title: Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.
abstract: Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ⩾5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 × more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 × more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy.
authors.affiliation: Unversity of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Frydenlund
authors.affiliation: Boston University School of Public Health and Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
authors.forename: Dominick
authors.initials: D
authors.lastname: Leone
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: April
authors.initials: A
authors.lastname: Deng
authors.affiliation: Miraca Life Sciences, Newton Upper Falls, MA, USA.
authors.forename: Marier
authors.initials: M
authors.lastname: Hernandez-Perez
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, Scotland.
authors.forename: Asok
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Aurora Diagnostics GPA Laboratories, Greensboro, NC, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Yaar
authors.affiliation: Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Integrated Service Networks (VISN1), West Roxbury, MA, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Mahalingam
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology*; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human