A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma

Abstract

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.

Figure 1

Nuclear features of epithelioid diffuse malignant pleural mesothelioma (H&E stain; original magnification, ×400: a–e, ×600: f). (a) Tumor cells showing mild nuclear atypia, fine granular chromatin, and indistinct nucleoli. (b) Tumor cells showing moderate nuclear atypia, intermediate N/C ratio, and distinct nucleoli. (c) Tumor cells showing severe atypia, coarse granular chromatin, and atypical mitosis (arrow). (d) Tumor cells showing low N/C ratio and large nucleoli. (e) Tumor cells showing high N/C ratio and homogeneous chromatin. (f) Tumor cells with intranuclear inclusion (arrow).

Figure 2

Overall survival by nuclear features in all patients. (a) Patients with severe nuclear atypia had the worst median overall survival, followed by moderate and mild. (b) Patients with coarse granular chromatin had the worst median overall survival, followed by fine granular and homogeneous. (c) Patients with large nucleoli had the worst median overall survival, followed by distinct and indistinct. (d) Patients with high mitotic count had the worst median overall survival, followed by intermediate and low.

Figure 3

Overall survival by nuclear grade in all patients. (a) Nuclear grading scores of 2 and 3 had the best overall survival. Score of 4 and 5 showed similar overall survival curves, with an intermediate overall survival. Total score of 6 showed the worst overall survival. (b) Patients with grade III had the worst median overall survival, followed by grade II and grade I.

Figure 4

Association of time to recurrence with nuclear grade in all patients. (a) Patients with severe nuclear atypia had the shortest median time to recurrence, followed by moderate and mild atypia. (b) Patients with high and intermediate mitotic count had shorter median time to recurrence than low. (c) Patients with nuclear grade II had shorter median time to recurrence than grade I.

Figure 5

Overall survival and time to recurrence by MIB-1 labeling index. (a) Patients with high MIB-1 labeling index had significantly worse median overall survival than low MIB-1 labeling index. (b) Among patients who underwent complete resection, patients with high MIB-1 labeling index had shorter median time to recurrence than low.