A 52-year-old Asian woman, previously healthy, presented with right hip joint pain. Her medical and family histories were unremarkable. Physical examination revealed painless enlarged lymph nodes in her neck. A full-body computed tomography (CT) scan showed diffuse pulmonary nodules, enlarged thyroid, and osteolytic changes in cervical vertebrae and right femur. Fluorodeoxyglucose-positron emission tomography/computed tomography detected fluorodeoxyglucose uptake in the thyroid, subclavicular lymph nodes, and multiple bones, including the cervical vertebrae and right femur. Brain magnetic resonance imaging showed multiple cerebral tumors (Fig. 1). However, these imaging evaluations plus endoscopy could not identify the primary location of the tumor. Significant laboratory investigations showed an elevated serum alkaline phosphatase (473 U/L; normal range: 115–359 U/L), anti-thyroglobulin antibody (77.8 IU/mL; normal range < 28.0 IU/mL), soluble interleukin-2 receptor (729 U/mL; normal range 145–519 U/mL), and carcinoembryonic antigen (207.7 ng/mL; normal range < 5.0 ng/mL). Thyroid-stimulating hormone (TSH),thyroglobulin, carbohydrate antigen 19–9 and carcinoma antigen 125 levels were within normal limits.
Pathological examination of tissue from an ultrasound-guided fine needle aspiration biopsy of the thyroid tumor and the left subclavicular lymph node showed high-grade malignant cells with no clear pattern of differentiation. Because the primary site could not be identified, we decided to treat the patient empirically with intravenous paclitaxel (80 mg/m2) plus carboplatin (area under the curve = 2) on days 1, 8, and 15 every 28 days. After 2 cycles of treatment, however, CT evaluation showed an increase in thyroid, lung and bone lesions. Because primary thyroid cancer remained a possibility, we performed a total thyroidectomy with consideration of isotope therapy and reexamination of the pathology. Histopathological examination of the whole thyroid revealed a tumor composed of differentiated cells with glandular lumens and scattered undifferentiated cells (Fig. 2a). On immunohistochemical examination, the cells stained positive for thyroid transcription factor 1, cyclin D1, and paired box 8, and negative for napsin A, BRAF(V600E), p53, and anaplastic lymphoma kinase (Fig. 2b). These findings suggested adenocarcinoma of thyroid or lung origin, but could not determine the primary location. Epidermal growth factor receptor (EGFR) gene mutation analysis using a polymerase chain reaction-single strand conformation polymorphism (PCR–SSCP) assay of the surgical specimen identified no actionable mutation in EGFR exon 18, exon 19, or exon 21. Subsequently, the metastatic lesions continued to enlarge. The patient underwent cranial irradiation (30 Gy/10 Fr) and palliative radiation therapy (30 Gy/10 Fr) for painful bone metastases in her cervical vertebrae.
Comprehensive genomic analysis using an NGS-based multiplex assay (Pan-cancer somatic panel PCSP-5.0. R0, Lifecode Health), which was designed to detect variants in 53 cancer-related genes (Supplementary Table 1) and certified concordant with the Clinical Laboratory Improvement Amendments, was performed on a formalin-fixed paraffin-embedded surgical sample of the patient’s thyroid tumor. This assay demonstrated the presence of an EGFR mutation, c.2573 T > G p.Leu858Arg (L858R). This mutation is well known to be a positive biomarker for EGFR tyrosine-kinase inhibitors (TKI) in non-small-cell lung carcinoma (NSCLC) [6, 7]. Because no standard treatment remained for this patient, we selected treatment with an EGFR-TKI, erlotinib, at 150 mg orally once a day, based on molecular profiling of the tumor. After the first 4 weeks of therapy, the lung lesions showed marked improvement on CT scan and the serum carcinoembryonic antigen level had decreased (Figs. 2 and 3). Fifteen months after the initiation of erlotinib, the patient’s disease progressed with elevation of serum carcinoembryonic antigen level and new cerebral metastasis. Therefore, a liquid biopsy using cell-free circulating tumor DNA was performed for assessment of EGFR mutation status, because there were no metastatic lesions accessible for rebiopsy. This analysis identified an additional EGFR mutation, c.2369C > T p.Thr790Met (T790M), as well as L858R. The T790M mutation is known to be a cause of acquired resistance to EGFR TKI. However, osimertinib, a third-generation EGFR TKI, is effective for patients with T790M-positive NSCLC, including those with central nervous system metastases [8]. Our patient received osimertinib at 80 mg orally once a day, and her serum carcinoembryonic antigen level decreased again (Fig. 3). She continued the EGFR-targeted therapy and survived for 2 years and 9 months after the first diagnosis, but died because of a general deterioration in her condition that was likely caused by leukoencephalopathy associated with late adverse events of radiotherapy.
