Reactive Angioendotheliomatosis with Atypical Features Following Immune Checkpoint Inhibitor Therapy: A Diagnostic Challenge

Abstract

Introduction: Reactive angioendotheliomatosis is a rare, benign cutaneous vascular proliferation that may mimic malignant vascular disorders. Atypical endothelial morphology can complicate diagnosis, particularly in patients receiving anticancer therapy. This case highlights an unusual palmoplantar presentation following nivolumab administration and the importance of clinicopathological correlation.

Case Presentation: A 65-year-old woman with colonic adenocarcinoma diagnosed three years earlier, receiving FOLFOX chemotherapy and nivolumab, presented with progressively enlarging, tender, erythematous palmoplantar plaques of 20 days’ duration. The lesions appeared approximately three weeks after a nivolumab cycle. Examination revealed firm, non-blanching plaques, some progressing to well-defined ulcers with purulent, exudative bases. Histopathology demonstrated complete epidermal denudation and proliferation of thin blood vessels in the upper and mid dermis, lined by cells with plump nuclei. Luminal formation was indistinct in some areas, and neutrophilic infiltration of sweat glands was absent. Immunohistochemistry showed strong CD31 positivity in arborizing vascular channels and low Ki-67 positivity. Differential diagnoses included Kaposi sarcoma, spindle cell hemangioma and angiosarcoma. Integrated assessment supported reactive angioendotheliomatosis with atypical features, with endothelial atypia interpreted as treatment-related. Conservative management comprised an emollient, topical antibiotics, oral antihistamines and an oral analgesic. At two weeks, the palmar and plantar lesions had significantly improved.

Results: Histopathology and immunohistochemistry supported a diagnosis of reactive angioendotheliomatosis with atypical features, with strong CD31 positivity and low Ki-67 expression. The palmoplantar lesions showed significant clinical improvement after two weeks of conservative treatment.

Conclusion: Reactive angioendotheliomatosis should be considered when atypical vascular lesions arise during anticancer therapy. Clinical findings, histopathology, immunohistochemistry and lesion evolution require integrated interpretation to distinguish reactive proliferation from malignant mimics. The temporal relationship with nivolumab suggested a possible association but did not establish causality, particularly with concurrent chemotherapy and underlying malignancy. Continued clinical follow-up remains important.

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