PD‐L1 and thyroid cytology: A possible diagnostic and prognostic marker

Abstract

Background Programmed death‐ligand 1 (PD‐L1) expression is emerging as an important predictive biomarker in anti–PD‐L1 cancer immunotherapy. Its role has been clearly defined in various human cancers and is linked to a poor prognosis and resistance to anticancer therapies. The role of PD‐L1 in thyroid cancers has not been well defined in fine‐needle aspiration cytology (FNAC). The authors examined the performance of PD‐L1 immunostaining in liquid‐based cytology (LBC) to determine whether it could be a biomarker of malignancy or aggressive disease. Methods From January 2018 to March 2019, 236 thyroid lesions, which had been diagnosed by FNAC as indeterminate lesions, suspicious for malignancy (SFM), and malignant, were enrolled. PD‐L1 immunostaining was performed on both LBC and corresponding histology samples. Results The FNAC cohort included 50 benign negative controls, 42 samples of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 33 samples of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 53 samples that were suspicious for malignancy (SFM), and 58 malignant samples. AUS/FLUS samples included 3 goiters, 32 follicular adenomas (FAs), 1 noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP), 5 invasive follicular variants of papillary thyroid carcinoma (I‐FVPTCs), and 1 follicular carcinoma; whereas FN/SFN samples included 24 FAs and 9 malignancies (4 I‐FVPTCs, 1 NIFTP, 3 papillary thyroid carcinomas [PTCs], and 1 oncocytic follicular carcinoma). The 53 SFM samples were diagnosed on histopathology as 2 FAs, 5 NIFTPs, 15 I‐FVPTCs, and 31 PTCs; whereas the 58 malignant specimens included 5 NIFTPs, 5 I‐FVPTCs, and 48 PTCs. Increased plasma membrane and cytoplasmic PD‐L1 expression was found in 79 cases (38.5%), including 61 PTCs (conventional and variants). Negative PD‐L1 expression was found in NIFTPs and FAs. A BRAF V600E mutation was identified in 15% of PD‐L1–positive malignancies. Conclusions The current data suggest that PD‐L1 expression in the thyroid gland might represent a marker of malignancy that correlates with PTC, but not with NIFTP. Thyroid neoplasms with PD‐L1 expression also ae enriched with BRAF V600E mutations, suggesting that they are associated with more aggressive behavior.

Update regarding the role of PD-L1 in oncocytic thyroid lesions on cytological samples

“…Some authors found PD-L1 expression only in invasive encapsulated follicular variant of PTC leading to the conclusion that PD-L1 might serve as a promising biomarker in predicting invasiveness 25. Recently we found that there is weak PD-L1 cytoplasmic positivity in some oncocytic thyroid neoplasms 9. Since then, however, PD-L1 expression in oncocyctic cells, to the best of our knowledge, has not been described in the literature.…”

“…Specifically, the FDA-approved-specific PD-L1 IHC tests as either companion or complementary diagnostic tests using different antibody clones and defined conditions 5–7. Most literature dealing with the role of PD-L1/PD-1 has focused on advanced stage lung cancer, mostly non-small cell lung cancer (NSCLC), as well as head and neck carcinoma, melanoma and urogenital cancers 8–15…”

Do we need PD‐L1 as a biomarker for thyroid cytologic and histologic specimens?

“…Oncocytic lesions have rarely been tested with PD-L1; Dell'Aquila et al found that 79% of their oncocytic neoplasms had PD-L1 expression. 12 Given the notorious "stickiness" of oncocytes, it is likely that, as for other immunostains, these cells may also pick up nonspecific PD-L1 cytoplasmic staining.…”

“…The study by Dell’Aquila and colleagues published in this issue of Cancer Cytopathology is a timely article that examines for the first time the performance of PD‐L1 immunostaining in liquid‐based cytology (LBC) from thyroid FNAs to determine whether this could be a biomarker of malignancy or aggressive disease. In total, 236 thyroid lesions that were diagnosed by FNAC as “benign,” “indeterminate,” “suspicious for malignancy,” or “malignant” were enrolled, and PD‐L1 immunostaining was performed both on LBC slides and on corresponding histology samples.…”

“…PD‐L1 expression can also be expressed in many cell types other than reactive TFCs, including histiocytes, dendritic cells, fibroblasts, as well as medullary thyroid carcinomas, parathyroid tumors, and metastases. Oncocytic lesions have rarely been tested with PD‐L1; Dell’Aquila et al found that 79% of their oncocytic neoplasms had PD‐L1 expression . Given the notorious “stickiness” of oncocytes, it is likely that, as for other immunostains, these cells may also pick up nonspecific PD‐L1 cytoplasmic staining.…”