Lymph Node Metastasis from Non-Small Cell Lung Cancer – Imaging, Resection, Enhanced Pathologic Detection and Survival Implications
Nwogu, Chukwumere Eugene
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Background: Lymph node staging is a critical prognostic factor in non-small cell lung cancer (NSCLC) patients. Many surgical patients have grossly inadequate lymph node (LN) sampling. A standard of care for lymph node sampling is essential. There are limitations in the ability to accurately identify all lymph node malignant disease in patients even after sufficient numbers of nodes are harvested. This results in understaging of patients. Radioguided selection of the most suspicious lymph nodes in a patient permits the use of advanced pathologic methods to detect micrometastases. Understanding the role of lymphangiogenic factors in the onset of lymphatic metastases may facilitate the application of novel therapies to improve NSCLC survival. Methods: We used the Surveillance, Epidemiology and End Results (SEER) database to perform multivariate cox proportional hazards assessment of the prognostic value of the number of resected LNs and metastatic lymph node ratio (LNR) in over 25,000 stages I-III NSCLC patients in the 1988-2007 SEER database. A gamma probe was used in 100 stage I or II patients with resectable lung cancers to detect increased fluorodeoxyglucose (FDG) uptake within thoracic lymph nodes during pulmonary resection procedures. We compared the accuracy of detecting LN metastases using either positron emission tomography-computed tomography (PET-CT) or the gamma probe and quantified the ability of the gamma probe to up-stage patients using IHC and RT-PCR for epithelial markers. We also correlated detection of LN micrometastases with VEGF A, C, D and VEGF-R3 expression. Clinical follow-up to correlate LN micrometastasis with survival is ongoing. Results: Fewer nodes examined corresponded with a worse prognosis. Prognosis improved as more LNs were examined. Patients with low or moderate ratios of positive to total LNs had better prognoses than those with high ratios. Following radioguided LN selection, IHC and RT-PCR detected micrometastatic lymph node disease in 4% and 47% of patients, respectively. Using RT-PCR as the gold standard, the sensitivity and specificity of PET-CT for detection of lymph node metastasis were 11% and 98% respectively, in contrast to 38% and 50% respectively for the gamma probe. There was a high correlation between detection of micrometastases and VEGF-A/C/D or VEGF-receptor-3 expression levels in LNs. Conclusions: More LNs resected and lower ratios of positive LNs to total examined LNs are associated with better patient survival after NSCLC resection independent of age, sex, grade and stage of disease. The intra-operative hand held gamma probe is more sensitive but less specific than PET-CT in identifying lymph node harboring micrometastases from lung cancer, resulting in limited up-staging of patients. Micrometastases correlate with the expression of VEGF in LNs in NSCLC patients. This may reflect the role of lymphangiogenesis in promoting metastases.