Dermatopathology
Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features

https://doi.org/10.1016/j.jaad.2020.04.105Get rights and content

Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte–associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.

Section snippets

Checkpoint inhibitors

Checkpoints maintain immunologic homeostasis by limiting T-lymphocyte activity toward host antigens but can also inadvertently decrease immune surveillance of cancer cells.3, 4, 5 CTLA-4, expressed on the cell surface of activated T cells, prevents continued T-cell activation when bound to costimulatory signals. Ipilimumab blocks this interaction, allowing the immune system to activate against neoplastic cells.6, 7, 8, 9 Similarly, binding of PD-1 expressed on activated T cells prevents T-cell

Predominantly superficial perivascular dermatitis

Maculopapular eruptions, occurring in up to 60% of patients treated with CTLA-4 inhibitor therapy, typically show superficial perivascular dermatitis on histopathology. Perivascular dermatitis, occasionally with eosinophils, may occur during PD-1 blockade but is less common.47 Patients demonstrate variably pruritic, erythematous macules and dome-shaped papules, some of which coalesce into patches and plaques.42,44,45,48 Reticulated patterns or koebnerization can be seen.43,44 Eruptions usually

Conclusions

Immune checkpoint blockade has demonstrated remarkable outcomes for patients with various types of cancer. Checkpoint inhibitors are associated with a range of cutaneous AEs, highlighting the complexity of the immune response and the importance of clinical-histopathologic correlation in accurate recognition of AEs, allowing for appropriate intervention and patient care.

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    Funding sources: The research reported in this publication was supported in part by the Dermatology Foundation, through Dermatopathology Career Development Award (Dr Kiuru); National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number K23AR074530 (Dr Kiuru); Berg, Lutris, Paxman, Novocure, US Biotest, and Veloce (Dr Lacouture); and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30-CA0-08748 and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number U01AR077511 (Dr Lacouture).

    Conflicts of interest: Dr Lacouture has a consultant/speaking role with Legacy Healthcare Services, Adgero, Amryt, Celldex, Debiopharm, Galderma, Johnson and Johnson, Novocure, Lindi, Merck Sharp and Dohme, BMS, Helsinn, Janssen, Menlo, Novartis, F. Hoffmann-La Roche AG, AbbVie Inc, Boehringer Ingelheim, Allergan, Amgen, E.R. Squibb & Sons LLC, EMD Serono, AstraZeneca, Genentech, LEO Pharma, Seattle Genetics, Bayer, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva, Parexel, OnQuality, Novartis, Harborside, Wiley, Azitra, NCODA, and Takeda Millenium. Drs Ellis, Vierra, Millsop, and Kiuru have no conflicts of interest to declare.

    IRB approval status: Not applicable.

    Reprints not available from the authors.

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