Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies.

Journal of Thoracic Oncology ® • Volume 8, Number 8, August 2013 CASE REPORT A 32-year-old man presented with cough and bloody sputum. Computed tomography (CT) showed a mass in the S6 segment and diffuse consolidation throughout the lower lobe of the left lung. Transbronchial lung biopsy revealed adenocarcinoma (AC) with lymphangiosis. Immunohistochemistry (IHC) showed anaplastic lymphoma kinase (ALK) protein expression, and break-apart fluorescent in situ hybridization showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started in June 2010. After tumor progression, the patient was enrolled in the randomized trial (PROFILE 1007) and was allocated to the pemetrexed arm. Subsequently, he was enrolled in PROFILE 1005 trial to receive crizotinib in July 2011 (Fig. 1A). After a partial response was observed, a nodule in the S9 segment developed in size to 2 cm, in February 2012 (Fig. 1B, C), and crizotinib was discontinued. CT scans performed after four cycles of carboplatin and gemcitabine showed a mixed response, with improvements in lymphadenopathy and lymphangiosis, but progression of the mass in S9. CT-guided core-needle biopsy revealed ALK-positive atypical cells, but it was impossible to distinguish histological types because of degeneration and necrosis. Thereafter, carboplatin, paclitaxel, and bevacizumab were administered, but the same mixed response was observed. The mass in S9 increased rapidly in size and reached 7 cm in August 2012 (Fig. 1D). Left lower lobectomy was performed in September 2012. The primary tumor in S6 was diagnosed as AC-positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1 negative sarcomatoid carcinoma (Figs. 2A-C, 3A-C). ALK was positive with IHC in both tumors, and fluorescent in situ hybridization revealed high-level gene amplification of the ALK gene only in the sarcomatoid carcinoma (Figs. 2D, E, 3D, E). Reverse-transcriptase polymerase chain reaction (RT-PCR) revealed the same variant of echinoderm microtubule-associated protein-like 4-ALK (E13; A20). Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23.