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Increased ERBB2 Gene Copy Numbers Reveal a Subset of Salivary Duct Carcinomas with High Densities of Tumor Infiltrating Lymphocytes and PD-L1 Expression

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Abstract

Salivary duct carcinoma (SDC) commonly expresses androgen receptor (AR) and HER2, giving rise to treatment implications. SDC may also express programmed-death-ligand-1 (PD-L1), a predictive marker of response to checkpoint inhibitors. PD-L1 can be associated with genomic instability and high density of tumor infiltrating lymphocytes (TILs). Evaluation of HER2 immunohistochemistry (IHC) in SDC is not standardized, and relationships between ERBB2 copy numbers, PD-L1 expression and TILs in SDC are unknown. We evaluated 32 SDCs for HER2, AR and PD-L1 expression (IHC), ERBB2 status (FISH) and TILs (slide review). HER2 was scored with three different systems (breast, gastric, proposed salivary gland). PD-L1 was evaluated with the combined positive score. Most patients were older men, presenting at advanced clinical stage with nodal or distant metastases. During follow-up (mean 5 years, range 6 months to 21 years), 25 of the 32 patients (78%) died of SDC. We propose a HER2 IHC scoring system which accurately predicts underlying ERBB2 amplification or increased copy numbers in SDC. Most tumors had increased ERBB2 copy numbers (19/32 amplification, 6/32 aneusomy), a finding associated with higher TIL densities (p = 0.045) and PD-L1 expression (p = 0.025). Patients with TILs ≥ 40% had better prognoses (Log-Rank p = 0.013), with TILs being favorable prognosticators in univariate analysis (Hazard ratio: 0.18, p = 0.024). A subset of SDCs with increased ERBB2 copy numbers have higher TILs and PD-L1 expression. TILs ≥ 40% are associated with better prognosis.

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Abbreviations

SDC:

Salivary duct carcinoma

AR:

Androgen receptor

FISH:

Fluorescent in situ hybridization

IHC:

Immunohistochemistry

PD-L1:

Programmed death-ligand 1

PD-1:

Programmed death 1

TILs:

Tumor infiltrating lymphocytes

FFPE:

Formalin fixed paraffin embedded

H&E:

Hematoxylin and eosin

CAP:

College of American Pathologists

CPS:

Combined positive score

ASCO:

American Society of Clinical Oncology

PA:

Pleomorphic adenoma

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Acknowledgements

The authors thank Mohamed A. Ibrahim with the Mayo Clinic DLMP Research and Innovation Office for the administrative support.

Funding

Institutional Research Funds from the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. The funders had no role in designing the study, collecting and analyzing the data, drafting the manuscript or making the decision to publish.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Kyriakos Chatzopoulos, Sotiris Sotiriou, Michael G. Keeney, Daniel W. Visscher, Michael Rivera, David J. Schembri-Wismayer, Jean E. Lewis, Patricia T. Greipp, William R. Sukov & Joaquin J. Garcia

  2. Mayo Clinic Alix School of Medicine, Rochester, MN, USA

    Andrea R. Collins

  3. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA

    Ashish V. Chintakuntlawar & Katharine A. Price

  4. Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA

    Joaquin J. Garcia

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  1. Kyriakos Chatzopoulos
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Contributions

KC reviewed the histologic material, interpreted immunohistochemical stains, performed the statistical analysis and wrote the manuscript. AC participated in data interpretation and drafted portions of the manuscript. SS participated in data interpretation and critically edited the manuscript. MK collected the histologic material, reviewed immunohistochemical stains and interpreted the data. DV participated in data interpretation and critically edited the manuscript. MR interpreted the data, critically revised and edited the manuscript. DS-W assisted in data interpretation, critically revised and edited the manuscript. JL assisted in data interpretation, critically revised and edited the manuscript. PG interpreted cytogenetics data. WS interpreted cytogenetics data and guided their incorporation into the study. AC collected clinical data, critically revised and edited the manuscript. KP collected clinical data. JG designed the study, collected histologic material, interpreted immunohistochemical stains and cytogenetics data, critically reviewed and edited the manuscript.

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Correspondence to Joaquin J. Garcia.

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The study was approved by the Mayo Clinic Institutional Review Board (Application Number 12-001311; Last approval date: 2/28/2017).

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Chatzopoulos, K., Collins, A.R., Sotiriou, S. et al. Increased ERBB2 Gene Copy Numbers Reveal a Subset of Salivary Duct Carcinomas with High Densities of Tumor Infiltrating Lymphocytes and PD-L1 Expression. Head and Neck Pathol 14, 951–965 (2020). https://doi.org/10.1007/s12105-020-01163-x

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