Original Article Epidermal Growth Factor Receptor Gene Amplification in Atypical Adenomatous Hyperplasia of the Lung
Maria G. McIntire, Sandro Santagata, Keith Ligon, Lucian R. Chirieac
Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
Received April 21, 2010; accepted May 10, 2010, available online May 16, 2010
Abstract: Atypical adenomatous hyperplasia (AAH) is postulated to be the earliest morphologic precursor lesion in lung carcinogenesis. The epidermal growth factor receptor (EGFR), one of the members of the Erb-2 family of receptors, is commonly expressed in non-small cell lung carcinoma (NSCLC). A subset of the patients with NSCLC has molecular abnormalities in the EGFR gene, including missense mutations and deletions and/or abnormal gene copy numbers, and the relative importance of each of these to patient outcome is an area of great interest. Recent reports show that EGFR mutations are rare or absent in AAH and are rare in bronchioloalveolar carcinoma (BAC). However, the EGFR gene copy number status in AAH is unknown. We examined the EGFR gene copy number status in lung adenocarcinomas, synchronous AAH, and BAC in surgical pathology resection specimens. EGFR gene copy number was analyzed by chromogenic in situ hybridization (CISH) using formalin fixed paraffin embedded tissue sections and EGFR probes as recommended by the manufacturer (Zymed Laboratories Inc.). A known positive case of high-grade glioma was used as a positive control. Results found that four of eight adenocarcinomas (50%) had more than five EGFR signals per nucleus, suggesting a gain in copy number. Interestingly, in four of nine cases of AAH (44.4%) more than three EGFR signals per nucleus were noted, with scattered cells showing up to 6 signals per nucleus. In addition, in five of 12 cases of BAC (42%), more than three EGFR signals per nucleus were noted. In the remaining cases two to three intranuclear dot-like peroxidase positive signals were present consistent with non-amplification of the gene. Our study reveals an abnormal EGFR gene copy gain in several cases of atypical adenomatous hyperplasia (AAH). In our cohort, the rate of EGFR gene copy abnormalities in AAH appears similar to BAC and lower than in ACA. These findings suggest that although EGFR gene copy abnormalities may be an early event in lung carcinogenesis, they are associated with tumor progression to invasive cancer and highlight the complexity of tumor morphogenesis. (AJTR1004005).
Keywords: EGFR, lung cancer, chromogenic in situ hybridization, copy number
Address all correspondence to: Lucian R. Chirieac, MD Department of Pathology Brigham and Women's Hospital 75 Francis Street, Boston, MA 02115 Tel: 617 732-8126, Fax: 617 264-5118 E-mail: email@example.com