Molecular Detection of TOP2A Gene Amplification in Archival Fine Needle Aspirates of Small Cell Lung Carcinoma.
Nikoletta Sidiropoulos, Zhihua Peng, Mark F Evans. Fletcher Allen Health Care/University of Vermont, Burlington, VT
Background: Small cell lung carcinoma (SCLC) is a cytologic disease that does not lend itself to surgical resection because it is typically metastatic at the time of diagnosis. Despite ongoing advances in the molecular pathology of non-small cell lung carcinoma, many of which have resulted in improved targeted therapeutics, the molecular aberrations of SCLC remain poorly understood. Recent reports suggest promising therapeutic results with a new synthetic anthracycline that acts as a potent topoisomerase IIα (TOP2A) inhibitor. The primary aim of this study was to evaluate cytologic SCLC cases for TOP2A gene amplification to gain insight into the potential of TOP2A inhibitors to treat SCLC.
Design: A search for all cases of SCLC diagnosed via fine needle aspiration (FNA) at our institute over the past decade was performed. Cases with at least one slide that could be maintained for diagnostic records were assayed. An alcohol-fixed, Papanicolaou-stained slide from each case was decoverslipped and assessed by fluorescence in situ hybridization (FISH) using a ZytoLight® triple probe for centromere 17(C17), human epidermal growth factor receptor 2 (HER2), and TOP2A (ZytoVision). Available corresponding formalin-fixed, paraffin-embedded (FFPE) samples from these tumors were also tested by triple probe FISH. The technique was optimized using decoverslipped, alcohol-fixed, Papanicolaou-stained cytologic smears of normal lung prepared from surgical bench specimens.
Results: FNAs from 37 patients and FFPE samples from 2 patients were evaluated. Of the FNA samples, 12 (32.4%) were disomic and 25 (67.6%) were aneusomic (trisomic up to sextasomic) for all three markers. Three specimens (8.1%) showed TOP2A amplification: two of these (5.4%) also showed HER2 amplification (undetected in any other samples) and were disomic for C17, and the third was trisomic for C17 and HER2. Of the 2 correlate FFPE samples examined, FNA data matched in one instance and the other specimen was FFPE disomic and FNA aneusomic at the probe loci.
Conclusions: This FISH survey of SCLC FNA smears is the first of its kind and has resulted in the identification of three molecular profiles a single morphologic disease. Given recent reports on subsets of SCLC with improved response to a novel synthetic TOP2A inhibitor, it is of interest that this study identified a small subset of SCLC cases that had TOP2A amplification. This molecular heterogeneity may lend itself to more tailored therapeutics that are based not strictly on morphology but instead on the underlying molecular defect.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 55, Monday Morning