AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Translational Res 2010;2(3):309-315

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.

Keywords: EGFR, lung cancer, chromogenic in situ hybridization, copy number

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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