Sarcomatoid Transformation of Pulmonary Mucinous Adenocarcinoma as a Mechanism of Immunotherapy Resistance

ABSTRACT Histological transformation to sarcomatoid carcinoma is an extremely rare mechanism of resistance to tyrosine kinase inhibitors. Among adenocarcinoma subtypes, transformation of pulmonary invasive mucinous carcinoma (IMA) into other histological types has not previously been reported. We present the case of a 74‐year‐old man referred to our hospital with abnormal lung shadows. Chest computed tomography (CT) revealed extensive consolidation predominantly in the right lower lobe. Transbronchial biopsy specimens confirmed IMA, which was negative for thyroid transcription factor‐1, and a BRAF D594G mutation was detected. As surgical resection was not feasible, first‐line treatment with ipilimumab plus nivolumab combined with chemotherapy was initiated, resulting in a partial response. After 19 cycles of maintenance therapy, treatment was discontinued because of suspected interstitial lung disease (ILD). Thirteen months later, the patient developed radiographic worsening of ILD, for which oral prednisolone was initiated. Two months later, CT imaging revealed rapid disease progression, with enlargement of right supraclavicular, mediastinal, and abdominal lymph nodes. Re‐biopsy of a mediastinal lymph node demonstrated sarcomatoid carcinoma positive for vimentin and pan‐cytokeratin AE1/AE3. Genomic analyses again identified the BRAF D594G mutation, confirming sarcomatous transformation of the original IMA. The patient received two cycles of nab‐paclitaxel plus carboplatin without response and subsequently died. These findings emphasize that clinicians should recognize that IMA may undergo sarcomatous transformation.