Prognostic significance of grading in lung adenocarcinoma

Abstract

Background: Although grading has prognostic significance for many tumor types, a prognostically significant grading system for lung adenocarcinoma has not yet been established. The aim of this study was to evaluate histologic characteristics included in tumor grading systems, establish optimal cutoff values that have the strongest association with overall survival, and develop a grading system incorporating the histopathologic characteristics that the authors found to have prognostic significance in patients with lung adenocarcinoma.

Methods: The authors studied lung adenocarcinomas from 85 consecutive patients, and evaluated the percentage of solid pattern (as a reflection of tumor architecture), the degree of cytologic atypia, and the mitotic count.

Results: In univariate analysis, overall survival was associated significantly with sex (P = .045), age (P = .0008), tumor status (P < .0001), lymph node status (P = .02), solid pattern (P = .046), and cytologic atypia (P = .01), but not with mitotic count (P = .26). On the basis of optimal cutoff values, the authors found that a solid pattern > or = 90% and severe cytologic atypia were the best discriminators of worse outcome. A grading score, computed as the sum of the architecture score and cytologic atypia score (2 = well differentiated, 3 = moderately differentiated, 4 = poorly differentiated), was a significant predictor of overall survival in univariate analysis (median overall survival times, 72.4, 39.5, and 8.7 months for well, moderately, and poorly differentiated adenocarcinoma, respectively; P = .0001). Moreover, grading was an independent predictor of survival in multivariate analysis (P = .002).

Conclusions: The authors describe a grading system that incorporates the percentage of solid pattern and degree of the cytologic atypia that is an independent predictor of survival in patients with lung adenocarcinoma.

Figure 1

Examples of lung adenocarcinomas with a solid pattern. Solid growth was defined as (A) sheets of tumor cells or (B) nests of tumor with intervening fibrous tissue.

Figure 2

Examples of mild, moderate, and severe cytologic atypia. (A) Mild atypia: uniform nuclei with indistinct nucleoli at 100× magnification. (B) Moderate atypia: relatively uniform nuclei with distinct nucleoli at 100× magnification (C) Severe atypia: bizarre, enlarged nuclei of varied sizes, with some nuclei at least twice as large as others.

Figure 3

Distribution of cases based on the individual histologic characteristics. (A) There is a bimodal distribution of cases based on solid pattern, with the highest number of cases having either no solid component or entirely solid component. (B) Distribution of cases based on cytologic atypia. Twenty-seven cases (31.8%) had mild cytologic atypia, 40 cases (47.1%) had moderate cytologic atypia, and 18 cases (21.2%) had severe cytologic atypia. (C) Distribution of cases based on the number mitoses per 10 HPF. The mean number of mitoses/10 HPF was 8.6.

Figure 4

Scatter diagram illustrating the direct correlation between cytologic atypia and the amount of solid pattern (P=0.0002, Kruskal-Wallis test). However, a subset of adenocarcinomas has solid growth but low atypia or alternatively, severe atypia and a low solid growth component. Horizontal lines represent the mean values and whiskers the standard error of the mean.

Figure 5

Survival analysis based on individual histologic parameters. (A) The overall survival was significantly better for patients with tumors with a solid growth <90% than for patients with tumors with >90% solid growth (P=0.046). Patients with tumors with a solid growth <90% had a median overall survival of 69.4 months and those with tumors with >90% solid growth had a median overall survival of 21.4 months. (B) The overall survival was significantly better for patients with tumors with mild/moderate cytologic atypia as compared with patients with tumors with severe atypia (P=0.01). The median overall survival was 71.0 months for patients with tumors with mild/moderate cytologic atypia and 30.5 months for patients with tumors with severe cytologic atypia. The overall survival was the same for patients with tumors with mild/moderate cytologic atypia (P=0.74). (C) The overall survival was not significantly different between patients with tumors with ≤13 mitoses/10 HPF and patients with >13 mitoses/10 HPF (P=0.26).

Figure 6

Grading score, computed as the sum of the architecture score and cytologic atypia score was a significant predictor of overall survival in univariate analysis (P=0.0001). The median overall survival times were 72.4, 39.5, and 8.7 months for well, moderately and poorly differentiated adenocarcinoma, respectively.