A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma

The International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) has recently proposed a new lung adenocarcinoma classification. We investigated whether nuclear features can stratify prognostic subsets. Slides of 485 stage I lung adenocarcinoma patients were reviewed. We evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count/10 high-power fields (HPFs) or 2.4 mm(2), and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (P = 0.007), nuclear atypia (P = 0.006), mitotic count (P<0.001), and atypical mitoses (P<0.001) were significant predictors of recurrence. The recurrence-free probability of patients with high mitotic count (>= 5/10HPF: n = 175) was the lowest (5-year recurrence-free probability = 73%), followed by intermediate (2-4/10HPF: n = 106, 80%), and low (0-1/10HPF: n = 204, 91%, P<0.001). Combined architectural/mitotic grading system stratified patient outcomes (P<0.001): low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n = 201, 5-year recurrence-free probability = 92%), intermediate grade (intermediate architectural grade with intermediate-high mitotic counts: n = 206, 78%), and high grade (high architectural grade with any mitotic count: n = 78, 68%). The advantage of adding mitotic count to architectural grade is in stratifying patients with intermediate architectural grade into two prognostically distinct categories (P = 0.001). After adjusting for clinicopathologic factors including sex, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (P = 0.178). However, patients with the high architectural/mitotic grade remained at significantly increased risk of recurrence (high vs low: P = 0.005) after adjusting for clinical factors. We proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice. Modern Pathology (2012) 25, 1117-1127; doi:10.1038/modpathol.2012.58; published online 13 April 2012