Case report: small cell transformation and metastasis to the breast in a patient with lung adenocarcinoma following maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitors

A 49-year-old man with 20 years’ history of smoking presented with cough and shortness of breath in September 2012. Chest computed tomography (CT) scan revealed a mass in the lingular segment of the left lung with mediastinal lymphadenopathy and moderate left pleural effusion (Fig. 1a). Serum tumor markers were elevated including CEA: 101 ng/mL (normal range, 0-5 ng/mL), CA19-9: 4018.2 u/L (normal range, 0- 35u/L), CYFRA21-1: 3.3 ng/mL (normal range, 0-2.0 ng/mL), but NSE: 13.8 ng/ml was in normal range (normal range, 0-14 ng/ml). Bronchoscopy examination showed bronchial narrowing/obstruction in the lingular segment, the biopsy of which confirmed adenocarcinoma of the lung (Fig. 2a–c). The cytological examination of pleural effusion was positive for malignant cells. The patient was staged as a stage IV tumor (cT2a, N2, M1a). The patient received four cycles of chemotherapy with cisplatin and pemetrexed and his symptoms including cough and dyspnea gradually improved. The tumor response was evaluated and considered as partial response in December 2012 (PR) (Fig. 1b). EGFR mutational analysis performed on the lung biopsy specimen revealed a L858R mutation in the exon 21 of EGFR. According to the NCCN guideline, gefitinib was given for maintenance therapy started in January 2013. The patient remained asymptomatic and the lung mass was stable until May 2013 (Fig. 1c) when the lung tumor started to grow slowly. In July 2013, repeat CT scan demonstrated that tumor increased its size (Fig. 1d). Serum tumor markers were then measured with the following results: CEA, 11 ng/mL; CA19-9, 10.8 u/L; and NSE, 14.3 ng/mL. Repeat biopsy of the re-growing lung mass was performed, which showed poorly differentiated carcinoma (Fig. 2d, e). Repeat EGFR mutational analysis revealed the same exon 21 mutation without additional mutations including T790M mutation. Two weeks later, serum tumor markers NSE were elevated (Fig. 1). In addition to the gefitinib the patient received four cycles of chemotherapy with cisplatin and docetaxel, which resulted in a partial response (PR) (Fig. 1e). He was followed up and received gefitinib treatment alone (250 mg daily). In March 2014, the patient complained of his right breast enlargement. Physical examination and chest CT scan revealed a 5-cm firm round mobile mass in his right breast at the 3 o’clock position (Fig. 1f). The breast mass was biopsied and showed poorly differentiated carcinoma with positive immunostaining for chomogranin A, synaptophysin, CD56, TTF-1 and negative for estrogen receptor(ER), GCDFP-15, HER2 (Fig. 2h, l). The second biopsy specimen from lingular segment was reassessed, confirming that the lung tumor was also positive for synaptophysin and CD56 (Fig. 2f, g). Thus, a diagnosis of metastatic small cell lung cancer (SCLC) was rendered for the breast tumor based on the morphologic and immunophenotypic features. The breast tumor also harbored the same EGFR exon 21 mutation. Repeat serum tumor marker test revealed that the level of NSE was increased to 51.2 ng/mL. Repeat CT scan showed lung mass enlargement and new multiple liver masses, considered as liver metastasis (Fig. 1g). Overall, the patient was considered to have acquired resistance to EGFR-TKI and transformation to SCLC. Gefitinib was discontinued and chemotherapy with regimen of cisplatin and etoposide was given. The patient showed initial clinical responses including shrinkage of lung and right breast tumors and the level of NSE decreased to 30.1 ng/mL (Fig. 1h). Unfortunately, the patient declined to have further treatment after he received six cycles of chemotherapy. Shortly after that, the patient developed bone and brain metastasis and died in Nov 2014.