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J. Park



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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-008 - Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib and received subsequent chemotherapies (ID 1723)

      09:30 - 09:30  |  Author(s): J. Park

      • Abstract

      Background
      Non-small-cell lung cancers (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement are highly sensitive to the ALK kinase inhibitor crizotinib, but drug resistance invariably emerges. Morphological transformation from adenocarcinoma to SCLC represents one acquired resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors. We present the case of transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib.

      Methods
      not applicable

      Results
      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 with lymphangiosis. Immunohistochemistry (IHC) showed ALK protein expression and break-apart fluorescent in-situ hybridization (FISH) showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started. After tumor progression, the patient was enrolled in the clinical trial and was allocated to the pemetrexed arm. Subsequently, he was enrolled in other trial to receive crizotinib in July 2011. After partial response was observed, a nodule in the S9 segment developed to 2cm in February 2012, and crizotinib was discontinued. CT scans performed after 4 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 and reached 7 cm.  Left lower lobectomy was performed. The primary tumor in S6 was diagnosed as adenocarcinoma positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1-negative sarcomatoid carcinoma. ALK was positive with IHC in both tumors, and FISH revealed high-level gene amplification of the ALK fusion gene only in the sarcomatoid carcinoma. Reverse transcriptase polymerase chain reaction revealed the same variant of echinoderm microtubule-associated protein like 4-ALK (E13; A20) and it indicated that these tumors have the same origin. Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23. Brain metastases occurred 2 months after pulmonary resection and he underwent brain surgery. The tumor was diagnosed as sarcomatoid carcinoma. Ten days later, he died due to exacerbation of lymphangiosis To discuss potential epithelial-to-mesenchymal transition (EMT), we performed E-cadherin and keratin staining as epithelial markers, and vimentin staining as a mesenchymal marker in 4 specimens. The specimens were pre-crizotinib specimen in S6, surgical specimen in S6, rebiopsied specimen in S9 after carboplatin and gemcitabine, and surgical specimen in S9. Rebiopsied specimen in S9 was unevaluable for IHC staining because of degeneration and necrosis. All of the 3 evaluable specimens showed positive expression of vimentin and only surgical specimen in S9 showed negative of epithelial markers.

      Conclusion
      The transformation from adenocarcinoma to sarcomatoid carcinoma could be interpreted as kind of EMT. This transformation might represent a novel acquired resistance mechanism to crizotinib, although there is another possibility that subsequent chemotherapies induced this transformation.