A 39-year-old never-smoker female without prior relevant medical history was admitted to the hospital with progressive symptoms of abdominal pain, dyspnea, and bilateral leg edema. A computed tomography scan revealed pericardial effusion; bilateral pleural effusion; a 3 cm mass in the right lung; hilar, mediastinal, and retroperitoneal lymphadenopa-thies; and ascitis (Figure 1). Pericardial and pleural fluids were positive for adenocarcinoma cells, and the patient was diagnosed with lung adenocarcinoma stage IV.
A core biopsy of the lung mass was performed. Molecular analysis of the EGFR and the KRAS genes revealed absence of mutations. Immunostaining with IHC VENTANA clone DF53 identified overexpression of ALK, and fluorescence in situ hybridization using Vysis LSI ALK dual-color break-apart probe demonstrated an ALK rearrangement. When the sample was analyzed by nCounter, it showed a 3'/5' imbalance indicative of an ALK rearrangement, but failed to give a positive signal for the EML4-ALK v1, v2, v3, or v5; TFG-ALK_T5:A20; KIF5B-ALK_K17:A20; or KIF5BALK_K24:A20 fusions. Finally, a band with a molecular weight higher than expected (239 bp) appeared after reverse transcriptase-polymerase chain reaction analysis (RT-PCR) with primers specific for EML4-ALK v1. No additional bands were apparent. The 239 bp band was submitted to Sanger sequencing revealing an atypical EML4-ALK fusion gene with a 129 bp insertion in the canonical junction of v1. A 115 bp segment of the insertion corresponded to an intronic region of LTBP1, a gene located in the short arm of chromosome 2, between the ALK and EML4 genes. The in silico translation of this new variant, which will be referred to as v1insLTBP1, showed an in-frame insertion of 43 aminoacids (Figure 1).
The patient started crizotinib with good tolerance. The computed tomography scan performed a month later showed a reduction of the primary lesion, disappearance of hilary and reroperitoneal lymphadenopathies, and a reduction of the mediastinal lymph nodes. After 14 months, the patient continues to demonstrate partial response.
Written informed consent has been provided by the patient to have the case details and any accompanying images published.