Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition

摘要

a Timeline demonstrating the treatment course of the patient and time points of tumor (T) collection. Numbers represent months since initial diagnosis. SBRT stereotactic body radiation therapy, FISH fluorescence in situ hybridization, IHC immunohistochemistry, NGS next-generation sequencing. b Representative axial computed tomography images demonstrating the progression of hepatic metastases during the disease course. c Schematic of the tumor samples collected. d Immunostains of the treatment-naive lung primary demonstrating thyroid transcription factor-1 (TTF-1)-positive adenocarcinoma, and of the representative autopsy tumor specimen demonstrating small cell morphology with positive stains for synaptophysin and chromogranin. H&E hematoxylin and eosin. ROS1 FISH demonstrates that the ROS1 fusion is retained in both treatment-naive and autopsy samples; representative split signals indicative of ROS1 fusion are highlighted by white arrows. ROS1 IHC illustrates detectable ROS1 protein expression in the treatment-naive tumor, but undetectable ROS1 expression in the small cell tumor. Immunostains for TP53 and RB1 reveal wild-type RB1 (red arrows indicating positive nuclear staining) and loss of TP53 expression in the treatment-naive tumor, and lack of RB1 and TP53 expression in the small cell-transformed tumor. The scale bar represents 100 µm in all panels except for the ROS1 FISH panel, in which it represents 30 µm. Magnification: ×200 for H&E and TTF-1, synaptophysin, chromogranin, and ROS1, and ×400 for TP53 and RB, of the initial biopsy sample; ×100 for H&E and TTF-1, synaptophysin, chromogranin, ROS1, TP53, and RB immunostains of the autopsy sample.