RESUMO
Background: Cells with stem cell features have been described in pituitary neuroendocrine tumours (PitNETs). Transcription factors SOX2 and SOX9 are stem cell-associated markers while the pituitary progenitor marker PROP1 is involved in anterior pituitary development. We characterised the presence of these markers known to be present in the human pituitary in non-functioning (NF) PitNETs. Methods: We investigated the pituitary transcription factors SOX2, SOX9 and PROP1 by immunohistochemistry (IHC) (N = 125) and RT-qPCR (N = 78) in a retrospective cohort of clinically NF-PitNETs. The markers were scored based on the percentage of immunolabeled cells. IHC staining scores were compared to reintervention rates for the whole cohort, and to expression of FSH, LH or ER in gonadotroph NF-PitNETs. Results: Most tumours showed no or few cells positive for SOX2, SOX9 and PROP1. More patients with SOX2-negative tumours went through reintervention (40 % vs 19 %, p = 0.03). SOX2, SOX9 and PROP1 staining correlated positively to each other (SOX2 and SOX9 rs = 0.666, SOX2 and PROP1 rs = 0.704, SOX9 and PROP1 rs = 0.570, and p < 0.001 for all). In gonadotroph NF-PitNETs, staining for SOX2 and PROP1 was positively associated to FSHß staining (p < 0.001 for both). Staining for SOX2, SOX9 and PROP1 was positively associated with gene expression of Estrogen Receptor 1 (ESR1) (p < 0.001, p = 0.004 and p < 0.001) and IHC staining for ERα (p = 0.001, p = 0.03 and p = 0.05, respectively). Conclusion: SOX2, SOX9 and PROP1 were present at low levels in NF-PitNETs. Absence of SOX2 staining was associated with a higher reintervention rate. The stem cell markers correlated positively with markers of gonadotroph differentiation in gonadotroph NF-PitNETs. SOX2 and SOX9 were frequently coexpressed and showed positivity in intratumoural cells with epithelial features, however without coexpression of pituitary transcription factors.
RESUMO
Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown. We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization. Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs. Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.