title: Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants.
abstract: Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1- patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as a prognostic marker for PTC.
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Veyhl
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Fatima
authors.initials: F
authors.lastname: Jessa
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada.
authors.forename: Olena
authors.initials: O
authors.lastname: Polyakova
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alenzi
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.|Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.|Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.|Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada.|Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002291:Carcinoma, Papillary / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D016009:Chi-Square Distribution; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006044:Goiter, Nodular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009864:Ontario; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: benign nodule; programmed death-ligand 1; protein biomarkers; subcellular localization; thyroid cancer