A 60-year-old Japanese female with a history of depression and tuberculosis was referred to our hospital due to a lung nodule in the right lower lobe on computed tomography (CT) upon medical examination. She quit smoking 10 years ago with an 8 pack-year history and no family history of cancer. Imaging examinations revealed pleural dissemination and mediastinal lymph node adenopathy (cT4N2M1a Stage IVA). Endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal lymph nodes revealed adenocarcinoma. Molecular diagnostics of the tumor sample revealed ROS1 gene rearrangement without EGFR or anaplastic lymphoma kinase gene alteration.
Based on the presence of ROS1 gene rearrangement, oral crizotinib treatment was started. Crizotinib achieved a partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 and maintained its effectiveness with minimal adverse events.
However, CT 12 months after crizotinib initiation revealed a mass in the upper pole of the right kidney protruding toward perirenal fat (shown in Fig. 1a). Contrast-enhanced CT showed a polycystic mass with enhanced edges and septa. Considering that only a small lesion was detected 4 months prior but not at the time of crizotinib initiation, partial nephrectomy was performed by the Department of Urology to diagnose the mass. Pathology revealed xanthogranulomatous inflammation characterized by infiltration of lipid-laden macrophages and other inflammatory cells, fibrosis with hyalinization, and vasculation without malignancy or microbes (shown in Fig. 2a, b), which was consistent with CARCs. The day after surgery, crizotinib was restarted. Twenty-two days after restarting crizotinib, the patient developed fever. Laboratory data revealed elevated C-reactive protein, with subsequent CT showing abscess-like inflammation in the abdominal wall near the surgical wound and around right kidney (shown in Fig. 1b). Considering that antibiotic administration (cefaclor) had no effect, crizotinib was stopped and surgical cleaning was performed. No bacteria were detected from the culture of either the swab from the wound before starting antibiotics or the specimen from surgical cleaning, suggesting that these disseminated aseptic lesions were similar to CARCs, although pathological evaluation was not performed in the second surgery.
Given the improved laboratory findings after the second surgery, crizotinib was started again. However, the patient developed fever again, prompting crizotinib to be abandoned. After crizotinib was stopped, C-reactive protein and fever improved spontaneously. CT upon crizotinib cessation showed only a well-controlled primary tumor without any other obvious lesions, including those in the brain.
On day 25 after discontinuation, however, she was referred to the emergency department with a convulsive seizure and right hemiparesis. Enhanced magnetic resonance imaging revealed multiple brain metastases with edema which were not detected from the CT images obtained 26 days before admission (Fig. 3a, b). Thus, the rapid disease progression after crizotinib discontinuation in the current case was considered to be a "disease flare." Anticonvulsive agent (levetiracetam), dexamethasone, concentrated glycerin administration, and whole-brain irradiation (30 Gy/10 fraction) was started. Given that dexamethasone promoted no improvement in right hemiparesis, another ROS1 tyrosine kinase inhibitor with high central nervous system (CNS) penetration, entrectinib, was started on day 10 after admission. Hemiparesis improved, with subsequent magnetic resonance imaging on day 14 of entrectinib administration, showing a remarkable regression of the brain metastases with surrounding brain edema (shown in Fig. 3c). As of 3 months after entrectinib treatment, the disease remained well controlled without recurrence of brain lesions.