Heterogeneity of PD-L1 expression and CD8 tumor-infiltrating lymphocytes among subtypes of cutaneous adnexal carcinomas
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Adnexal carcinomas are rare and heterogeneous skin tumors, for which no standard treatments exist for locally advanced or metastatic tumors.
Aim of the study
To evaluate the expression of PD-L1 and CD8 in adnexal carcinomas, and to study the association between PD-L1 expression, intra-tumoral T cell CD8+ infiltrate, and metastatic evolution.
Materials and methods
Eighty-three adnexal carcinomas were included. Immunohistochemistry using anti-PD-L1 monoclonal antibodies (E1L3N and 22C3) and CD8 was performed. PD-L1 expression in tumor and immune cells, and CD8+ tumor-infiltrating lymphocyte (TIL) density were analyzed semi-quantitatively.
Among the 60 sweat gland, 18 sebaceous and 5 trichoblastic carcinomas, 11% expressed PD-L1 in ≥ 1% tumor cells, more frequently sweat gland carcinomas (13%, 8/60) including apocrine carcinoma (40%, 2/5) and invasive extramammary Paget disease (57%, 4/7). Immune cells expressed significantly more PD-L1 than tumor cells (p < 0.01). Dense CD8+ TILs were present in 60% trichoblastic, 43% sweat gland, and 39% sebaceous carcinomas. CD8+ TILs were associated with PD-L1 expression by tumor cells (p < 0.01). Thirteen patients out of 47 developed metastases (27%) with a median follow-up of 30.5 months (range 7–36). Expression of PD-L1 by tumor cells was associated with the development of metastasis in univariate analysis (HR 4.0, 95% CI 1.1–15, p = 0.0377) but not in multivariate analysis (HR 4.1, 95% CI 0.6–29, p = 0.15).
PD-L1 expression is highly heterogeneous among adnexal carcinoma subtypes, higher in apocrine carcinoma and invasive extramammary Paget disease, and associated with CD8+ TILs. Our data suggest the interest of evaluating anti-PD1 immunotherapy in advanced or metastatic cutaneous adnexal carcinoma.
KeywordsCutaneous adnexal carcinoma Programmed cell death ligand 1 (PD-L1) Tumor-infiltrating lymphocytes (TILs) CD8
American Joint Committee on Cancer
Assistance Publique-Hôpitaux de Paris
Basal cell carcinoma
Centre hospitalier régional universitaire
Cutaneous squamous cell carcinoma
Extramammary Paget disease
No other specification
Tumor mutation burden
Unité mixte de recherche
World Health Organization
The authors thank the Tumorothèque of Saint Louis hospital for providing tissue material.
LD designed the study, acquired and analyzed data, drafted the work and revised it. AO acquired data and revised the work for important intellectual content. BC analyzed data and revised the work for important intellectual content. LM analyzed data and revised the work for important intellectual content. ADM acquired and analyzed data, did the statistical analysis, and revised the work for important intellectual content. NB-S acquired clinical data and revised the work for important intellectual content. CL acquired clinical data and revised the work for important intellectual content. MB designed the study, acquired and analyzed data, drafted the work, and revised the work for important intellectual content. All authors approved the final manuscript version.
No relevant funding.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All patients were informed that part of the remaining tissue material could be used for research, and gave their consent according to the Helsinki declaration. Samples were obtained from the Tumorothèque of Saint-Louis Hospital (Tumor bank registration number DC2009.929, Ministry of Health, France).
According to the bioethics French law of August 6th 2004, applicable at the time of the study, in the context of a retrospective monocentric non-interventional study, additional ethical committee approval was not necessary.
- 18.Dieci MV, Radosevic-Robin N, Fineberg S et al (2018) Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 52:16–25CrossRefGoogle Scholar
- 19.Hendry S, Salgado R, Gevaert T et al (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol 24(6):311–335CrossRefGoogle Scholar
- 39.Mahalingam M, Nguyen LP, Richards JE et al (2010) The diagnostic utility of immunohistochemistry in distinguishing primary skin adnexal carcinomas from metastatic adenocarcinoma to skin: an immunohistochemical reappraisal using cytokeratin 15, nestin, p63, D2-40, and calretinin. Mod Pathol 23(5):713–719CrossRefGoogle Scholar
- 52.Behr DS, Peitsch WK, Hametner C et al (2014) Prognostic value of immune cell infiltration, tertiary lymphoid structures and PD-L1 expression in Merkel cell carcinomas. Int J Clin Exp Pathol 7(11):7610–7621Google Scholar
- 61.Xu F, Xu L, Wang Q et al (2015) Clinicopathological and prognostic value of programmed death ligand-1 (PD-L1) in renal cell carcinoma: a meta-analysis. Int J Clin Exp Med 8(9):14595–14603Google Scholar
- 65.Toyokawa G, Takada K, Haratake N et al (2016) Favorable disease-free survival associated with programmed death ligand 1 expression in patients with surgically resected small-cell lung cancer. Anticancer Res 36(8):4329–4336Google Scholar
- 67.Mezger J, Remberger K, Schalhorn A et al (1986) Treatment of metastatic sweat gland carcinoma by a four drug combination chemotherapy: response in two cases. Med Oncol Tumor Pharmacother 3(1):29–34Google Scholar
- 69.De Iuliis F, Amoroso L, Taglieri L et al (2014) Chemotherapy of rare skin adnexal tumors: a review of literature. Anticancer Res 34(10):5263–5268Google Scholar