Correlation between morphology and EGFR mutations in lung adenocarcinomas: Significance of the micropapillary pattern and the hobnail cell type
Introduction
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that dimerizes and phosphorylates several tyrosine residues after binding of specific ligands. The phosphorylated tyrosines then play important roles in cell physiology and activation of downstream pathways of EGFR can lead to abnormal growth control and cellular transformation [18]. Gefitinib, an orally administered agent preventing binding of adenosine triphosphate (ATP) within the ATP-binding region of EGFR TK thus inhibits tyrosine residue phosphorylation and signaling. Blockade of EGFR-mediated effects induces apoptosis and reduces tumor growth. EGFR is highly expressed in solid carcinomas [16], including non-small cell lung cancers (NSCLCs), but despite of high expectations based on biological findings and data suggesting wide applicability [4], neither expression level nor phosphorylation of EGFR predict sensitivity to gefitinib in both preclinical and clinical data [2], [4].
There have been a number of reports referring to clinicopathological factors of lung tumors associated with EGFR mutations [2], [5], [7], [11], [13], [14], [19], [26]. In two early notable studies, Lynch et al. [11] and Paez et al. [19] reported that clinical responsiveness to gefitinib was associated with somatic mutations in the TK domain of the EGFR gene. Paez et al. indicated such mutations to be prevalent in adenocarcinoma cases of female gender and Japanese origin [19]. In terms of pathological subtypes, Miller et al. [14] reported the bronchioloalveolar carcinoma (BAC) to best respond to gefitinib in a study of 139 cases of non-small cell lung cancer. This subtype appears prevalent among female non-smokers and is genetically relatively simple. Yatabe et al. also described a terminal respiratory unit (TRU)-type adenocarcinoma, corresponding to the majority of non-mucinous BAC, to represent a distinct subset significantly related to EGFR mutations [26]. As the above previous reports proved, EGFR-mutated adenocarcinomas, forming a separate biologic entity depending on particular molecular pathways for its maintenance and survival, exhibit characteristic microscopic appearance presumably on that basis.
In the present study, we evaluated clinicopathologic characteristics of primary lung adenocarcinomas arising in Japanese, focusing on associations of EGFR mutations and specific pathological features, especially cytological subtype and micropapillary morphology.
Section snippets
Patients selection
Samples of primary lung tumors were obtained from 107 consecutive cases who underwent surgery during January 1998 and June 2002 at the Cancer Institute Hospital. All cases were adenocarcinomas and all but one underwent complete surgical resection. Cases with multiple and metachronous tumors at the time of surgery were excluded. We also reviewed the medical records and pathology slides to compare the characteristics of patients with or without EGFR gene mutations. All patients were analyzed for
Patient population
Among the population studies, 52 males and 55 females were included. The median age was 63 years (range: 43–83). There were 54 ever smokers (current or former smokers) and 53 never smokers Table 1. Details of clinical and pathological findings including response to treatment, mutation status, percentages of differentiation grades and histocytological features for cases with gefitinib treatment are given in Table 2, as examples of results.
Correlation with EGFR mutations and clinical factors
EGFR mutations in exons 18–21 were detected as follows: 2
Discussion
Close correlations have been noted between young age, female gender, never smoking status, East Asian ethnicity and clinical responsiveness to EGFR TK inhibitors [3], [4], [5], [7], [11], [13], [14], [19], [26]. Concerning pathological aspects, a BAC histology and w/d to m/d grades were earlier reported to predict the responsiveness to EGFR TKI or presence of EGFR mutations [7], [14]. In the present study, we found that the hobnail cell type and the micropapillary morphology predicted a higher
Conflict of interest
None.
Acknowledgements
Parts of this study were supported financially by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and grants from the Japan Society for the Promotion of Science, the Ministry of Health, Labour and Welfare, the Smoking Research Foundation, the National Institute of Biomedical Innovation, and the Vehicle Racing Commemorative Foundation. The authors thank Ms. Kazuko Yokokawa, Mr. Motoyoshi Iwakoshi, Ms. Miyuki Kogure, and Ms. Tomoyo
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