Hypertrophic plaques in a patient with pulmonary adenocarcinoma

An 85-year-old man was referred to our clinic because of itchy skin lesions on his upper and lower extremities persisting for four weeks. The skin lesions initially appeared on the dorsal aspects of both hands, where multiple cutaneous squamous cell carcinomas had recently been removed. They quickly spread to involve his forearms. Clinical examination revealed multiple hypertrophic red-brown to yellow-grey plaques with ulcerations, primarily on the dorsal surfaces of the forearms and the backs of the hands (Figure 1). There was no mucosal involvement. The patient had previously been diagnosed with stage IVB pulmonary adenocarcinoma and had received pembrolizumab for one year. Your diagnosis? … Diagnosis: Checkpoint inhibitor therapy-related hypertrophic lichen planus Laboratory evaluation revealed no abnormalities. A punch biopsy was obtained from the back of the right hand. Histopathology revealed marked acanthosis with irregular hypergranulosis and compact orthokeratosis, accompanied by a vacuolated basement membrane zone and a band-like lymphocytic infiltrate, as well as isolated intraepidermal cytoid bodies (Figure 2). Direct immunofluorescence showed clustered cytoid bodies in both IgA and IgM with linear fibrinogen deposits along the basement membrane zone. Treatment with acitretin 20 mg per day and topical 0.05% clobetasol propionate once daily was initiated. At the six-week follow-up, the patient achieved a complete response (Figure 3). Pembrolizumab was continued, resulting in metabolic remission of the pulmonary adenocarcinoma. Acitretin was reduced to 10 mg daily and a follow-up appointment was scheduled for three months later. Cutaneous side effects occur in 15 – 40 % of patients receiving programmed cell death 1 (PD-1) inhibitors such as pembrolizumab or nivolumab. These effects present with a broad clinical spectrum, including pruritus, maculopapular rashes, vitiligo and lichenoid dermatoses.1, 2 Lichenoid reactions are the most frequently reported inflammatory pattern, whereas hypertrophic variants are rare. The incidence varies depending on the underlying cancer,2 and recent studies show that immune signatures can influence the risk of adverse events in patients receiving PD-1 inhibitor therapy.3 Cutaneous side effects are partly associated with a better oncological outcome.4 Due to its verrucous morphology, hypertrophic lichen planus poses a particular diagnostic challenge. In patients with a history of non-melanoma skin cancer, these lesions can clinically resemble verrucous squamous cell carcinoma. In this case, the occurrence of pronounced hyperkeratosis and ulceration within the area of excised cutaneous squamous cell carcinomas further complicated the diagnosis and emphasized the importance of histopathological evaluation. It should be noted that checkpoint inhibitor therapy-related lichen planus can mimic cutaneous squamous cell carcinoma not only clinically but also histologically.5 For this reason the previous histological slides of the cutaneous squamous cell carcinomas were re-evaluated by an experienced dermatopathologist. After careful clinical correlation and retrospective examination of these histological sections, the initial diagnosis of squamous cell carcinoma was revised to hypertrophic lichen ruber. The exacerbation was most likely induced by the prior surgical procedures, consistent with the Koebner phenomenon. The pathogenesis of checkpoint inhibitor-related lichen planus is thought to involve enhanced cytotoxic T-cell activity following PD-1 blockade. PD-1 typically acts as a key inhibitory receptor for the autoreactive T-cell response. Upregulated CD4+ and CD8+ lymphocytes then infiltrate the dermal-epidermal junction zone, damaging basal keratinocytes. This results in interface dermatitis with cytoid body formation.6 Direct immunofluorescence findings typically show these cytoid bodies in the superficial dermis, alongside granular deposits of IgM and fibrinogen at the dermal-epidermal junction.7 Management of checkpoint inhibitor therapy-related hypertrophic lichen planus depends on the severity and extent of the disease. Topical high-potency corticosteroids are the first-line therapy for localized disease, whereas systemic corticosteroids or other immunomodulatory agents may be necessary for severe or refractory cases. In most cases, checkpoint inhibitor therapy can be maintained with appropriate control of cutaneous adverse events.8 Acitretin, a systemic retinoid, has been shown to be effective in randomized controlled trials for treating cutaneous idiopathic lichen planus. This is of particular significance because, unlike systemic corticosteroids or other immunosuppressive therapies, it does not appear to impair the anti-tumor efficacy of immunotherapy.9 Recent data has shown that checkpoint inhibitor therapy-related lichen planus has an inflammatory signature driven by IFN-γ, highlighting topical JAK inhibitors as a promising new treatment.10 In this patient, a combination of topical corticosteroids and systemic acitretin resulted in complete clinical improvement within six weeks, with no discontinuation of checkpoint immunotherapy required. This case report highlights the importance of recognizing checkpoint inhibitor therapy-related hypertrophic lichen planus as a rare immune-related cutaneous adverse event and distinguishing it from other possible diagnoses, particularly cutaneous squamous cell carcinoma. An early diagnosis facilitates the initiation of appropriate therapy while avoiding unnecessary discontinuation of potentially life-prolonging oncological treatment. None.