An 83-year-old man was admitted to the Respiratory Department of the Affiliated Kunshan Hospital of Jiangsu University on October 30, 2019, due to cough and expectoration accompanying hemoptysis for 1 week. The patient had a history of tuberculosis for more than 30 years and chronic bronchitis and emphysema for 10 years. Chest computed tomography (CT) revealed an irregular mass (5.3x2.6 cm) in the upper lobe of his left lung (Figure 1A). Furthermore, positron emission tomography/computed tomography (PET/CT) showed multiple lymph node and bone metastases (Figure 1B). The patient underwent a transthoracic core needle biopsy of the lung mass. Histological staining of lung tissue showed obvious tumor cell characteristics with adenoid and stratified structures and visible nuclear division (Figure 1C). Immunohistochemistry analysis revealed positivity for thyroid transcription factor 1(TTF-1), CK7, SPA, napsin-A and Ki-67 (about 10%), but negativity for villin, P63 and P40. Taken together, he was diagnosed with stage IV (T4aN2M1) invasive lung adenocarcinoma.
On December 6, 2019, a novel PTH2R-ALK fusion was identified in the patient's tumor tissue by NGS (Figure 2A), which was composed of exon 1 of PTH2R (parathyroid hormone second receptor) gene and exon 20-29 of ALK gene (Figure 2B). Fluorescence in situ hybridization further confirmed the ALK positive (Figure 2C). It contained the entire kinase domain of ALK and may activate ALK signaling to play a role in tumor genesis and development. Based on the results of NGS test, the patient started oral crizotinib 250 mg BID from December 12, 2019. After taking crizotinib for 10 days, the patient developed mild nausea without vomiting. Reexamination of liver function revealed that the level of alanine transaminase (ALT) and aspartate transaminase (AST) was 3-4 times higher than baseline (Table 1), suggesting mild liver function impairment. Thus, the patient was treated with polyene phosphatidylcholine for liver protection. The irregular mass shadow of the upper lobe of the left lung shrank significantly to 1.47x0.89 cm when reexamined by CT on January 18, 2020, indicating that this patient achieved a partial response. 
However, considering the intolerable hepatotoxicity, the patient switched to take alectinib 1200 mg BID from January 20, 2020. After 1 week, the clinician reduced the dosage to 600 mg BID, but the patient still had swelling in his legs and felt fatigued. His uncomfortable symptoms were slightly eased after symptomatic treatment of spironolactone. Carcinoembryonic antigen decreased obviously after treatment for a month. However, the total bilirubin of this patient reached up to three times of reference range (Table 1). Furthermore, he did not respond to symptomatic treatment of liver protection. On June 20, 2020, the patient started ceritinib orally 450 mg QD with food. He suffered from diarrhea and antidiarrheal drugs were ineffective. Then, the clinician reduced the dosage of ceritinib to 300 mg QD. During treatment with dose reduction of ceritinib, the patient's blood routine tests and liver function tests were normal, and chest CT scan demonstrated stable disease. The patients were followed up several times, with the last follow-up on June 13, 2021. The tumor lesion in the left lung remained stable and PFS was nearly 12 months.
Diagnosis results by CT scan and pathology. (A) CT diagnosis of lung tissue.