br Patient clinical course A
Patient 1: clinical course A Japanese 45-year-old man visited our hospital complaining of wet cough with hemoptysis, facial swelling, and right upper leg pain. He was a current smoker with 54 pack-years. A chest X-ray and computed tomography (CT) scan revealed an 11-cm mass in the lung field and paraseptal Latrunculin A (Fig. 1A). Positron emission tomography (PET)-CT imaging demonstrated abnormal uptakes (Fig. 1B). Endobronchial ultrasound-guided transbronchial needle aspiration was performed and histopathological analysis of the specimen revealed undifferentiated non-small cell lung carcinoma (NSCLC). An MRI scan of the right thigh revealed an impending pathologic fracture in the right femur (Fig. 1C). An EGFR mutation and ALK and ROS1 fusions were not detected and the PD-L1 tumor proportion score (TPS) was 0%. Nab-PTX plus CBDCA therapy with concurrent radiotherapy (60 Gy/30 fr) for the mediastinal mass and intramedullary nailing fixation were respectively performed. After two courses of chemotherapy, abdominal lymph node metastases progressed (Fig. 1D) and the second biopsy was performed. Histopathological analysis revealed an undifferentiated round cell tumor without spindle cell tumor (Fig. 2A). Immunohistochemical analysis was shown in (Fig. 2). The Ion AmpliSeq™ comprehensive cancer panel (Thermo Fisher Scientific, Massachusetts, USA) identified a frameshift mutation in P299fs (896delC) in SMARCA4 (Table 1). Collectively, a diagnosis of SMARCA4-DTS was finally made. All following chemotherapy regimens including immune checkpoint inhibitor (ICI) failed after two courses and 11 months after the first visit, the patient died.
Patient 2: clinical course A Japanese 45-year-old man visited our hospital complaining of worsening back pain. He was a current smoker with 29 pack-years. A chest X-ray and CT scan revealed a 5-cm mass in the lung field (Fig. 3A). PET-CT imaging demonstrated abnormal uptakes (Fig. 3B). Transbronchial lung biopsy was performed from the mass and histopathological analysis revealed undifferentiated NSCLC. The patient was diagnosed with NSCLC (cStage IV) with no EGFR mutation or ALK and ROS1 fusion genes, and with a PD-L1 TPS of 0%. A combination therapy of CBDCA plus nab-PTX and an ICI was administered followed by ICI maintenance therapy. After two courses of maintenance therapy, the patient complained of progressive left leg weakness. An emergent MRI scan of the entire spine revealed spinal tumor compression (Fig. 3C) resulting in emergent laminectomy for decompression of the spine. Histopathological analysis revealed rhabdoid cells were focally observed without spindle cell tumor. Immunohistochemical analysis was shown in (Fig. 4). The comprehensive cancer panel sequencing identified frameshift mutations at Q758H and Q822H (2774 G > T and 2466 G > T, respectively; Table 1). Unfortunately, the emergent surgery could not improve his symptoms and eleven months after the first visit, the patient died from his cancer under palliative care, similar to Patient 1.
Discussion Clinical and histological features of our cases were highly similar to those described in a previous study and exhibited sufficient characteristics to suspect SMARCA4-DTS [2,3]. Prototypical cases of SMARCA4-DTS showed the features of poorly differentiated neoplasms with epithelioid/rhabdoid cell tumors different from typical sarcoma derived from mesenchymal tissue . Histopathological analysis of our cases revealed some histopathologic features associated with sarcoma including small round cell tumor (Patient. 1) and rhabdoid cell tumor (Patient. 2). Both cases showed lack of Claudin-4 expression, which distinguishes SMARCA4-DTS from SMARCA4 mutated carcinomas . Our cases highlighted the fact that for the early diagnosis of SMARCA4-DTS, the integrated analysis is necessary and that SMARCA4-DTS has tends to be associated with severe SREs requiring emergent surgical and radiological treatment.