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Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of advanced melanoma, but many patients do not respond to ICIs alone, and thus there is need for additional treatment options. Topical immunomodulators such as diphencyprone (DPCP) also have clinical use in advanced melanoma, particularly in the treatment of cutaneous metastases. In a previous report, we characterized the enhanced clinical response to dual agent immunotherapy with pembrolizumab and DPCP in a patient with cutaneous melanoma metastases. To improve mechanistic understanding of this response, we analyzed proteomic data using the Olink immuno-oncology panel of 96 biomarkers from tissue and serum samples of this patient throughout his treatment course. Particular attention was paid to programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) given they are all targeted by ICIs in clinical practice. These proteins were upregulated during the period of DPCP monotherapy, then downregulated during pembrolizumab monotherapy, and then robustly upregulated again during dual therapy. Although not exclusively, the induction of checkpoint inhibitor proteins in the presence of DPCP suggests potential synergy between this agent and ICIs in the treatment of cutaneous melanoma metastases. Large-scale investigation is warranted to further evaluate this potential novel combination therapeutic approach.

A woman in her 50s presented with a 4-day history of a diffuse, progressive, and pruritic rash. She had no known allergies and did not take any medications. She had no exposures to chemicals, detergents, or new personal care products; however, the patient consumed raw shiitake mushrooms several days before symptom onset. An examination revealed dozens of long flagellate streaks composed of red papules distributed across the trunk and extremities (Figure). She denied fever, malaise, or dyspnea. Laboratory results were remarkable for eosinophilia. The findings and history were consistent with flagellate mushroom dermatitis. The patient was treated with topical steroids, oral antihistamines, and raw shiitake mushroom avoidance, and the condition improved without sequelae.Flagellate mushroom dermatitis, also known as shiitake mushroom dermatitis, is thought to be caused by lentinan, a thermolabile toxin in shiitake mushrooms (Lentinula edodes). 1 Proposed pathogenesis includes delayed T-cell-mediated and toxinmediated reactions, as lentinan has T-cell-mediated antitumor properties, inducing vasodilation and hemorrhage reactions that can manifest as skin findings. However, the exact mechanism remains unknown. 2,3 Characteristic linear streaks of small erythematous pruritic papules appear 1 to 2 days following raw mushroom ingestion. It has been hypothesized that the linear pattern is partially produced by scratching; however, this has been disputed, as there are documented cases in which this pattern appears in the absence of scratching. 4 The distribution is commonly on the trunk and extremities. 1 The differential diagnosis for these findings is narrow and includes adult-onset Still disease, dermatomyositis, and flagellate erythema from chemotherapeutic agents, such as bleomycin. 3,4 Diagnosis of flagellate dermatitis is based on history and physical examination findings. Histology results are often nonspecific and may show spongiosis, perivascular lymphocytic and neutrophilic infiltrate, or eosinophils. 1,3 Flagellate mushroom dermatitis is self-limited, although treatment with topical steroids and oral antihistamines can be helpful. Resolution typically occurs within 1 to 8 weeks of mushroom avoidance, and thoroughly cooking mushrooms can prevent this dermatitis. Recognition of this condition may help guide patients to avoid triggers and minimize unnecessary testing.