The epigenetic landscape and tumor microenvironment (TME) interactions of non-functioning pituitary adenomas (NFPAs), benign tumors with high morbidity and recurrence rates, are not well characterized. We completed single-nucleus (sn) multiomics assays on 4 gonadotrope NFPAs (34,819 cells) and 11 non-diseased postmortem control pituitaries (51,535 cells), finding decreased proportions of tumor-associated endothelial cells and pericytes and increased proportions of macrophages. We identified bidirectional tumor-macrophage crosstalk comprising nine ligand-receptor interactions and experimentally validated the macrophage-initiated SFRP1-FZD6 interaction, whose predicted target genes CCND1, CDK6, SGK1, and TGFBR2 were linked to tumorigenesis. We uncovered coordinated gene expression and chromatin accessibility programs, which distinguished adenoma cells from gonadotropes. Integrated transcriptome-chromatin modeling revealed gene regulatory circuits (GRCs) that showed altered activity in adenoma cells and were regulated by transcription factors (TFs), including PBX3 and MEF2C. Our study provides insight into the altered epigenetic gene control landscape and TME processes of the NFPA tumor phenotype. Our data are freely available at https://rstudio-connect.hpc.mssm.edu/nfpa_browser/.

Pituitary adenomas are the most frequent cause of hypopituitarism in adults, due to the mass effect of the lesion on the pituitary gland, and/or their treatments (particularly surgery and/or radiotherapy). Prolactinomas represent the most frequent histotype of hormone-secreting pituitary adenomas. As is well known, high prolactin levels induce a suppression of the gonadotropic axis and subsequent hypogonadotropic hypogonadism. Overall, the reported prevalence of hypopituitarism is highly heterogeneous in the different studies, depending on the definition used and the cohort examined. Treatment of prolactinomas, whether medical or surgical, can lead to improvement or recovery of pituitary function in a substantial proportion of patients, particularly of the gonadal axis. Conversely, new pituitary deficits can also develop after surgical treatment or, more frequently, radiotherapy. In this review, we aim to summarize the currently available literature data on hypopituitarism in patients with prolactinoma, in order to better characterize patients requiring replacement therapy.

This study was conducted to evaluate the association between the implementation of the WHO 2017 and 2022 classification updates for pituitary tumours and the validity of ICD-10 codes in identifying nonfunctioning and functioning subtypes of pituitary neuroendocrine tumours (PitNETs) in a real-world surgical cohort. We analysed data from 1,096 surgically treated PitNET patients at a major Chinese medical centre between January 2020 and April 2024. The validity of the ICD-10 codes for identifying nonfunctioning and functioning PitNET subtypes was assessed using prepathological discharge diagnoses as the reference standard. The performance metrics, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Youden index, F1 score, and kappa statistic, were calculated for each subtype. These validity measures were then compared between cases classified according to the 2017/2022 WHO criteria and those classified using the pre-2017 criteria in pathological reports. ICD-10 code sensitivity was lowest for nonfunctioning PitNETs (72.9%; 95% CI: 69.1-76.3), followed by functioning gonadotrophs (83.3%; 95% CI: 36.5-99.1) and corticotrophs (84.0%; 95% CI: 77.4-89.0), while other subtypes maintained high sensitivity (97.9%-100%). Most subtypes had low PPVs (6.3-75.0%), except for nonfunctioning and somatotroph PitNETs. The nonfunctioning PitNET code also had a low NPV (73.8%; 95% CI: 70.1-77.2). When cases were pathologically classified using the updated 2017/2022 WHO criteria, a substantial decrease in sensitivity for nonfunctioning PitNETs was observed (94.7% to 63.0%, p < 0.001), which coincided with a reduced NPV, F1 score, and kappa, despite increased specificity (95.8% vs. 86.8%, p < 0.01). Similarly, under the new classification, corticotroph PitNETs had decreased specificity (100.0% to 92.8%, p < 0.001), PPV (94.8% to 64.6%, p < 0.001), and composite metrics. Notably, low PPVs persisted for lactotroph (59.2%) and gonadotroph (5.1%) PitNETs. Coding discrepancies primarily involved confusion with new pathological terminology and misapplication of endocrine codes for pituitary stalk compression effects. The updated WHO classifications enhance pathological detail but should not guide clinical ICD coding, as misapplication reduces coding accuracy in surgically managed PitNETs. Future frameworks must align pathological nomenclature with clinical endocrine function in the ICD, maintaining a clear distinction between these domains. Multidisciplinary collaboration and standardized coding protocols are essential for improving accuracy. Not applicable.

Gonadotroph pituitary tumors (GnPiT) represent 70-75% of clinically non-functioning tumors in surgical series. Their proportion has increased with the diagnostic use of transcription factors in addition to gonadotropin immunostaining, but the prevalence of functioning cases has not been re-evaluated. The aim is to provide a comprehensive, up-to-date characterization of GnPiT, including pathological subtyping and search for whispering/functioning cases (w/fGnPiT). A single-center retrospective study of patients who received a pathological diagnosis of GnPiT between 2020 and 2022. Clinical, hormonal, and pathological data were analyzed according to sex and age, with short-term post-operative re-evaluation. Histological subtypes were defined according to hormone immunostaining. 151 patients (103 M, 48 F) were studied. The diagnosis was incidental in 72 cases (48.0%). Age distribution at diagnosis was normal in males (median 63 years (25-89)), and bimodal in females (median age 58 years (26-84)). A single case of overt hyperfunction, revealed by ovarian hyperstimulation syndrome, occurred. The prevalence of likely w/fGnPiT was estimated at 6.0% (M: 7.7%, F: 2.1%) including nine cases showing characteristics consistent with pre-operative mild hormone secretion (1 F, 8 M). FSH hypersecretion was predominant, all but two w/fGnPiT had FSH/LH immunostaining. FSH/LH tumors were also the most prevalent in the whole series (63.6%) followed by FSH-, LH- and hormone-negative cases (27.1%, 4.0% and 5.3%, respectively). No significant differences in macroscopic or pathological characteristics were found among pathological subtypes. Clinically relevant hypersecretion remains uncommon in GnPiT but may be under-evaluated. No significant differences in tumor behavior emerged among pathological subtypes.

Pituitary neuroendocrine tumors (PitNETs) are among the most common tumors encountered in neurooncology. While the majority of PitNETs demonstrate indolent behavior, a subset of tumors demonstrates aggressive behavior, including invasion into surrounding structures. As traditional imaging has limited capacity to distinguish tumor from post-operative changes, better methods of tumor delineation are needed to guide management. Somatotroph adenomas are known to express high levels of SSTR2, and SSTR2-targeting PET imaging has shown clinical utility in the management of neuroendocrine tumors and meningiomas. In this retrospective study of archival PitNETs (n = 271) and autopsy controls (AC) (n = 20), we show that although significant differences in SSTR2 immunostaining are appreciable between adenoma subtypes and ACs, high-staining cases are encountered in all subtypes. In ACs, females demonstrated significantly stronger SSTR2 staining than males. Weak age-related trends towards increasing labelling in females and decreasing labelling in males were noted but these did not reach statistical significance. Decreasing age-related trends were seen in gonadotrophs in both sexes; this was statistically significant in females. Our findings suggest that SSTR2-targeting imaging modalities may assist clinical management of a subset of PitNETs and that these results may need to be interpreted with consideration of patient age and sex.