A case of Merkel cell carcinoma mimicking cellulitis during Janus kinase inhibitor therapy

Dear Editor, Merkel cell carcinoma (MCC) is a highly aggressive, rare cutaneous neuroendocrine carcinoma prone to for local recurrence and distant metastasis.Although Merkel cell polyomavirus (MCPyV) asymptomatically infects mostof the general population, its clonal integration acts as the primary oncogenic driver in approximately 80% of MCC cases, with the remainder linked to ultraviolet radiation exposure. Immunosuppression is a well-established risk factor for MCPyV-positive MCC, highlighting the critical role of host immunosurveillance in suppressing this viral oncogenesis. Janus kinase (JAK) inhibitors are increasingly used for various inflammatory and autoimmune conditions, including rheumatoid arthritis (RA). While large-scale clinical trials have demonstrated that JAK inhibitors do not significantly increase the overall risk of common non-melanoma skin cancers (1), sporadic MCC cases during JAK inhibitor therapy have been recently reported (2)(3)(4)(5). Herein, we report a rapidly progressing, stage IV MCC with an atypical cellulitis-like presentation that developed during combined treatment with a JAK inhibitor and methotrexate (MTX).A 74-year-old female with a history of RA had received long-term MTX (8 mg/week), with tofacitinib (10 mg/day) added four years prior. Two months before presentation, localized erythema and swelling developed on her right lower leg. Initially diagnosed as cellulitis and treated with oral antibiotics at a local clinic, the lesion failed to respond, rapidly expanding with multiple erythematous papules emerging within and around the plaque. Tofacitinib was discontinued, and avelumab (10 mg/kg) was initiated. Within one month, the leg lesions completely cleared, the inguinal lymph nodes significantly regressed (Figure 1g), and the NSE level normalized to 11.1 ng/mL. She subsequently developed Grade 3 immune-related interstitial pneumonia (CTCAE v5.0), leading to permanent avelumab discontinuation after five doses.Two courses of systemic corticosteroid pulse therapy (methylprednisolone 1,000 mg/day for 3 days), and a gradual tapering regimen, successfully resolved the pneumonia. Notably, the patient remains completely recurrence-free 36 months after avelumab discontinuation, without resuming JAK inhibitor therapy. This case highlights the atypical cellulitis-like manifestation and specific patient characteristics associated with JAK inhibitor therapy. Typical MCC predominantly affects patients > 75 years) on sun-exposed areas like the head and neck. In contrast, JAK inhibitor-associated cases (2-5), frequently occur in younger individuals (<75 years) and often emerge at sun-protected sites such as the trunk or lower extremities. Furthermore, our patient presented with circumferential erythema and induration of the lower leg, which we attributed primarily to severe lymphedema secondary to right inguinal lymph node metastasis which likely facilitated extensive dermal lymphatic invasion by tumor cells, resulting in a "carcinoma erysipelatoides"-like presentation. The absence of elevated inflammatory markers, combined with the lack of response to initial antibiotic therapy, was a crucial clue prompting a diagnostic skin biopsy.Regarding etiology, large-scale clinical trials indicate that tofacitinib does not significantly increase the overall incidence of non-melanoma skin cancers in RA (1). However, subsequent long-term data revealed that higher doses of JAK inhibitors are associated with an increased risk of these malignancies, suggesting a dose-dependent relationship reflecting the degree of pharmacological JAK suppression. This implies that while the general risk remains low at standard doses, a more profound pharmacological JAK suppression may specifically disrupt antiviral immunosurveillance in susceptible individuals. Indeed, as observed in our case and others (2)(3)(4)(5), individual instances of MCC during JAK inhibitor therapy exhibit a distinct pattern of younger age and atypical distribution. Among the four previously reported cases, the administered agents were ruxolitinib (two cases) and tofacitinib (two cases). Notably, similar to our patient, both tofacitinib-treated cases were MCPyV-positive. Although our patient was receiving concomitant MTX, making it difficult to completely exclude its contribution, it is highly notable that previously reported cases of tofacitinib-associated MCC developed during tofacitinib monotherapy after MTX discontinuation. These observations suggest that pharmacological JAK inhibition may play a more prominent role than MTX in disrupting antiviral immunosurveillance. Tofacitinib inhibits JAK1 and JAK3, thereby suppressing interferon signaling and natural killer cell functions, which are pivotal in the host defense against MCPyV. In our case, the synergistic effect of baseline MTX and the specific anti-viral impairment by tofacitinib likely permitted the uncontrolled oncogenic proliferation of MCPyV.