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Prognostic Value of Genetically Diagnosed Lymph Node Micrometastasis in Non-Small Cell Lung Carcinoma Cases¹

Laboratory of Cancer Diagnosis and Therapy, Saitama Cancer Center Research Institute, Saitama 362-0806 [T. H., Y. T., M. H., S. H., E. T.]; Department of Pathology, Saitama Cancer Center Hospital, Saitama 362-0806 [Y. K., K. Ni., E. T.]; Department of Pathology, Cancer Institute, Tokyo 170-0012 [Y. I.]; Department of Chest Surgery, Cancer Institute Hospital, Tokyo 170-0012 [S. T., S. O., K. Na.]; and Department of Thoracic and Cardiovascular Surgery, Niigata University School of Medicine, Niigata 951-8122 [T. H., J. H.], Japan

The predictive value of lymph node micrometastasis, detected by immunohistochemical or genetic methods, is well appreciated in terms of prognosis. However, a major problem is high false-positive rates, because most methods focus on cytokeratin, which is a component not only of carcinoma but also normal epithelial and nonepithelial cells. Mutant allele-specific amplification (MASA) can detect DNAs derived from cancer cells itself, reportedly with high sensitivity. It was, therefore, used with nested-PCR using p53 or K-ras mutation for analysis of lymph node micrometastasis in non-small cell lung carcinoma (NSCLC) patients in the present study, in comparison with the immunohistochemical method using an anti-cytokeratin reagent for the same samples. Lymph nodes from 31 NSCLC patients with p53 and K-ras mutated tumors (30 and 1, respectively) staged as pathological (p)-T_1–4 N_0–1 and M₀ were examined. Genetic and immunohistochemical methods demonstrated positive reactions in 34 (15%) and 61 (27%) of 229 lymph nodes, respectively (9 cases, 29%, and 24 cases, 77%). The concordance with the two methods was 77%, but 13 (39%) of 34 genetically positive lymph nodes could not be detected by immunohistochemistry (IHC). Of 22 cases with p-N₀ disease, 6 (27%) were genetically positive in hilar and/or mediastinal lymph nodes, and 4 (67%) of them died after cancer relapse. In contrast, none of the patients without micrometastasis died of cancer (P < 0.001, log rank analysis). Of the same p-N₀ patients, 17 (77%) were positive by IHC, and 4 (24%) of them died of cancer, whereas 5 negative patients did not suffer cancer relapse. Survival did not significantly differ between cases positive and negative (P = 0.246) by IHC. According to the g-N (N factor restaged by a genetic method), patients with g-N₁ and g-N₂ disease had a shorter survival than those with g-N₀ disease (P = 0.042 and P < 0.001, respectively). However, no significant difference was observed with grading by IHC. Thus, detection of micrometastasis in regional lymph nodes with the MASA method, in other words with a carcinoma-specific marker, is of greater prognostic significance for early stage NSCLC patients than immunohistochemical results. This approach should facilitate selection of patients for whom postoperative adjuvant chemotherapy should be performed.

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