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Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a ‘classical’ pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition.Anterior pituitary tumours (APTs) are usually benign but sometimes exhibit aggressive behaviour. In very rare cases, they metastasize and are termed pituitary carcinomas. Here, the authors provide an overview of APTs and pituitary carcinomas, including their epidemiology, diagnosis, predictive markers, and current and emerging therapeutic approaches.

Abstract Aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs) are heterogeneous with regard to clinical presentation, proliferative markers, clinical course, and response to therapy. Half of them show an aggressive course only many years after the first apparently benign presentation. APTs and PCs share several properties, but a Ki67 index greater than or equal to 10% and extensive p53 expression are more prevalent in PCs. Mutations in TP53 and ATRX are the most common genetic alterations; their detection might be of value for early identification of aggressiveness. Treatment requires a multimodal approach including surgery, radiotherapy, and drugs. Temozolomide is the recommended first-line chemotherapy, with response rates of about 40%. Immune checkpoint inhibitors have emerged as second-line treatment in PCs, with currently no evidence for a superior effect of dual therapy compared to monotherapy with PD-1 blockers. Bevacizumab has resulted in partial response (PR) in few patients; tyrosine kinase inhibitors and everolimus have generally not been useful. The effect of peptide receptor radionuclide therapy is limited as well. Management of APT/PC is challenging and should be discussed within an expert team with consideration of clinical and pathological findings, age, and general condition of the patient. Considering that APT/PCs are rare, new therapies should preferably be evaluated in shared standardized protocols. Prognostic and predictive markers to guide treatment decisions are needed and are the scope of ongoing research.

Abstract Context Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Abstract Objective To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. Methods In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. Results Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). Conclusion This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

Abstract Context Recent studies suggest that the clinical characteristics and biological behavior of pituitary tumors (PITs) in patients with multiple endocrine neoplasia type 1 (MEN1) may not be as aggressive as previously reported. Increased imaging of the pituitary as recommended by screening guidelines identifies more tumors, potentially at an earlier stage. However, it is unknown if these tumors have different clinical characteristics in different MEN1 mutations. Objective To assess characteristics of patients with MEN1 with and without PITs, and compare among different MEN1 mutations. Methods Data of patients with MEN1 in a tertiary referral center from 2010 to 2023 were retrospectively analyzed. Results Forty-two patients with MEN1 were included. Twenty-four patients had PITs, 3 of which were invasive and managed with transsphenoidal surgery. One PIT enlarged during follow-up. Patients with PITs had a higher median age at MEN1 diagnosis than those without PITs. MEN1 mutations were identified in 57.1% of patients, including 5 novel mutations. In patients with PITs, those with MEN1 mutations (mutation+/PIT+ group) had more additional MEN1-associated tumors than those without (mutation−/PIT+ group). The mutation+/PIT+ group had a higher incidence of adrenal tumors and a lower median age at initial manifestation of MEN1 than the mutation−/PIT+ group. The most common neuroendocrine neoplasm was nonfunctional in the mutation+/PIT+ group and insulin-secreting in the mutation−/PIT+ group. Conclusion This is the first study comparing characteristics of patients with MEN1 with and without PITs harboring different mutations. Patients without MEN1 mutations tended to have less organ involvement and it might be reasonable for them to receive less intensive follow-up.

Abstract Purpose Pituitary gangliocytomas (GCs) are rare neuronal tumors that present with endocrinological disorders, such as acromegaly, amenorrhea-galactorrhea syndrome, and Cushing’s disease. Most pituitary GCs coexist with pituitary adenomas pathologically and are diagnosed as mixed gangliocytoma-adenomas. Herein, we report a case of 45-year-old man who presented with the syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) and discuss the pathogenesis of pituitary GCs. Methods Pituitary magnetic resonance imaging showed an 8-mm homogeneous and poorly enhanced mass inside the pituitary gland. Endoscopic transsphenoidal surgery was performed under a preoperative diagnosis of thyrotroph adenoma. However, the tumor was finally diagnosed as gangliocytoma without an adenomatous component. The tumor was further analyzed via immunohistochemistry and electron microscopy. Additionally, we searched MEDLINE and PubMed for previously published cases of isolated pituitary GCs and analyzed the reported clinicopathological findings. Results The patient showed complete clinical and endocrinological recovery after an operation. The tumor was positive for thyrotropin (TSH), TSH-releasing hormone (TRH), Pit-1, GATA-2, and most neuronal markers. Electron microscopy demonstrated the presence of intracytoplasmic secretory granules and neuronal processes. Co-secreting hypothalamic and pituitary hormone inside the tumor indicated autocrine/paracrine endocrinological stimulation. Conclusion Herein, we report a case of SITSH caused by an isolated pituitary gangliocytoma, expressing both TSH and TRH, which, to our best knowledge, is the first reported case of such a condition. The multidirectional differentiation and multihormonal endocrine characteristics of these tumors indicate that they are a member of neuroendocrine neoplasms, further supporting that they are derived from neural crest cells.

Abstract Context The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. Objective Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). Methods We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. Results Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. Conclusion This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.

Key Words: pituitary adenoma, pituitary tumor, pituitary neuroendocrine tumor

The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein ( AIP ) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP -mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip -knockout ( Aip Flox/Flox ;Hesx1 Cre/+ ) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIP pos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip -knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP -mutation-positive human adenomas. Aip -knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP -mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.