Metastatic extramammary Paget’s disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget’s disease, with an ERBB2S310F mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3A232V and PIK3CAG106V point mutations as well as MET and CDK6 amplification, providing a potential mechanism of acquired treatment resistance. Therefore, ERBB family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of ERBB2S310F mutated, metastatic extramammary Paget’s disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget’s disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.

Summary Mycosis fungoides (MF) is a primary cutaneous T‐cell lymphoma with unfavourable prognosis for patients with advanced stages of the disease. Refractory disease and advanced‐stage disease require systemic therapy. We report on a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59‐year‐old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization–European Organisation for Research and Treatment of Cancer classification. First‐line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa‐2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high‐dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Interestingly, readministration of interferon alfa‐2a as a maintenance treatment after the salvage autologous SCT resulted in a durable complete remission during the follow‐up period of currently 17 months after autologous SCT. What's already known about this topic? Mycosis fungoides is a primary cutaneous T‐cell lymphoma with unfavourable prognosis for the advanced stages of the disease. A refractory course of disease requires systemic therapy. What does this study add? We report on an unusual case of a patient with mycosis fungoides with cerebral involvement, in which a durable complete remission was achieved upon autologous stem cell therapy and interferon alfa‐2a maintenance therapy.

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