The Roles of PD-L1, Ki-67, P53, and Cyclin D1 in PitNETs: Diagnostic and Prognostic Implications in a Series of 74 Patients

Abstract

Pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas, are rare tumors that are usually benign. At present, the WHO PitNET classification based on transcription factors is in force. A problem is caused by invasive tumors and silent tumors which, despite a lack of obvious clinical symptoms, tend to behave aggressively. Factors influencing the clinical course of these tumors are currently being sought. The aim of our study was to assess the expression of programmed death-ligand 1 (PD-L1) and proliferation biomarkers (Ki-67, cyclin D1, and P53) in PitNETs depending on the transcription factor and adenoma subtype. The analysis was performed in seventy-four patients operated on in a single neurosurgical center for pituitary tumors. Immunohistochemistry was performed for transcription factors and biomarkers-PD-L1, Ki-67, P53, and cyclin D1-in tissue microarray format. Membranous expression of PD-L1 was scored as 0 (no expression) and ≥1%. Nuclear expression of Ki-67 was scored at <3% and ≥3%, and the expression of P53 and cyclin D1 was scored at <10% and ≥10%. The following tumors expressed PD-L1 at ≥1%: gonadotroph, 21 (28.4%); corticotroph, 5 (6.7%); gonadotroph/lactotroph, 2 (2.7%); null cell adenoma, 3 (4.0%); multiple synchronous PitNET, 2 (2.7%); immature PIT-1 tumor, 1 (1.3%); mature PIT-1 tumor, 1 (1.5%). Ki-67 ≥ 3% was found in the following PitNETs: gonadotroph, 3 (4.0%); corticotroph, 2 (2.7%); lactotroph, 1 (1.3%); multiple synchronous PitNET, 1 (1.3%); immature PIT-1 tumor, 1 (1.3%); and mature PIT-1 tumor, 1 (1.3%). Patients with Ki-67 ≥ 3% were statistically significantly younger (p = 0.03). All tumors (100%) with a combination of cyclin D1 ≥ 10% and P53 < 10% were invasive on the Hardy scale. Of the four factors, PD-L1 increased the odds of invasiveness the most (adjusted OR = 2.35; 95% CI: 0.56-9.90). PD-L1 expression was present in some types of PitNETs. PD-L1 expression may help in identifying null cell adenomas. High cyclin D1 with low P53 may indicate greater tumor invasiveness.

Keywords: Cyclin D1; Ki-67; P53; PD-L1; PitNETs; biomarkers; invasiveness; transcription factors.

Figure 1

Results of the multivariate logistic regression analysis: odds ratios (ORs) and 95% confidence intervals (CIs) for biomarkers (PD-L1, P53, Ki-67, cyclin D1) in association with tumor invasiveness. Model fit statistics: Hosmer–Lemeshow χ² = 3.63, p = 0.60; AUC = 0.64 (SE = 0.10); Cox–Snell R² = 0.04; Nagelkerke R² = 0.06.

Figure 2

Microphotographs of immunohistochemical staining of pituitary adenocarcinoma. (A) Membranous staining for PD-L1. (B) Nuclear staining for Ki-67. (C) Nuclear staining for P53. (D) Nuclear staining for cyclin D1. Magnification: 400×. In the upper-right corner of each micrograph, 1000× magnification is shown to visualize individual positively stained cells.