Higher frequency of occult lymph node metastasis in clinical N0 pulmonary adenocarcinoma with ALK rearrangement

OBJECTIVES: There have been few studies that have fully elucidated the relationship between genomic mutations in pulmonary adenocarcinomas and occult lymph node (LN) metastases (pN1-2) despite a preoperative clinical N0 stage (cN0). It is well known that anaplastic lymphoma kinase (ALK) rearrangements are more likely to occur in younger patients with high grade tumors. The aim of this study was to investigate the genomic status, examine the clinicopathologic features, and evaluate whether ALK mutations are associated with occult LN metastases. MATERIALS AND METHODS: We retrospectively evaluated 459 Japanese patients who underwent pulmonary resection of cN0 adenocarcinomas between January 2012 and December 2015. The clinicopathologic characteristics, including age, sex, smoking index, tumor maximum diameter and consolidation/tumor ratio on computed tomography (CT), maximum standardized uptake value on positron emission tomography (PET) and gene mutations (epidermal growth factor receptor [EGFR], ALK, and kirsten ras genes (KRAS), were evaluated. RESULTS: ALK and EGFR and KRAS mutations were all mutually exclusive. Among 324 patients found to have mutations, ALK was involved in 19 (5.9%), EGFR in 266 (82.1%), and KRAS in 39 (12.0%). The incidence of occult LN metastases did not differ significantly between those with or without mutations (p=0.27). On univariate and multivariate analyses, tumors with ALK were more likely to have occult LN metastases (p=0.03). In cN0 tumors with ALK, pN1 was diagnosed in 26.3% and pN2 in 10.5%, whereas pN1 or pN2 stage was found in <10.0% in those with EGFR or KRAS mutations or with no mutations at all. No significant difference was found in the 2-year disease-free survival among those with gene mutations (p=0.08). CONCLUSION: This study highlights the frequency of PET- and CT-negative occult LN metastases in resected adenocarcinomas with ALK rearrangement. Our multivariate analysis showed that ALK rearrangements were associated with a significantly higher incidence of occult LN metastasis compared with ALK-negative adenocarcinomas.