PD-L1 Expression in Pituitary Neuroendocrine Tumors/Pituitary Adenomas

Abstract

Background and aim: About a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.

Methods: We performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.

Results: Eighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.

Conclusions: PD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.

Keywords: PD-L1; PitNET; biological behavior; gonadotroph pituitary tumors; immune checkpoint inhibitors; immunotherapy; pituitary adenoma; prognosis; somatotroph pituitary tumors.

Figure 1

Flow-chart showing the process of patients’ selection and inclusion in our analysis.

Figure 2

A higher PD-L1 expression was associated with proliferative grades of Trouillas’ classification along with a higher expression of P53 (more than 10 cells with a strong nuclear staining per 10 HPF). No association was found with other proliferative markers, namely Ki67 labeling index or mitotic count (left panel). Considering a cut-off of 30% of cells expressing PD-L1, a very strong association was found with proliferative Trouillas’ grades (p = 0.004; right panel).

Figure 3

No relationship was found between PD-L1 expression and radiological or pathological features of invasion. Bone erosion was evaluated on preoperative CT and during surgery, while dural infiltration was evaluated through histopathological analysis.

Figure 4

Concerning the hormonal expression at immunohistochemistry, a strong positive association was found between PD-L1 expression and GH expression (somatotroph tumors), while an inverse relationship was found with FSH/LH expression, as gonadotroph tumors were associated with a very low expression of PD-L1. No relationship was found between ACTH- and PRL-expressing tumors and PD-L1 expression.

Figure 5

On the left, the role of PD-L1 (programmed-death ligand 1) in tumoral cells is shown. It binds to PD-1 expressed by T-cells to inhibit their functions. The tumor can thus evade host immunity and continue to proliferate. The blockade of this cascade (PD-L1) allows the activation of T cell stimulatory signaling, thereby enhancing antitumor T cell cytotoxicity and proinflammatory cytokine production, promoting tumor destruction. On the right, we provided a UMAP plot of single-cell RNA sequencing data showing PD-L1 normalized expression (CD274) in a somatotroph PitNET.