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J Thorac Cardiovasc Surg 2002;123:466-474
© 2002 The American Association for Thoracic Surgery

General Thoraic Surgery (GTS)

Molecular assessment of lymph nodes in patients with resected stage I non–small cell lung cancer: Preliminary results of a prospective study

From the Department of Surgery,^a University of Rochester, Rochester, NY, and the Division of Thoracic Surgery,^b the Department of Otolaryngology-Head and Neck Surgery,^c and the Department of Pathology,^d The Johns Hopkins Medical Institutions, Baltimore, Md.

Supported in part by the American Association for Thoracic Surgery Research Scholarship, Lung Spore grant CA-58184-01, and Public Health Service grant K08CA76452-01 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Received for publication May 14, 2001 revisions requested July 3, 2001; revisions received Aug 7, 2001; accepted for publication Aug 15, 2001. Address for reprints: Steven A. Ahrendt, MD, Department of Surgery, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642 (E-mail: Steven_Ahrendt{at}urmc rochester.edu

Objectives: Routine histologic examination of resected lymph nodes in patients with stage I non–small cell lung cancer may underestimate the incidence of advanced disease. The presence of occult lymph node metastases may predict a higher risk of recurrence after intended curative resection. The purpose of this study was to determine the prognostic significance of TP53 and K-ras mutations in histologically determined negative lymph nodes from patients with stage I non–small cell lung cancer who underwent intended curative surgical resection.
Methods: Between July 1995 and March 1998, clinical data and tissue samples of primary tumors and lymph nodes were collected in a prospective fashion from 102 patients undergoing resection for non–small cell lung cancer (stage I, n = 55; stage II, n = 32; stage IIIA, n = 15). TP53 and K-ras mutations were detected by direct sequencing. If molecular alterations were found in the primary tumor, the corresponding lymph nodes were examined for these same TP53 (by oligonucleotide hybridization) and K-ras (by allele-specific ligation) mutations.
Results: TP53 mutations were found in 47 of 94 primary tumors (50%), and K-ras mutations were present in 26 of 55 adenocarcinomas (47%). A total of 134 lymph nodes from 32 patients with stage I disease were analyzed. In 9 cases (28%) the same TP53 or K-ras mutations were found in tumor and lymph node specimens, suggesting occult metastasis. On the basis of nodal location, 7 patients had their disease upstaged by a single stage and 2 patients by two stages. All 28 patients with stage II or III disease had pathologically determined positive nodes that were confirmed as positive by molecular analysis. Standard histopathologic assessment of regional lymph nodes failed to detect metastases at levels below 0.9% tumor-specific mutant TP53 clones per node. No statistically significant difference in disease-specific or overall survival was observed between patients with stage I disease with and without molecular lymph node metastases.
Conclusions: Occult lymph node metastases are present in a significant percentage of patients with stage I non–small cell lung cancer. These data suggest that molecular analysis allows a more accurate assessment of staging. However, larger studies are needed to determine the clinical role of molecular staging.

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