Association of the IASLC histologic grading system with aggressive pathologic features in invasive non-mucinous lung adenocarcinoma

The IASLC three-tiered histologic grading system for invasive non-mucinous lung adenocarcinoma, which combines the predominant subtype with a ≥ 20% high-grade pattern threshold, remains insufficiently validated in screening-era populations dominated by small nodules. We examined its association with lymph node metastasis and visceral pleural invasion in a large single-center surgical cohort.

We retrospectively enrolled 7,806 patients who underwent resection of invasive non-mucinous lung adenocarcinoma between 2011 and 2025 without neoadjuvant therapy and could be graded per IASLC criteria (grade 1, 3,435; grade 2, 3,875; grade 3, 496). Multivariable logistic regression adjusted for tumor diameter, age, sex, and year of surgery, with trend tests, a grade-by-size interaction test, and prespecified subgroup analyses.

Across grades 1-3, lymph node metastasis rates were 0.7%, 4.9%, and 31.0%, and visceral pleural invasion rates were 2.0%, 9.6%, and 33.6% (all P < 0.001); versus grade 1, adjusted ORs for grade 3 were 37.48 (95% CI 22.06-63.70) and 14.10 (95% CI 9.81-20.27). In the ≤ 2 cm subgroup, lymph node metastasis rates were 0.3%, 2.8%, and 19.9%, with a grade 3 adjusted OR of 48.66 (95% CI 21.88-108.25); the discriminatory performance of grade for lymph node metastasis was stronger in tumors ≤ 2 cm (P for interaction = 0.006). A micropapillary component of any proportion remained independently associated with lymph node metastasis after adjustment for grade (OR 1.84, 95% CI 1.33-2.56; ≤2 cm subgroup: OR 1.78, 95% CI 1.06-3.00).

Higher IASLC grade was directly associated with lymph node metastasis and visceral pleural invasion in invasive non-mucinous lung adenocarcinoma, including among ≤ 2 cm nodules; grade 3 identifies a very-high-risk subgroup. Histologic grading may inform surgical strategy and lymph node dissection in small-nodule lung cancer.