Research Topic Diagnosis and Treatment of Non-Functioning Pituitary Tumors

Murat Aydin Sav ^*

• Yeditepe University, Istanbul, Türkiye

As defined in the WHO 2017 classification, pituitary adenoma evolved into PitNET in the recent WHO Classification by WHO 2022. In the relevant literature, PA (pituitary adenoma) and PitNET (pituitary neuroendocrine tumor) have been used interchangeably, and NFPA and NF-PitNET for nonfunctioning pituitary adenoma. Nonfunctioning pituitary adenoma (NF PitNET) is a relatively rare anterior pituitary tumor originating from hormone-producing neuroendocrine cells of the adenohypophysis. Clinical implications depend on the mass effect of sellar or parasellar locations unaccompanied by any clinical signs of hormonal hypersecretion. The most typical manifestations are visual disturbances, headaches, cranial nerve dysfunction, and hypopituitarism. They might be discovered incidentally. [1] Non-functioning pituitary adenomas (NFPAs) are among the most common tumors in the sellar region. They account for 15-30% of pituitary adenomas. These lesions do not cause hyperpituitarism. In most cases, they are found incidentally (particularly microadenomas), or their mass effect gives rise to compressive symptoms such as headache and visual field defects, as well as hypopituitarism. The clinical term "non-functioning" is not a diagnosis but a description of a clinical scenario with many differential diagnoses. The most common lesion is a gonadotroph tumor, as described above; they constitute about 70-75% of clinically non-functioning pituitary adenomas. [1,2]. Non-functioning pituitary adenomas are segregated depending on age. Silent PitNETs are silent corticotroph tumors among adult tumors. [1]. Immature PIT1-lineage tumors are predominantly seen in younger age groups among non-functioning NFPAs. [3]. Clinically silent corticotroph and silent PIT1-lineage tumors, including the non-functional immature PIT1-lineage tumors, show a biological aggressive pattern. [4] Diagnosis is usually made in the context of mass effect due to a macroadenoma or, increasingly, fortuitously during imaging performed for unrelated purposes; the latter case is known as pituitary incidentaloma. Surgery is indisputably indicated in the case of tumoral syndrome. However, other aspects of NFPA (hormonal work-up, follow-up, especially postoperative follow-up, management of remnant or recurrence, the special case of incidentaloma, or apoplexy) remain controversial. [5] Invasive non-functional pituitary adenomas constitute 35% of NFPAs. Although a vast number of ongoing studies have investigated the complete underlying molecular mechanisms of the invasive potential of NFPA, they have not yet deciphered the underlying molecular mechanisms of invasiveness. [6] Diagnostic issues of NF-PitNET are problematic in pathology and clinical science. Chang et al. investigated bioactive molecules carrying small vesicles and exosomes, imparting RNA to regulate recipient cells. Exosomes bear a specific microRNA, hsa-miR-1180, as an early tumor NF-PitNET biomarker. The hsa-miR-21-5p accelerates distant osteogenesis in GHPA. Exosomal protein transcripts are potential invasive biomarkers, such as MMP1, N-cadherin, CDK6, RHOU, INSM1, and RASSF10. In review, Tumor suppressors in the exosome constitute novel therapeutic applications of exosomes, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. Divergent contents of exosomes, such as long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p, participate in cells of NF-PitNETs mechanisms to be used in clinical diagnosis and their treatment. https://doi.org/10.3389/fendo.2023.1142494 Recent classification by WHO emphasizes the importance of transcription factors (TF) in diagnosing and treating neoplasms originating from the pituitary gland, namely PitNET. TFs are designated as their molecular profiles, steroidogenic factor (SF-1), T-box family member TBX19 (TPIT), and POU class 1 homeobox 1 (Pit-1). Woo et al. investigated a selected cohort of NF-PitNET cases (n=113) and classified the profiles based on TF distribution. Distribution of NF-PitNET TF profiles was found as the majority of NF-PitNET was SF-1-lineage tumors (58.4%), followed by TPIT-lineage tumors (18.6%), tumors with no distinct lineage (16.8%) and Pit-1-lineage tumors (6.2%). COX regression showed no lineage difference between SF1 and PitNET without any evidence of lineage profile. There was no correlation between tumor volume and PitNet without any lineage, and they were accepted as independent predictors of a composite of residual or recurrent disease. The WHO 2022 classification adds the importance of TFs and lineage-based systems for subtyping in predicting and prognosticating NF-PitNETs. https://doi.org/10.3389/fendo.2024.1368944 As the previous studies showed, NF-PitNETs have little response to therapeutics. Gil et al. 's study linked epithelial-mesenchymal transition (EMT) to resistance to medical treatment in a group of pituitary adenomas. Their research revealed the potential usefulness of medical treatment for NF-PitNET in the detailed study of the expression of somatostatin receptors and dopamine-associated genes. Moreover, SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were accompanied to invasive NF-PitNET. The EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Genetically, PEBP1 overexpression was remarkably high in recurrent NF-PitNETs, giving the impression that it could predict growth recurrence with 100% sensitivity but only 43% specificity. Conclusively, EMT has a place in NF PitNETs. SSTR3 targeting could be a potential therapeutic target in selected cases other than corticotropinoma with low expression of SSTR3. Due to its presence, this molecule could be a predictive indicator of recurrence in NF-PitNETs. https://doi.org/10.3389/fendo.2023.1129213 The well-defined preoperatively and postoperative complications of pituitary adenoma patients were analyzed based on their several signs, such as headache, vomiting, and visual field defects based on improvement. Wang et al. searched the difference between young (<73) and elderly (>73) patients who were classified as functioning and non-nonfunctioning pituitary adenomas. The majority of nonfunctioning pituitary adenoma patients were elderly patients (73,7%) who showed a high degree of suprasellar invasion but a low degree of parasellar invasion (P<0.0001). Older patients suffered from a high incidence of suprasellar invasion, poor postoperative vision improvement, a higher rate of intratumoral bleeding, and comorbid postoperative complications, such as cerebrospinal fluid leakage and fever. Conclusively, specific signs and symptoms associated with the postoperative period of the elderly NFPA cohort needed instant surgical attempts to upright their health conditions. https://doi.org/10.3389/fendo.2024.1385813 NF-PitNETs are resistant to medical therapeutics. Therefore, the intention is to provide knowledge of the biological properties of PitNETs. Wu et al. explored immune infiltration-associated differentially expressed genes (DEGs) by deciphering high/low immune scores calculated by the ESTIMATE algorithm. Also, WGCNA analysis to construct a coexpression network of immune cell-related genes. Random forest analysis selection of candidate genes associated with invasion. Finally, external validation verified gene expressivity using quantitative real-time polymerase chain reaction (qRT-PCR). In conclusion, the 8-gene (BMP6, CIB2, FABP5, HOMER2, MAML3, NIN, PRKG2, and SIDT2) classification model was correlated with acceptable scores verified by qRT-PCR. All of those pivoted roles in invasion and progression may be used as attentive targets for immunotherapy. https://doi.org/10.3389/fendo.2023.1131693