Gonadotroph tumours with a low SF‐1 labelling index are more likely to recur and are associated with enrichment of the PI3K‐AKT pathway

Abstract

Aims: The gonadotroph tumour (GT) is the most frequently resected pituitary neuroendocrine tumour. Although many symptomatic GT are successfully resected, some recur. We sought to identify histological biomarkers that may predict recurrence and explore biological mechanisms that explain this difference in behaviour. Methods: SF-1 immunohistochemistry of 51 GT, a subset belonging to a longitudinal prospective cohort study (n = 25), was reviewed. Four groups were defined: Group 1recently diagnosed GT (n = 20), Group 2-non-recurrent GT with long-term follow up (n = 11), Group 3-initial resections of GT that recur (n = 7) and Group 4-recurrent GT (n = 13). The percentage of SF-1 immunolabelling in the lowest staining fields (SF-1 labelling index (SLI)) was assessed and RNA sequencing was performed on 5 GT with SLI <80% and 5 GT with SLI >80%. Results: Diffuse, strong SF-1 immunolabelling was the most frequent pattern in Groups 1/2, whereas patchy SF-1 staining predominated in Groups 3/4. There was a lower median SLI in Groups 3/4 than 1/2. Overall, GT with SLI <80% recurred earlier than GT with SLI >80%. Differential expression analysis identified 89 statistically significant differentially expressed genes (FDR <0.05) including over-expression of pituitary stem cell genes (SOX2, GFRA3) and various oncogenes (e.g. BCL2, ERRB4) in patchy SF-1 GT. Gene set enrichment analysis identified significant enrichment of genes involved in the PI3K-AKT pathway. Conclusions: We speculate that patchy SF-1 labelling in GT reflects intratumoural heterogeneity and are less differentiated tumours than diffusely staining GT. SF-1 immunolabelling patterns may have prognostic significance in GT, but confirmatory studies are needed for further validation.

Unveiling the identities of null cell tumours: Epigenomics corroborate subtle histological cues in pituitary neuroendocrine tumour/adenoma classification

“…Future studies should investigate if and how attenuated TF expression is associated with tumour behaviour across and within defined pituitary lineages. Only recently, a study described patchy SF1 immunolabelling in gonadotroph tumours to be associated with increased rates of recurrence [29]. Similar investigations have not been made in corticotroph or PIT1‐positive PitNET/adenomas to date.…”

Clinical and Molecular Characteristics of Gonadotroph Pituitary Tumors According to the WHO Classification

“…In a recent study, “null cell” pituitary tumors were still reported to be more at risk than GnPT (which included pSF1 cases), albeit due to the retrospective nature of the study, the expression of lineage-specific transcription factors was not available on all “null cell” tumors [ 22 ]. A lower, patchy expression of SF1 in GnPT was also found to be more frequently associated with post-operative recurrences than a higher, diffuse expression of SF1 and that the transcriptional profile of low SF1-expressing tumors suggested an increased activation of the PI3K/Akt pathway [ 23 ]. According to this study, the SF1 labeling index was more accurate than Ki67 in predicting short-term recurrences [ 23 ].…”

“…A lower, patchy expression of SF1 in GnPT was also found to be more frequently associated with post-operative recurrences than a higher, diffuse expression of SF1 and that the transcriptional profile of low SF1-expressing tumors suggested an increased activation of the PI3K/Akt pathway [ 23 ]. According to this study, the SF1 labeling index was more accurate than Ki67 in predicting short-term recurrences [ 23 ]. Nonetheless, data from the current study suggest that SF1 gene expression is similar in the two groups of GnPT and that pSF1 tumors do not represent per se a distinct “high-risk” tumor phenotype.…”

Intratumoural spatial distribution of S100B + folliculostellate cells is associated with proliferation and expression of FSH and ERα in gonadotroph tumours

“…The concepts of intratumoural, intertumoural and interpatient heterogeneity are intensively studied and acknowledged to be of tremendous importance in cancer biology [ 31 , 32 ]. In PitNETs, tumour heterogeneity has only started to be unravelled by recent studies [ 30 , 33 , 34 ]. Here, our work contributes to extending this knowledge by providing an insight into the heterogeneity of PitNETs through the cartography of a rare TME component, namely S100B-expressing FS cells.…”