Endocrine Abstracts

Introduction

AIP is a predisposing gene for GH/PRL-secreting PitNETs. Clinically non-functioning PitNETs (NFPT) occasionally occur in the setting of AIP germline mutations, sometimes arising from Pit-1 lineages. However, AIP overexpression has been observed in unselected NFPT and associations with the gonadotroph phenotype and/or tumour aggressiveness were suggested. We wished to evaluate the significance of AIP expression in gonadotroph tumours defined by the WHO 2017 classification.

Material and methods

Thirty-seven gonadotroph Pit-NETs (GnPT) were studied, displaying positive immunostaining for FSH/LH (n = 30) or SF1 only (n = 7). Male patients predominated (26M, 11F, median age 57 years (IQR 46-66)). Tumours were characterized for size, invasiveness and Ki-67 immunostaining. Gene expression of AIP, β-FSH, β-LH, SF1, Cyclins A2, B1 and D1 was evaluated in surgical samples and in 3 normal pituitaries (NP) by Real-Time qRT-PCR, based on a Taqman methodology using commercial probes and β-bactin as a housekeeping gene (Applied Biosystems). AIP immunostaining (AIP-IHC) was evaluated on paraffin-embedded sections by a semi-quantitative score (n = 31). Non-parametric tests (Wilcoxon and Spearman correlation) were used for statistical analysis.

Results

Gene overexpression of AIP was found in 18/37 GnPT (48.6%), tended to be more frequent in M (57.7 vs 27.3% in F, P = 0.09), and not significantly correlated with tumour size, invasiveness or Ki67. A single case of AIP downregulation was observed. AIP transcripts were significantly correlated with β-LH (ρ = 0.54, P = 0.0019) and cyclin A2 ( = 0.35, P = 0.031), with a similar trend for β-FSH and SF1 (P = 0.06 each), but unrelated to Cyclin D1 or B1. AIP-IHC was significantly associated with AIP transcripts (ρ = 0.51, P = 0.010) and classified as high/moderate/low in 38.7%, 41.9%, 19.3% of the cases, with no male predominance and irrespective of tumour characteristics.

Discussion

Compared to NP, the proportion of AIP gene overexpression in GnPT (48.6%) is probably underestimated due to its normal mammo-somatotroph localization. Indeed, 80% of NFPT displayed clear AIP immunostaining (38.7% with a high score). Neither AIP gene or protein overexpression was significantly associated with tumour aggressiveness. A significant correlation was also found between AIP and Cyclin A2 transcripts. However, unlike cyclins D1 and B1, Cyclin A2 overexpression has not yet been associated with NFPT proliferation or invasion. Rather, AIP transcripts were associated with gonadotroph features, in particular β-LH.

Conclusion

AIP expression appears to be associated with the endocrine phenotype of GnPT rather than with their volume or invasiveness. The potential implications of these findings in the natural history of GnPT should be better defined.