tumor regrowth and a positive octreotide scan prompted treatment with long-acting octreotide for 1 year. Given absent tumor response, 12 cycles (4 treatment cycles and 8 maintenance cycles) of PRRT with 177Lutetium-DOTATATE were pursued. This resulted in partial response with significant tumor shrinkage. Notably, there was no tumor regrowth 40 months after treatment discontinuation. This is only the second report on the effectiveness of PRRT in patients with aggressive gonadotroph PitNETs. We also provide an overview of PRRT for PitNETs and describe clinical outcomes previously reported in the literature.

Introduction  Pituitary neuroendocrine tumors (PitNETs) are rare skull base tumors which can impart significant disability owing to their locally invasive potential. To date, the gamut of PitNET subtypes remains ill-understood at the ligand-receptor (LR) interactome level, potentially limiting therapeutic options. Here, we present findings from in silico analysis of LR complexes formed by PitNETs with clinical presentations of acromegaly, Cushing\'s disease, high prolactin production, and without symptoms of hormone hypersecretion. Methods  Previously published PitNET gene expression data was acquired from ArrayExpress. These data represented all secretion types. LR interactions were analyzed via a crosstalk score approach. Results  Cortisol (CORT) ligand was significantly involved in tumor-to-tumor signaling across all PitNET subtypes but prolactinomas, which evidenced active CORT depletion. Likewise, CCL25 ligand was implicated in 20% of the top LR complex interactions along the tumor-to-stroma signaling axis, but silent PitNETs reported unique depletion of the CCL25 ligand. Along the stroma-to-tumor signaling axis, all clinical PitNET subtypes enriched stromal vasoactive intestinal polypeptide ligand interactions with tumor secretin receptor. All clinical PitNET subtypes enriched stromal DEFB103B (human β-defensin 103B) ligand interactions with stromal chemokine receptors along the stroma-to-stroma signaling axis. In PitNETs causing Cushing\'s disease, immune checkpoint ligand CD274 reported high stromal expression, and prolactinomas reported low stromal expression. Moreover, prolactinomas evidenced distinctly high stromal expression of immune-exhausted T cell response marker IL10RA compared with other clinical subtypes. Conclusion  Relative crosstalk score analysis revealed a great diversity of LR complex interactions across clinical PitNET subtypes and between solid tumor compartments. More data are needed to validate these findings and exact clinical importance.

BACKGROUND: Invasion of the CS is one of the limiting factors for total resection for PitNet tumors with cure rates less than 30%. Extended approaches may be considered in selective and well-studied cases of secreting adenomas.
METHODS: We describe the key steps of the endoscopic transcavernous approach for functional pituitary adenomas with a video illustration. The surgical anatomy is described along with the advantages and limitations of this approach.
CONCLUSIONS: A detailed knowledge of CS anatomy and familiarity with this surgical approach acquired in the laboratory is essential. Proper instrumentation is critical to decrease the risks of vascular injury.

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.
Несмотря на медленный рост большинства опухолей гипофиза, высокие показатели их радикального удаления и/или эффективность медикаментозных методов лечения, в 10% случаев опухоли гипофиза проявляют «агрессивное поведение» с высокой скоростью роста, частыми рецидивами и резистентностью к стандартным методам лечения. В современных классификациях опухолей центральной нервной системы и эндокринных и нейроэндокринных опухолей Всемирной организации здравоохранения вместо ранее применяемого термина «аденома гипофиза» предложено использовать дефиницию «гипофизарная нейроэндокринная опухоль», вместо термина «карцинома гипофиза» — «метастазирующая гипофизарная нейроэндокринная опухоль». В настоящее время отсутствуют надежные прогностические маркеры агрессивного поведения опухолей, вследствие чего их ранняя диагностика затруднена. Предлагается применять пятиступенчатую прогностическую классификацию, основанную на оценке пролиферации (включая количество митозов, индекс мечения Ki-67 и иммуноэкспрессию p53) в сочетании с морфометрическими маркерами инвазивности, всех удаленных новообразований гипофиза для более раннего выявления агрессивных опухолей и карцином гипофиза. Компрессия зрительных путей, III желудочка, ствола мозга вследствие быстрого роста агрессивных опухолей в большинстве случаев требует повторных операций с последующим проведением лучевого лечения, в случае гормонально-активных опухолей — терапии аналогами соматостатина, агонистами дофамина в максимально переносимых дозах. При неэффективности стандартных методов лечения рекомендована химиотерапия, первой линией которой является темозоломид. В качестве альтернативных направлений в лечении применяется пептидная рецепторная радионуклидная терапия, молекулярно-таргетная терапия (бевацизумаб, ингибиторы тирозинкиназы, эверолимус и ингибиторы циклинзависимых киназ), а также иммунотерапия (ингибиторы контрольных точек иммунного ответа). Учитывая необходимость комбинированного лечения, эти случаи всегда должны обсуждаться мультидисциплинарной командой экспертов (нейрохирург, эндокринолог, радиотерапевт, онколог, патоморфолог), обладающих необходимой квалификацией и имеющих опыт лечения больных с этой патологией. Лечение агрессивных опухолей и карцином гипофиза становится активной и быстро развивающейся областью нейрохирургии, эндокринологии и онкологии.

The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation.

GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16-1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.

Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown. We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization. Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs. Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.