Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients

Abstract

This study aims to determine whether a semi-quantitative assessment of inflammatory response in tumor and stroma on routine hematoxylin and eosin-stained (H&E) slides can predict survival in patients with epithelioid malignant pleural mesothelioma (MPM). H&E sections of 175 epithelioid MPM specimens from a single institution (1989-2009) were reviewed. Patients who received neoadjuvant chemotherapy were excluded from analysis. Each tumor was histologically assessed for acute and chronic inflammatory response both within the tumor and the stromal component. Inflammatory response was graded: low (none to mild infiltrate) or high (moderate to severe infiltrate). Log-rank test and Cox proportional hazards regression were used to investigate the association between the degree of inflammation (acute/tumor, acute/stroma, chronic/tumor, and chronic/stroma) and overall survival (OS). Patients with high chronic inflammatory response in stroma (n = 59) had improved survival compared to low (n = 116) (median OS = 19.4 vs. 15.0 months, P = 0.01). This prognostic stratification remained significant in stage III patients (median OS = 16.0 vs. 9.3 months, P = 0.03). In multivariate analysis, chronic inflammation in stroma was an independent predictor of survival (HR = 0.659, 95% CI 0.464-0.937, P = 0.02). While high degree of chronic inflammatory cell infiltration in the stromal component was associated with improved overall survival, degree of other inflammatory responses did not show significant correlation with OS. Our study for the first time investigates inflammatory response in tumor and stroma and not only suggests the prognostic value of inflammatory response in epithelioid MPM but also provides rationale for investigation of immunotherapy to benefit epithelioid MPM patients.

Fig. 1

Patient disposition by treatment. Breakdown of patients by treatment they received. Main study cohort consisted of 175 patients who did not receive neoadjuvant chemotherapy

Fig. 2

Assessed pathologic features in epithelioid MPM (hematoxylin and eosin stain; original magnification, a × 400, b, c, d × 200). a Acute inflammatory response: near absence of acute inflammatory cells on left, representing a score 1 and abundance on right, representing a score 3. b Chronic inflammatory response: near absence of chronic inflammatory cells on left, representing a score 1 and abundance on right, representing a score 3. c MPM tumor cells surrounded by an abundance of fibrotic stroma. d MPM tumor cells with a large area of necrotic center

Fig. 3

Distribution by type and location of inflammation. Distribution of each inflammatory response by the degree of infiltration on a scale of 0–3. For acute response, scores of 0 and 1 were grouped as low and 3 and 4 grouped as high. For chronic response, scores of 0, a, and 2 were grouped as low and 3 as high

Fig. 4

Overall survival by type & location of inflammatory response. a Overall survival by chronic inflammatory response in stroma. Patients with high response had a median survival of 19.4 months compared to 15 months for low, P = 0.012. b Overall survival by acute inflammatory response in tumor. Patients with high response had a median survival of 13.2 months compared to 16.9 months for low, P = 0.57. c Overall survival by acute inflammatory response in stroma. Patients with high response had a median survival of 10.5 months compared to 17.4 months for low, P = 0.90. d Overall survival by chronic inflammatory response in tumor. Patients with high response had a median survival of 14.5 months compared to 16.2 months for low, P = 0.51