Pituitary neuroendocrine tumors (PitNETs) can be invasive or aggressive, yet the mechanisms behind these behaviors remain poorly understood, impeding treatment advancements. Here, we integrat single-cell RNA sequencing and spatial transcriptomics, analyzing over 177,000 cells and 35,000 spots across 57 tissue samples. This comprehensive approach facilitates the identification of PitNETs tumor populations and characterizes the reconfiguration of the tumor microenvironment (TME) as PitNETs progress and invade. We trace the trajectory of TPIT-lineage PitNETs and identify an aggressive tumor cluster marked by elevated p53-mediated proliferation and a higher Trouillas classification, both associated with tumor progression. Additionally, we document the heterogeneity of immune stromal cells within PitNETs, particularly noting the enrichment of SPP1+ tumor associated macrophages (TAMs) in invasive tumors. These TAMs facilitate tumor invasion through the SPP1-ITGAV/ITGB1 signaling pathway. Our in-depth single-cell and spatial analysis of PitNETs uncovers the molecular dynamics within the TME, suggesting potential targets for therapeutic intervention.

Objective The etiologic diagnosis of pituitary stalk thickening (PST) remains a major challenge because biopsies of the pituitary stalk are difficult to obtain. This study summarized the etiologies of PST and the natural course of indistinguishable PST. Methods Patients with magnetic resonance imaging (MRI)-confirmed PST at Peking Union Medical College Hospital from January 2014 to May 2017 were reviewed. Clinical information, including the symptoms at onset and laboratory, imaging, operative, pathological and follow-up data, was collected. Results Of 321 eligible PST patients, 28.3% were pediatric patients under 18 years of age. Central diabetes insipidus was the initial symptom in 68.8% of patients. A total of 57.6% of patients had at least one anterior pituitary hormone deficit. The adjusted OR of panhypopituitarism associated with hypothalamus involvement was 7.3 (95% CI 3.0-17.8, p<0.001). Confirmed diagnoses were established in 137 (42.7%) patients, including neoplasms (n=103, 75.2%), inflammation (n=18, 13.1%) and congenital anomalies (n=16, 11.7%). Intracranial germ cell tumors (66.7%) were the leading cause among pediatric patients, while histiocytoses (20.0%) and malignant metastases (14.7%) were the most common causes in adults. Thirty-eight patients with indistinguishable PST underwent a second MRI at a median time of 4.4 months (0.8-9.7). After a median time of 8.5 months (0.8-35.2), spontaneous remission was observed in 17 of these patients (44.7%), with complete remission in 14 (36.8%) and partial remission in 3 (7.0%); five (13.2%) patients exhibited progression, and the remaining 16 (42.1%) stabilized. Conclusion PST is highly heterogeneous, and most confirmed cases are attributed to neoplasms. The etiology spectrum varies greatly with age. Physicians must be familiar with the major differential diagnoses, necessary investigations and follow-up. Biopsy is indicated when radiological progression and/or worsening of pituitary function is detected.