Review Article | DOI: https://doi.org/10.31579/2642-973X/185
1 Dental Surgeon (DDSc),
-Oncologist (MSc), Specialized in Clinical Oncology, Cytology and Histopathology, Dept. of Pathological Anatomy, Medical School, University of Athens, Athens, Greece.
-Resident in Maxillofacial and Oral Surgery, 401 General Military Hospital of Athens, Athens, Greece.
-PhD in Oncology (cand).
-Registrar in Dentistry, NHS of Greece.
2 MD, Registrar in Pathology, Ilioupoli Health Centre – NHS of Greece. Athens, Greece.
*Corresponding Author: Nikolaos Andreas Chrysanthakopoulos, Dental Surgeon (DDSc), Oncologist (MSc), Specialized in Clinical Oncology, Cytology and Histopathology, Dept. of Pathological Anatomy, Medical School, University of Athens, Athens, Greece.
Citation: Nikolaos A. Chrysanthakopoulos, Vassiliki Vazintari, (2026), Molecular Biology of Pituitary Carcinoma and Aggressive Pituitary Neuroendocrine Tumors: A Contemporary Review, J. Brain and Neurological Disorders, 9(5): DOI:10.31579/2642-973X/185
Copyright: © 2026, Nikolaos Andreas Chrysanthakopoulos. This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 01 August 2026 | Accepted: 25 August 2026 | Published: 30 September 2026
Keywords: Pituitary tumors, Molecular profiling, Somatic mutations, TP53, Ki-67 index
Aggressive pituitary neuroendocrine tumors (PitNETs/APTs) and pituitary carcinomas (PCs) represent distinct clinical challenges characterized by profound heterogeneity regarding clinical presentation, proliferative markers, and therapeutic response. Importantly, approximately half of these neoplasms manifest an aggressive clinical course only years subsequent to an initially indolent or apparently benign presentation. While APTs and PCs share overlapping phenotypic and histopathological properties, a Ki67 proliferation index >10% and extensive p53 expression are significantly more prevalent in carcinomas. At the genomic level, somatic mutations within TP53 and ATRX constitute the most frequent genetic alterations, making their early molecular detection a potentially invaluable tool for identifying aggressive behavior prior to overt clinical progression. These underlying oncogenic drivers encompass chromosomal and genomic instability, compromised DNA repair machinery, cell cycle dysregulation, epigenetic aberrations, altered intracellular signaling cascades, and remodeling of the tumor immune microenvironment Elucidating the intricate mechanisms driving pituitary tumorigenesis is critical for developing effective therapeutic strategies specific to these refractory subtypes, which are classically characterized by local invasiveness, high proliferative indices, frequent relapse, and resistance to conventional treatments. Although novel systemic modalities, specifically VEGF-targeted agents and immune checkpoint inhibitors, have been deployed with heterogeneous clinical efficacy, the clinical management of these tumors remains constrained by limited therapeutic options. Therefore, the systematic histopathological and molecular analysis of established prognostic markers must be comprehensively integrated into routine clinical practice.
Pituitary carcinoma (PC) is a rare, malignant intracranial neoplasm defined by distant metastasis of pituitary adenoma (PA). Despite low incidence, PC carries a poor prognosis, with 66% of patients dying within the first year. Current treatments, including surgery, chemotherapy, and radiotherapy, have limited efficacy due to an incomplete understanding of PC’s molecular pathogenesis [1,2,3].
PCs are strictly defined by the presence of non-contiguous cranio-spinal or systemic metastases. While PCs remain exceedingly rare, accounting for a mere 0.1% to 0.4% of all pituitary neoplasms, aggressive pituitary tumors (APTs/ pituitary neuroendocrine tumors-PitNETs) exhibit a higher prevalence, comprising up to 15% of cases depending on the diagnostic criteria employed [1,4].
Typically evolving from pre-existing pituitary macro-adenomas, the APT/PC spectrum demonstrates a peak incidence during the fifth decade of life, with corticotroph and lactotroph lineages predominating. Current diagnostic algorithms rely on a multimodal approach encompassing magnetic resonance imaging (MRI), comprehensive endocrinological evaluations, and meticulous histopathological assessment. The latter systematically includes the Ki67 proliferation index, hormone immunohistochemistry, and the newly integrated lineage-specific transcription factors. A multitude of structural and molecular mechanisms have been implicated in the pathogenesis of the APT/PC spectrum, with the elucidation of its genetic architecture representing a rapidly expanding field. Specifically, somatic variants within TP53, ATRX, and SF3B1 serve as established oncogenic drivers in APT/PC [5-7], whereas the exact pathogenetic contribution of germline predisposition genes, such as MEN1 and AIP, remains less definitive [4,8].
Histologically, PCs manifest as well-differentiated neuroendocrine neoplasms, closely mirroring the microscopic architecture of benign pituitary neuroendocrine tumors (Pit NETs). Although PCs frequently exhibit prominent cytological features, including hypercellularity, nuclear pleomorphism, geographic necrosis, focal hemorrhage, and local tissue invasion, these histopathological hallmarks demonstrate substantial overlapping characteristics with aggressive PitNETs, thereby precluding a definitive diagnosis of malignancy based solely on primary tumor morphology. Furthermore, exceptional histopathological variations, such as neuronal metaplasia, have been documented within the PC microenvironment, albeit remaining an exceedingly rare phenomenon [9].
Current histopathological, immunohistochemical, and ultrastructural paradigms preclude the reliable differentiation of PCs from benign or aggressive PitNETs based solely on cytomorphological criteria [9]. Furthermore, a profound discordance often exists between the microscopic features of metastatic lesions and their actual clinical behavior [10]. Consequently, the primary objective in the histopathological evaluation of a suspected PC shifts from establishing a localized diagnosis of malignancy to definitively confirming the adenohypophyseal origin of the metastatic foci.
In the initial European Society of Endocrinology (ESE) registry, PCs demonstrated a significantly higher mortality rate (43%) compared to aggressive PitNETs (28%) [11].
Conversely, the median survival assessed from the time of initial diagnosis was comparable between the two cohorts, spanning 11 years for aggressive PitNETs and 12 years for PCs [8]. However, a distinct divergence in survival outcomes emerged in the subsequent ESE survey, where the median survival extended to 17 years for aggressive Pit NETs but contracted to 11 years for PCs [12]. Regarding the kinetics of disease progression, Pernicone et al. documented that the interval from definitive PC diagnosis to mortality spanned from 7 days to 8 years, reflecting a poor 1-year survival rate of 66% [13].
Correspondingly, Yoo et al. reported a 55% mortality rate, with a strikingly abbreviated mean interval to death of merely 10 months post-PC diagnosis [14]. Within the broader landscape of endocrine malignancies, PC exhibits the most pronounced age-dependent decline in overall survival [15]. Crucially, the long-term prognosis is profoundly unfavorable in patients presenting with corticotroph-lineage PCs, systemic metastases, or disease progression during temozolomide (TMZ) therapy [8,9,13].
This review aims to summarize research on gene and protein expression in PC, clarifying the mechanisms behind its genesis and development to identify new diagnostic bio-markers and therapeutic targets for personalized treatment.
Epidemiology of Aggressive Pituitary Tumors/Pituitary Carcinomas
PCs are exceedingly rare malignancies, accounting for a mere 0.1% to 0.4% of all pituitary neoplasms [2,13,16], with an estimated incidence of approximately 4 cases per 1,000,000 person-years [15]. These epidemiological figures potentially represent an underestimation of the true disease burden, given that up to 75% of historical PC diagnoses were established exclusively at autopsy [17]. The clinical manifestation of PC typically peaks between the fourth and sixth decades of life, demonstrating a mean age at diagnosis of 44 years [9,18], though exceptional pediatric cases have been documented [19].
Importantly, while clinically silent corticotroph tumors account for only approximately 7% of all PitNETs [16], functioning neoplasms that have transited from such silent pre-cursors comprise 25% of the aggressive PitNET/PC spectrum [8].
Pathologically, the most prevalent PC subtypes are derived from corticotroph and lactotroph lineages [13,18]. In a comprehensive review of 72 published PC cases conducted by Yoo et al., immune-histochemical (IHC) profiling revealed positivity for ACTH in 35%, PRL in 24%, GH in 14%, TSH in 6%, FSH in 7%, and LH in 4% of cases, while 15% demonstrated a null cell phenotype [14]. This specific prevalence of null cell PCs is lower than alternative literature reports which estimate it at 30% [13,18], a discrepancy potentially attributable to the restricted availability or sensitivity of prolactin IHC in historical investigations [20]. Characteristically, when compared to pure benign PitNET cohorts, lactotroph- and corticotroph-derived neoplasms are significantly overrepresented, whereas somatotroph and null cell lineages remain markedly underrepresented within the PC landscape [8,16].
Regarding gender distribution, a pronounced male predominance is observed within the aggressive APT/PC cohorts. Importantly, males accounted for 63% of the cases documented in the second ESE survey [12]. This demographic disparity is particularly evident among neoplasms derived from lactotroph and corticotroph lineages. Conversely, a distinct female predominance characterizes the indolent or non-aggressive forms of these specific tumor subtypes, highlighting a potential link between biological gender and the risk of clinical progression [12].
Molecular Biology of Pituitary Carcinomas and PitNETs
At the molecular level, the pathogenesis of PCs is driven by distinct somatic alterations and profound genomic instability, contrastingly diverging from the low mutation burden typical of indolent PitNETs. PC is a devastating malignancy characterized by an unfavorable prognosis, presenting a one-year mortality rate of 66% that escalates to 80% over an 8-year period [13,21]. Yet, the precise mechanisms governing metastasis remain largely elusive, historically documented only in sporadic case reports and restricted gene-sequencing series [6,22-25].
Among the leading molecular hallmarks of malignancy, somatic mutations within the TP53 gene and the concomitant immune-histochemical over-expression of p53 critically disrupt cell cycle checkpoints and promote tumor progression, particularly within corticotroph lineages. This genomic instability is further compounded by ATRX mutations, which trigger the alternative lengthening of telomeres (ALT) pathway, thereby granting replicative immortality to neoplastic cells. Additionally, recurrent hotspot mutations in the splicing factor SF3B1 have emerged as lineage-specific drivers. Although no definitive association with generalized aggressiveness has been established, SF3B1 variants are critically implicated in refractory lactotroph tumors, where they induce aberrant pre-mRNA splicing and drive therapeutic resistance [8,26-28].
Inextricably linked with the up-regulation of proto-oncogenes like PTTG1 and the epigenetic silencing of RB1, these aberrations delineate the complex molecular landscape underlying the transition from benign adenohypophyseal tissue to invasive and metastatic carcinomas [16].
The mutational landscape shifts progressively during tumor evolution. Primary tumors have been found to harbor ATRX, CDKN2A, CDKN2B, SDHB, and TP53 [22,24] mutations. In contrast, metastatic lesions are frequently characterized by ATRX, CDKN2A, CDKN2B, and H-Ras [25] alterations. In parallel, variants in PTEN or DAXX have been shown to co-occur alongside TP53 and/or ATRX variants in mutant aggressive corticotroph tumors and corticotroph carcinomas [6,29-31]. While variants in RB1, HRAS, and PIK3CA have been identified in aggressive phenotypes and carcinomas within isolated case reports, they remain rarely reported in whole-exome sequencing series [29]. Furthermore, sporadic mutations in mismatch repair genes, including a germline MSH2 mutation delineated in a single case report, alongside MSH6 and MLH1 alterations, have been documented, while PTEN aberrations have been documented without specified anatomical localization [31].
Given this complex genetic architecture, it has been proposed the integrating Next-Generation Sequencing (NGS) into standard clinical practice whenever PC is suspected. Expanding diagnostic assays to encompass key PC-associated genes (ATRX, CDKN2A, CDKN2B, H-Ras, NF1, PTEN, SDHB, MSH2, TP53) as well as those implicated in aggressive PitNET biology (USP8, USP48) is vital for identifying oncogenic drivers and mapping targeted pharmacological interventions [31].
From a therapeutic standpoint, mutations in NF1, TP53, and PTEN trigger the hyperactivation of well-established downstream signaling pathways, including the RAS/RAF/MAPK/ERK and PI3K/Akt/mTOR cascades [30,32-40]. Consequently, these cascades offer viable targets for small-molecule intervention, as RAF-, MEK-, ERK-, PI3K-, and Akt-inhibitors have already demonstrated translational success in multiple clinical trials [41,42]. For TP53-mutant tumors, novel agents like APR-246, which refracts mutant p53 back to a wild-type conformation, or mutation-specific bispecific antibodies represent promising oncological strategies. Finally, in tumors exhibiting ATRX loss-of-function, and the subsequent induction of the ALT pathway alongside impaired DNA repair, epigenetic therapies utilizing G-quadruplex-interacting compounds could be highly effective in restoring genomic stability [43].
The role of TP53 gene in PCs
Pituitary tumors are predominantly benign. However, a small subset exhibits aggressive clinical behavior during the course of the disease [44,45]. The 2018 European Society of Endocrinology (ESE) guidelines define APTs by an unusually rapid growth rate or objective tumor progression documented via magnetic resonance imaging (MRI), despite standard optimal therapies [3]. The Revised 2025 ESE Clinical Practice Guidelines define APTs as invasive lesions showing unusually rapid progression, often within 6 months or clinically relevant progression despite optimal standard treatments [5]. Metastatic PCs are exceedingly rare, constituting approximately 0.2% of all pituitary neoplasms. Conversely, APTs are more prevalent, with an estimated frequency ranging from 0.5% to 1% of clinically apparent pituitary tumors [16, 29, 44-50]. Corticotroph tumors, which present the smallest group of all pituitary tumor types, are the most common type when considering only APTs and PCs, with a prevalence of 40%, followed by lactotroph tumors, approximately 26% [8,12,29].
The tumor-suppressor gene TP53, which encodes the tumor protein p53, is the most fre-quently altered gene in human malignancies, including central nervous system and neuroendocrine tumors. These alterations primarily consist of missense mutations that induce a loss of p53 function [51,52]. TP53 mutations in pituitary neoplasms were considered exceptionally rare events, isolated to sporadic cases of aggressive corticotroph tumors and carcinomas [24, 30, 53-57]. Early investigations into an aggressive corticotroph phenotype were limited by small cohort sizes and study heterogeneity, which prevented the establishment of statistically significant clinical associations [6,30,58] (Table 1).
| Molecular Driver/Bio-marker | Primary Mechanism | Clinical/Pathological Significance | Lineage Association | Key References |
| TP53/p53 | Somatic missense mutations, Loss of cell cycle control at G1/S checkpoint | High nuclear accumulation (>3-5%), Biomarker for local invasiveness, Recurrence, Metastatic potential | Predominantly Corticotroph | 57,131 |
| ATRX | Loss-of-function mutations, Chromatin remodeling alterations | Triggers the Alternative Lengthening of Telomeres (ALT) pathway, Loss of nuclear expression via IHC | Aggressive APT/PC spectrum | 74,76,85 |
| SF3B1 | Hotspot mutations (K700E), Spliceosome disruption | Induces aberrant pre-mRNA splicing, Associated with aggressive behavior and dopamine agonist resistance | Predominantly Lactotroph | 7,26,86, 87 |
| PTTG1 | Proto-oncogene amplification and overexpression | Disrupt sister chromatid separation, Drives chromosomal instability, aneuloidy, and high Ki-67 index | Pan-lineage agressive tumors | 102,113 |
| RB1 | Epigenetic promoter hyper-methylation or loss of etero-zygosity (LOH) | Complete loss of retino-blastoma protein-mediated cell cycle suppression, Accelerates tumor proliferation | Highly prevalent in PCs vs. Benign PitNETs | 105,125, 126,127 |
| H-RAS | Activating mutations (specifically at codons 12, 18, 61) | Constitutive activation of the MAPK/ERK signaling cascade, Strongly linked to distal | Exclusively documented in metastatic PCs | 116,117, 118 |
Table 1: Key Molecular Drivers and Biomarkers in the Pathogenesis of Aggressive PitNETs and Pituitary Carcinomas.
Subsequent molecular screening utilizing NGS and whole-exome sequencing (WES) demonstrated that TP53 variants are more prevalent in selected cohorts than previously assumed. Somatic TP53 mutations have been identified in up to 33% of cases across cohorts of 18 USP8 wild-type corticotroph macro-adenomas, 27 aggressive corticotroph tumors, and 22 aggressive corticotroph tumors and carcinomas [6,30,58]. Specific reports have identified TP53 mutations in primary tumors, including 14% (9/66) of macro-adenomas and 24% (8/34) [59] of invasive tumors, thereby validating data from smaller series [30,58]. Furthermore, TP53 missense variants have been confirmed in aggressive corticotroph and somatotroph phenotypes, as well as in metastatic corticotroph and lactotroph tumors presenting with high Ki-67 proliferation indices, elevated mitotic counts, and strong p53 immuno-reactivity. Case studies and reports indicated that aggressive and metastatic pituitary tumors, including corticotroph and lactotroph types, often harbor somatic TP53 variants, frequently accompanied by high Ki-67 indices and increased mitotic figures [31,49]. Additionally, these tumors may exhibit concurrent mutations in genes such as NF1, PTEN, and ATRX, as well as specific TP53 missense variants [31, 60].
The Ki-67 proliferation index, mitotic count, and p53 immuno-staining are established histological markers used to evaluate pituitary tumor aggressiveness [61]. TP53 mutations typically result in the accumulation and high nuclear expression of the encoded p53 protein due to decreased degradation, though they can occasionally cause a complete absence of the protein. Consequently, a TP53 mutation may be suspected when a substantial proportion of tumor cells exhibit p53 expression, although the precise threshold for its use as a surrogate marker in APTs/PCs remains undefined [62]. Clinical data demonstrated that the Ki-67 index is significantly elevated in TP53-mutant tumors, reinforcing prior observations of a higher mutation frequency within the Ki-67 ≥ 3% cohort [30]. Moreover, in tumors with documented p53 immuno-positivity, expression levels were higher in the TP53-mutant group, aligning with previous evidence showing strong p53 immuno-reactivity across all TP53-mutant tumors.
Somatic TP53 and ATRX (alpha thalassemia/mental retardation syndrome, X-linked) mutations represent the most consistently altered genes in APTs and PCs. While early reports identified somatic TP53 mutations in only five APT/PC cases [24,55], current literature confirms they are frequent in corticotroph APTs/PCs and, to a lesser extent, in aggressive Pit-1 lineage tumors [6,30,49,58-60]. For example, a study of 86 corticotroph tumors, including 24 APTs, identified TP53 mutations in 9 cases, linking them to aggressive features and poor clinical outcomes [58]. (Table 1).
Concurrently, ATRX mutations resulting in a loss of ATRX protein expression, originally described in a single corticotroph carcinoma, have been evaluated. While absent in large cohorts of standard PitNETs [22], immune-histochemical screening of 48 aggressive PitNETs (including 18 PCs) revealed a loss of ATRX expression in 9 tumors (7/22 corticotrophs and 2/24 Pit-1 lineage), with loss-of-function ATRX alterations confirmed genetically. These mutations are more frequent in PCs compared to APTs (5/18 vs. 4/30) [6]. Crucially, a strong association exists between TP53 and ATRX variants. A high frequency of missense TP53 variants (55.6%; 5/9) was reported in a series of 9 aggressive tumors and carcinomas carrying ATRX mutations, further linking this mutational status to an unfavorable prognosis [6]. The coexistence of TP53 and ATRX alterations has been documented in 6 tumors from an aggressive cohort, alongside 5 additional APT/PC cases in the literature [30,31,63]. The presence of concurrent PTEN, TP53, ATRX, NF1, and/or DAXX mutations emphasizes the critical involvement of the p53, ATRX/ DAXX, and mTOR pathways in the pathogenesis and malignant transformation of APTs and PCs [31, 53,58,60].
Analysis of serial patient samples indicated that TP53 and ATRX mutations were frequently present at the time of the initial surgery [6,58,59]. This suggests that the molecular events predisposing tumors to malignant behavior occur early during tumorigenesis. Furthermore, NGS has demonstrated high variant allele fractions (VAF) for most TP53 and ATRX mutations, supporting a clonal origin [6,30,58,60]. Consequently, TP 53 and ATRX likely act as drivers of tumorigenesis and serve as valuable biomarkers for the early identification of patients at high risk for developing APT or PC.
Beyond TP53 and ATRX, other lineage-specific mutations determine pituitary tumor behavior. USP8 is the most frequently altered gene in corticotroph tumors [53]. Although USP8 mutations are highly common in benign, non-APTs [64-66], they have been detected in a small number of APT/PC cases [59,60,67]. Notably, USP8 and TP53 mutations are mutually exclusive [58,59], potentially defining two distinct molecular and clinical entities within corticotroph tumors. In lactotroph tumors, SF3B1 is currently the only recurrently mutated gene identified in a few APTs and one PC [26,28], where it is associated with significantly shorter disease-free survival [26].
Other rare or isolated gene variants have been described [68], and either occur in non-APTs, present in combination with TP53, ATRX, or SF3B1, or are extremely rare. Finally, chromosomal and genomic rearrangements contribute to tumor behavior. While macroscopic genomic rearrangements seem to be associated with specific tumor lineages rather than recurrence or aggressiveness directly [69], chromosomal instability in pediatric Cushing's disease is associated with larger, invasive phenotypes [70]. In adult populations, a higher degree of aneuploidy, copy number variation (CNV), and micro-satellite instability is observed specifically in TP53-mutant corticotroph tumors [58].
Additionally, the loss of chromosomal regions 1q and 11p has been linked to recurrence in non-functioning tumors and aggressiveness in lactotroph tumors, respectively [71].
Loss of function mutations of ATRX gene
ATRX gene acts as a critical transcriptional regulator that interacts directly with death domain-associated protein (DAXX) and the histone H3.3 variant in heterochromatin remodeling and maintenance of telomere structure and function [72,73]. Loss-of-function mutations and molecular abnormalities of the ATRX gene have been characterized both in primary and metastatic PCs [6,22]. At the molecular level, the inactivation of ATRX or, less frequently, DAXX in ATRX/DAXX-mutating tumors leads to telomere destabilization and facilitates the process of alternative lengthening of telomeres (ALTs), a pathway that provides replicative immortality to cancer cells [74-76] (Table 1).
Somatic ATRX gene mutations are associated with several different tumor types, including astrocytomas in adults [77] and neuroendocrine tumors (NETs) such as pancreatic NETs [44, 78], neuroblastomas [79], and paragangliomas/ pheochromocytomas [80,81]. Notably, in neuroendocrine neoplasia, ATRX abnormalities seem to predict a malignant tumor phenotype, demonstrating enrichment in high-grade malignant tumors such as neuroblastomas [79], or strongly associated with unfavorable prognosis and/or metastatic potential in pancreatic NETs [82] and pheochromocytomas/paragangliomas [81].
Immunohistochemical (IHC) profiling serves as a valuable tool in evaluating tumor behavior. Previous research demonstrated normal IHC expression of the ATRX protein in a large cohort of 246 well-characterized PitNETs localized to the sellar region, including 37 corticotroph tumors. Conversely, evaluation of PCs revealed that 1 of 2 studied PCs, specifically a corticotroph carcinoma in a patient with Cushing’s disease, did not express the protein due to a large deletion of the ATRX gene [22].
A higher incidence of ATRX mutations among recurrent compared to primary PitNETs has been noted, which may indicate a possible contribution to clinical tumor progression [83]. Consequently, combined ATRX, p53, and Ki-67 immuno-stains provide high diagnostic utility and may be useful in the early diagnostic screening of PC. While a loss of ATRX expression effectively indicates PC in immuno-chemistry, given that around 20% of PCs harbor loss-of-function mutations of this gene, elevated expression of proliferation and tumor-suppressor markers exceeding established cut-off values (Ki-67 ≥ 4% and p53 ≥ 2%) strongly suggest aggressive PitNETs, with even higher values signaling progression to definitive PC [40].
However, inconsistent IHC and molecular findings can occur. Tumor cells harboring an ATRX p.N682D mutation in a metastatic lesion were shown to retain ATRX expression in immuno-stains, suggesting the potential preservation of protein function. Additionally, atypical syndromic presentations have been documented, such as one patient presenting with PC who harbored a loss-of-function SDHB mutation alongside a clinical history of paraganglioma [23].
Comprehensive genomic analysis of 9 ATRX-immuno-negative tumors confirmed underlying loss-of-function ATRX gene abnormalities across all 9 cases [84]. Detailed mutational mapping showed that all identified ATRX single nucleotide variants and small indels were positioned throughout the coding sequence of the ATRX gene. On the contrary, three tumors did not show any ATRX single nucleotide variants or small indels, but exhibited large, intragenic deletions corresponding to most of the coding sequences (encompassing 22-28 of the 36 exons) [84]. Structurally, one of these deletions corresponded to the corticotroph tumor previously reported [22], whereas the remaining two occurred in a lactotroph and a somato-lactotroph tumor, respectively [84].
Genomic sequencing further revealed complex clonal heterogeneity and tumor evolution. In two carcinomas from male patients, two different damaging ATRX mutations displaying large differences in mutation frequencies were identified within the same primary tumor [84]. One of these two tumors demonstrated a partial lack of ATRX expression at IHC, and loss of nuclear expression [85] (Table 1). Although a secondary attempt to extract DNA separately from the ATRX-immuno-positive and ATRX-immuno-negative fractions was unsuccessful, as the same mutational status was confirmed in both fractions, longitudinal analysis revealed that only the predominant mutation from this primary pituitary tumor was present in the subsequent metastasis six years later with a frequency of 98%, strongly suggesting clonal heterogeneity and evolution of the primary tumor [84]. Furthermore, these ATRX alterations rarely occur in isolation. In addition to the ATRX mutations, 8 out of 9 ATRX-immuno-negative tumors exhibited other genetic abnormalities, including inactivating somatic mutations in prominent tumor suppressor genes, TP53 (6 cases), PTEN (2 cases), RB1 (1 case), NF2 (1 case), and a homozygous deletion of CDKN2A/B in both the primary tumor and metastasis of one patient [84].
Specifically, these additional cancer-related mutations associated with ATRX alterations presented as TP53 mutations in 6 cases (comprising 3 aggressive corticotroph tumors, 2 corticotroph carcinomas, and 1 aggressive lactotroph tumor), PTEN mutations in 2 cases, and RB1, NF2, and CDKN2A/B in single isolated cases. Recurrent CNVs estimated from the sequencing data were exclusively gains, involving chromosomes 5, 7, and 9p21. 3 (encompassing the CDKN2A/B loci), as well as the CIC locus on 19q [84].
While TP53 mutations have rarely been previously reported in pituitary tumors [24], recent molecular series have demonstrated TP53 mutations in 6 out of 18 corticotroph USP8 wild-type tumors, establishing a direct association with larger tumor volume and a higher Ki-67 proliferation index [30].
The role of SF3B1 gene in PCs
Splicing factor 3 subunit 1 (SF3B1) constitutes a core component of the U2-dependent major splicing complex and is functionally essential for branch site recognition during pre-mRNA splicing processes [86-88] (Table 1). Altered-function mutations within the SF3B1 gene disrupt this mechanism, resulting in aberrantly spliced transcripts and subsequent modification of global gene expression profiles [86,89,90]. Due to their impact on transcriptomic stability, SF3B1 variants have been widely reported across various human malignancies, including cutaneous, mucosal, and uveal melanoma, chronic myelomonocytic leukemia, chronic lymphocytic leukemia, breast, and pancreatic cancer [91-98].
In the context of pituitary oncology, molecular screening of lactotroph tumors has identified a recurrent mutational hotspot within the SF3B1 gene, specifically the p. Arg625His substitution, present in approximately 20% of evaluated cases [26]. On the contrary, independent whole-exome sequencing (WES) studies conducted across independent cohorts failed to identify any SF3B1 variants within similar phenotypes [99,100]. Therefore, the prevalence and clinical significance of these genomic variants require validation in larger, independent lactotroph tumor cohorts.
The role of PTTG1 gene in PCs
The identification of PTTG1 by Pei and Melmed in 1997 [101] in rat pituitary tumor cells, compared to normal pituitary tissue, is widely regarded as a landmark in pituitary oncology. Interestingly, in the same study, PTTG1 overexpression in mouse fibroblasts inhibited cell proliferation and induced transformation, suggesting its potential role in tumorigenesis [101]. The first study [102] investigating its expression in human pituitary glands and adenomas revealed that PTTG1 had pronounced expression in adenoma tissues (Table 1).
Targeted PTTG1 overexpression resulted in focal pituitary hyperplasia, suggesting a direct relationship between PTTG1 content and pituitary trophic status and tumorigenic potential [103]. The ‘interactome’ of PTTG1 in PitNETs includes PBF, bFGF, and its receptor FGF-R-1, which are known to be related to tumor invasiveness [104,105]. PTT G1 was also described as a target for epidermal growth factor receptor (EGFR)-mediated regulation of pituitary cell growth, emphasizing its role in cellular proliferation mediated by various signaling pathways and its role as an enhancer of the paracrine secretion of the folliculostellate cells [106].
The past 5 years have revealed new potential PTTG1 interactors, particularly important for pituitary tumor progression. Sirtuin 1 (SIRT1), a tumor suppressor, was shown to delay pituitary tumor progression by down-regulating PTTG1 expression, primarily through the de-acetylation of histone (H) 3 lysine (K) 9ac at the PTTG1 promoter, suggesting a possible central role for SIRT1/H3K9ac/PTTG1 axis in tumorigenesis [107]. In parallel, the long noncoding RNA colon cancer-associated transcript 2 (CCAT2), identified for its oncogenic properties, is significantly up-regulated in PitNETs [108]. CCAT2 interacts with PTTG1 promoting its stability, thus promoting tumor cell proliferation, migration, and invasion. This interaction indicates a complex gene regulation network where CCAT2 and PTTG1 collaboratively drive pituitary adenoma progression [108].
Moreover, it was demonstrated that the mammalian target of rapamycin (mTOR) signaling, known for its role in cell growth and proliferation, contributes to PitNETs development through the activation of PTTG1, suggesting that targeting the mTOR- PTTG1 signaling axis could offer a novel approach for treating tumors characterized by mTOR hyper-activation [109]. Finally, adding another layer to the regulatory mechanisms of PTTG1 in human PitNETs, the protein known as RWD-containing sumoylation enhancer (RSUME) was shown to stabilize PTTG1, enhancing its oncogenic potential [110].
PTTG1 expression was associated with invasiveness, age, and female gender, with no association with tumor growth and regrowth [111,112]. Previous research explored the association between PTTG1 expression and the invasiveness of Non-Functioning Pituitary Adenomas (NFPAs), revealing that PTTG1 expression is significantly associated with tumor invasiveness [113]. This finding supports the potential of PTTG1 as a valuable predictive biomarker for NFPA invasiveness [111,112]. Zhu et al. [114] contributed significantly to understanding the genetic predisposition to NFPAs by examining PTTG1 polymorphisms, specifically the rs2910200 variant.
The role of N- and K-ras genes in PCs
The molecular mechanisms driving pituitary tumorigenesis have been rigorously evaluated utilizing polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) coupled with direct DNA sequencing to screen for potential pathogenic mutations within ras proto-oncogenes and the tumor-suppressor gene p53 in highly invasive pituitary adenomas and carcinomas. Genomic sequencing of exons 5 through 8 of the p53 gene yielded entirely wild-type sequences with no identifiable mutations. Similarly, no mutational variants were detected within the N-ras or K-ras proto-oncogenes across four characterized pituitary carcinomas and their corresponding metastatic deposits [25].
In contrast, specific somatic point mutations within the H-ras gene were successfully identified in three distant metastatic pituitary tumor secondaries. Intriguingly, these H-ras mutations were completely absent within their respective primary PCs, as well as across six evaluated invasive adenomas. Distinct molecular profiles of these mutations revealed a G to C transversion at codon 12, resulting in a glycine to arginine amino acid substitution, and a G to A transition at codon 18, which induces an alanine to threonine structural change. A third molecular alteration involved a single base pair (adenine) deletion within codon 3 of H-ras, which causes a down-stream reading frame shift and results in a premature termination signal at codon 19 [25,31,115]. Collectively, these data demonstrate that point mutations within p53 and the ras family are not primarily associated with initial pituitary tumorigenesis. However, the selective acquisition of H-ras gene point mutations appears to play a critical functional role in the formation, clonal selection, and or growth of distant pituitary metastases [116-118] (Table 1). Consequently, this documented genomic instability serves as a valuable molecular tool for predicting the potential metastatic behavior and clinical progression of these highly APTs [29,119-121].
The precise molecular mechanisms driving adenohypophyseal tumorigenesis remain largely hypothetical. However, translational evidence has demonstrated that the aberrant nuclear accumulation of the p53 protein preferentially occurs in a subset of invasive adenomas and PCs [119]. On the contrary, somatic point mutations within the p53 gene [121] and the ras oncogene family [4] are not primary drivers associated with initial pituitary tumorigenesis, whereas specific point mutations within the H-ras gene appear to be actively involved in the subsequent formation or growth of distant metastatic deposits.
The role of MicroRNAs and Rb gene in PCs
Neoplastic progression in both pituitary adenomas and carcinomas is frequently characterized by a marked decrease in the expression of the p27 protein. Nonetheless, corresponding mRNA expression levels remain unaffected, and tumor-specific mutations within the p27 locus have not been identified [122,123].
Furthermore, compelling evidence from in vivo models utilizing mice with heterozygous deletions of the Rb gene, alongside Rb(+/−) chimeras [124], has revealed a high frequency of spontaneous PCs. These robust experimental findings strongly suggest the direct involvement and critical role of the Retinoblastoma (Rb) tumor-suppressor pathway in the development and malignant transformation of these aggressive tumors [125].
The RB1 tumor suppressor gene, localized on chromosome 13q14, exerts a crucial role in cell cycle regulation by arresting cellular progression within the G1 phase through the molecular binding of E2F transcription factors. Consequently, functional disruption of the pRB-p16 regulatory axis represents an established pathological hallmark in the molecular pathogenesis of aggressive PitNETs and malignant PCs. Although somatic point mutations within the RB1 genomic locus constitute rare events in pituitary neoplasms, functional inactivation of the encoded pRB protein frequently occurs via epigenetic mechanisms, specifically promoter hyper-methylation [126] or loss of heterozygosity (LOH) at the RB1 locus [29,119,121,127] (Table 1).
Remarkably, a complete loss or a marked reduction of pRB expression, as demonstrated via IHC profiling, is strongly associated with a highly invasive phenotype, elevated Ki-67 proliferation indices, and distant metastatic dissemination. This establishes pRB down-regulation as a valuable predictive biomarker for malignant transformation. Furthermore, this epigenetic silencing frequently co-occurs with the functional inactivation of CDKN 2A (p16) [128]. This co-occurring loss leads to the subsequent hyper-phosphorylation of pRB by CDK4/6 oncogenic complexes, which synergistically accelerates uncontrolled tumor growth and drives clinical resistance to conventional therapeutic regimens [29,119, 129,130].
Elucidating the molecular pathology of pituitary malignancies requires a comprehensive understanding of intertwined signaling networks. The oncogenic transformation in these tumors is orchestrated by complex genetic and epigenetic modifications. These alterations serve as potential markers to assist in diagnostic stratification. In contrast to familial PitNETs, which possess a more delineated biomolecular background, the genomic land-scape of PCs remains less defined. Nevertheless, recent advances in molecular genetics are progressively unveiling specific mutational signatures responsible for tumor development. Current classification systems stratify these neoplasms based on lineage-specific transcription factors and functional hormone expression. Given that emerging data under-scores the role of epigenetic modulators in tumor etiopathogenesis, further investigative efforts are essential. Mapping this molecular architecture will be crucial to fully decode subtype-specific tumor biology.
Declaration of Interest
I herewith acknowledge that: I have no economic or added individual interests, straightforwardly or obliquely, in some matter that conceivably influence or bias my trustworthiness as a journalist concerning this book
Conflicts of Interest
The authors profess that they have no conflicts of interest to reveal.
Financial Support and Protection
No external funding for a project was taken to assist with the preparation of this manuscript.
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Dear Mayra Duenas, Editorial Coordinator of ‘International Journal of Clinical Case Reports and Reviews Herewith I confirm an optimal peer review process and a great support of the editorial office of the present journal
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Dr Hala Al Shaikh This is to acknowledge that the peer review process for the article ’ A Novel Gnrh1 Gene Mutation in Four Omani Male Siblings, Presentation and Management ’ sent to the International Journal of Clinical Case Reports and Reviews was quick and smooth. The editorial office was prompt with easy communication.
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To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina
My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.
We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.
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"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".
To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.
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I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
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Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
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Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
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I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
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I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
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