Use of Epidermal Growth Factor Receptor/Kirsten Rat Sarcoma 2 Viral Oncogene Homolog Mutation Testing to Define Clonal Relationships Among Multiple Lung Adenocarcinomas: Comparison With Clinical Guidelines

doi:10.1378/chest.09-0325

Chest

Volume 137, Issue 1, January 2010, Pages 46-52

https://doi.org/10.1378/chest.09-0325 Get rights and content

Background

The incidence of multiple lung adenocarcinomas is rising, making it difficult to determine the stage and assign treatment in an increasing number of patients following surgery. Clinical guidelines have been developed to distinguish independent non-small cell lung cancers from metastases, that is, criteria developed by Martini and Melamed and the American College of Chest Physicians (ACCP). However, these guidelines can be difficult to apply and may give conflicting results. Here, we report on seven patients in whom epidermal growth factor receptor (EGFR) and Kirsten-rat sarcoma 2 viral oncogene homolog (KRAS) tumor mutation status was used to determine clonal relationships among multiple lung lesions.

Methods

We identified seven patients whose paired lung adenocarcinomas were found to harbor distinct EGFR or KRAS mutations. We assessed these patients' disease status using established clinical guidelines. We also explored the use of comprehensive histologic subtyping (CHS) of tumor sections to distinguish multiple primaries.

Results

According to the Martini-Melamed criteria, six of the seven patients had multiple primary lung tumors. By ACCP criteria, three patients had multiple primaries, and three patients had metastases. Classification of the seventh patient by ACCP criteria was indeterminate. Mutational testing suggested that all paired tumors were multiple primary adenocarcinomas, which was consistent with results from CHS.

Conclusions

Assuming that independent tumor clones harbor distinct mutations, these seven cases highlight discrepancies between the existing clinical criteria used to distinguish independent tumor foci from metastases. EGFR/KRAS mutation testing of multiple lung adenocarcinomas can assist in differentiating multiple primary lung adenocarcinomas from metastatic lesions. Use of CHS in this setting should also be further explored.

Section snippets

Selection of Patients and Clinical Review

Patients included in this report underwent surgery at Memorial Sloan-Kettering Cancer Center (MSKCC) between 2003 and 2008 for multiple NSCLCs. Resected tumors were found by routine clinical EGFR/KRAS-mutation testing to harbor different alterations in EGFR or KRAS. A retrospective review of the clinical history of these patients was subsequently done under a waiver of authorization approved by the MSKCC Institutional Review Board. To differentiate multiple primary NSCLCs from metastatic NSCLC

Patient Characteristics

We identified seven patients with multiple resected lung lesions whose individual adenocarcinomas were found to harbor distinct KRAS or EGFR mutations (Table 2). Four had synchronous lung tumors, and three had metachronous lung tumors. Among 14 tumors, 13 were staged as T1 and one as T2 (patient 3, first tumor). Loco-regional lymph node tumor invasion (N1) was present at the time of the first diagnosis in three cases. No patient had extrapulmonary metastases.

EGFR/KRAS Mutation Status of Tumors

Four patients had multiple lung

Discussion

The seven case histories here highlight the inconsistency of clinical guidelines used to distinguish multiple primary lung adenocarcinomas from metastases. Using the Martini-Melamed and ACCP criteria, only six and three patients, respectively, were considered to have multiple primary NSCLCs. Assuming that different mutations found in separate lung tumors reflect independent clones,¹² the molecular results in these paired tumors suggest that all seven patients have independent primaries, not

Acknowledgments

Author contributions: Dr Girard: conceived and designed the study, obtained financial support, collected and assembled the data, analyzed and interpreted the data, helped write the manuscript, and approved the final manuscript.

Dr Deshpande: assisted in the provision of study material and patients, collected and assembled the data, helped write the manuscript, and approved the final manuscript.

Dr Azzoli: assisted in the provision of study material and patients, collected and assembled the data,

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Funding/Support: This work was supported by the Rosalind Warren Memorial Fund.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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