Vascular invasion identifies the most aggressive histologic subset of stage I lung adenocarcinoma: Implications for adjuvant therapy

Abstract

Objectives: Approximately 15% of stage I lung adenocarcinomas will recur despite adequate surgical therapy. Adjuvant therapy may benefit specific high-risk subsets; however, it is unclear which patients are sufficiently predisposed to recurrence to warrant intensified therapy.

Materials and methods: 517 AJCC 8th edition stage I/0 lung adenocarcinomas ≤ 4 cm total size were graded (WHO-2015 and WHO-2021) and compared to stage subgroupings using 7-year recurrence free (RFS), disease specific (DSS), and overall survival (OS). Low malignant potential (LMP) adenocarcinoma was assigned as previously defined. Univariate/multivariate analysis was performed to assess risk factors associated with aggressive behavior.

Results: Vascular invasion was the most significant histologic feature on multivariate analysis for both RFS (HR = 4.68, p < 0.001) and DSS (HR = 3.67, p = 0.001) and nearly reached significance for OS (HR = 1.47, p = 0.060). Angioinvasive adenocarcinomas comprised 26 % of the cohort and exhibited a 7-year 64 % RFS, 73 % DSS, and 50 % OS; in contrast to 20 % WHO-2015-G3 (7-year 71 % RFS, 79 % DSS, & 54 % OS), 44 % WHO-2021-G3 (7-year 79 % RFS, 85 % DSS, & 56 % OS), and 21 % stage IB (7-year 72 % RFS, 79 % DSS, and 50 % OS) adenocarcinomas. The majority (>50 %) of overall mortality was disease specific for angioinvasive adenocarcinoma whereas ≤25 % of overall mortality was disease specific for the remaining tumors. Angioinvasive adenocarcinomas were proportionally more common among those still smoking at diagnosis (49 %), male sex (49 %), and black race (16 %) than other subtypes.

Conclusion: Patients with AJCC 8th ed. stage I angioinvasive lung adenocarcinomas are at high-risk of cancer-specific mortality and should be considered for clinical trials evaluating benefit of adjuvant therapy.

Keywords: Adenocarcinoma; Angioinvasion; LMP; Vascular invasion; WHO grade.