Jornal de Patologia Médica e Cirúrgica
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Parathyroid Carcinoma has a PD-L1 Expression, and Share with Atypical Neoplasms an Abundant Intratumoral Macrophagic Infiltration - A Short Commentary

Angelica M. Silva-Figueroa and Nancy D. Perrier

Background: In the era of immunotherapy as a therapeutic option for solid tumors, the immuno-tumor characterization of parathyroid neoplasms is timely and necessary. Since conventional therapeutic options are limited for controlling the progression of parathyroid carcinoma, new modalities of treatment are desperately needed. Four distinct tumor microenvironments have been proposed based on the existence of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1); type I (TILs+/PD-L1+), type II (TILs-/PD-L-), type III (TILs-/PD-L1+), and type IV (TILs+/PD-L1-). These immunogenic subtypes may predict responses to these therapies.
Aim: The aim of this study was characterized programmed death-ligand 1 (PD-L1) expression and tumoralinfiltrating lymphocytes (TILs) in parathyroid carcinoma (PC) and atypical parathyroid neoplasms (ANs).
Methods: Our tissue samples constitute 30 parathyroid tumors (17 PC and 13 ANs) which were available from a prospectively collected database at the University of Texas M.D Anderson Cancer Center from 1996 to 2016. All samples were meticulously reviewed utilizing the current World Health Organization histopathological criteria. Each of the samples was immunohistochemically analysed for PD-L1, CD3, CD8 and CD68 with an automated staining system (BOND-MAX, Leica Biosystems, Buffalo Grove, IL). The Novocastra Bond Polymer Refine Detection Kit (Leica Biosystems) was used to detect PD-L1, CD3, CD8, and CD68 expression in tumor cells. Digital image analysis was performed using Aperio software (Leica Biosystems); PD-L1 expression was analysed with a tumor membrane-specific algorithm, CD3 and CD8 expression with a tumor nuclear staining algorithm, and CD68 expression was evaluated with a tumor cytoplasmic staining algorithm. The PD-L1 H score was calculated using the formula (1 × (% cells 1+))+(2 × (% cells 2+))+(3 × (% cells 3+)) and the other immunomarkers were calculated in accordance with the number of TILs positive by mm² of the parathyroid tumor. For the immuno-classification of the PC in this study, a PD-L1 ≥ 1 was used as a cut-off for positivity. High expression of TILs was defined as cases with CD3+ and CD8+ density higher than that in the median PC group.
Results: The biochemical and immunogenic characteristics of the PCs compared with ANs. The analysis of the immuno-data showed no difference in the median of PD-L1 H score between PC and ANs. All locoregional recurrences (n=6), distant metastases (n=5), and deaths due to disease (n=3) occurred in the PC group. We found four cases with a PD-L1 H score ≥ 1 associated with high expression of CD3+ (median 59.9 (27.4-986.8) cells/mm²), CD8+ (median=50.6 (4.5-1107.1) cells/mm²), and CD68+ (median 221.7 (53.0-741.1) cells/mm²) tumor cell density, and two had distant metastases (lung and liver). We identified 9 PC with a median CD68 tumor cell density>194 cells/mm², and four in this PC group developed locoregional recurrences with or without distant metastases. We immuno-classify PC based on the four immunotypes. 14 PC cases were in the immunotype with PD-L1 negative and 4 PC cases had PD-L1 H score ≥ 1 with or without TILs positive.
Conclusions: PCs tend to display immune tolerance tumor microenvironment (type IV). Additionally, 22% of PCs had patterns of PD-L1 and TILs expression in their microenvironment (type I) suggesting a potential benefit from immunotherapy. Thus, tumor microenvironment profiling could be useful to identify PC cases that could benefit from immunotherapy, and additional investigation is warranted.