Title: Pembrolizumab-Induced Epidermotropic CD8+ Dermatitis in a Patient with Multiple Squamous Cell Carcinomas

Background: Pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been increasingly associated with dermatologic immune-related adverse events (irAEs), varying from benign rashes to severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. While the literature describes various dermatologic manifestations like lichenoid dermatitis and granuloma annulare as pembrolizumab side effects, we report a distinctive case of pembrolizumab-induced epidermotropic CD8+ dermatitis in a patient with a history of multiple squamous cell carcinomas (SCCs) and a keratin-positive malignant spindle cell neoplasm. This case adds to the evolving spectrum of pembrolizumab's dermatologic irAEs, underscoring the need for vigilance in patients receiving immune checkpoint inhibitors (ICIs).

A 69-year-old female with a history of multiple SCCs treated across various anatomical sites presented with complaints of a widespread rash. The patient reports that the rash had persisted for 20-30 years but had notably worsened following the initiation of pembrolizumab treatment two years prior. Pembrolizumab was administered as part of her treatment regimen for a keratin-positive malignant spindle cell neoplasm of the right proximal femur. She described the rash as intensely pruritic, worsening during winter months, with mild improvement during summer.

Methods: Compiled through a retrospective review of medical records with patient consent. Diagnostic assessments were conducted using standard histological and immunohistochemical techniques, supplemented by PCR for T-cell receptor gene rearrangements to evaluate T-cell clonality.

Results On skin examination, extensive coalescing, ill-defined erythematous patches with associated xerosis were observed. A biopsy of an eczematous lesion on the left lower back was performed to further investigate the rash's etiology. Histopathological analysis revealed hyperkeratosis, parakeratosis, and infiltration of epidermotropic lymphocytes within the epidermis. The infiltrate was predominantly composed of CD8+ T cells. Further molecular studies were negative for clonal T-cell receptor rearrangements.

Conclusion Given the lack of T-cell clonality and the CD8+ cell-rich infiltrate, a diagnosis of pembrolizumab-induced epidermotropic CD8+ dermatitis was favored over other dermatologic conditions such as mycosis fungoides. The chronicity and the pre-existing nature of the rash, coupled with the exacerbation post-pembrolizumab therapy, underscore its drug-induced origin, distinct from typical dermatologic irAEs reported with ICIs. This case is particularly unique due to the uncommon histopathological feature of epidermotropism of CD8+ T cells, divergent from the more common CD4+ presentations seen in other cases of pembrolizumab-induced dermatitis.

The patient continued with pembrolizumab therapy for her underlying malignancy and her rash was managed with triamcinolone 0.1% topical ointment.This case adds to the literature on pembrolizumab-induced skin reactions, emphasizing the nuanced understanding needed for diagnosis and treatment, particularly in the context of a pre-existing dermatologic condition exacerbated by ICI therapy.