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

Division of Thoracic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 07/2011; 60(12):1721-8. DOI: 10.1007/s00262-011-1073-8
Source: PubMed


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.

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    • "Immune cells are found to be a prognostic factor in MPM. Especially tumor infiltrating CD8 + T lymphocytes (TILs) [14,15] were described to inhibit tumor growth whilst tumor associated macrophages (TAMs) [16,17] can influence tumor growth. Macrophages can develop towards an M1 or M2 subtype [18]. "
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    ABSTRACT: In patients with malignant pleural mesothelioma (MPM), local tumor outgrowth (LTO) after invasive procedures is a well-known complication. Currently, no biomarker is available to predict the occurrence of LTO. This study aims to investigate whether the tumor macrophage infiltration and phenotype of and/or the infiltration of CD8(+) T-cells predicts LTO. Ten mesothelioma patients who developed LTO were clinically and pathologically matched with 10 non-LTO mesothelioma patients. Immunohistochemistry was performed on diagnostic biopsies to determine the total TAM (CD68), the M2 TAM (CD163) and CD8(+) T-cell count (CD8). The mean M2/total TAM ratio differed between the two groups: 0.90±0.09 in the LTO group versus 0.63±0.09 in patients without LTO (p<0.001). In addition, the mean CD8(+) T-cell count was significantly different between the two groups: 30 per 0.025cm(2) (range 2-60) in the LTO group and 140 per 0.025cm(2) (range 23-314) in the patients without LTO (p<0.01). This study shows that patients who develop LTO after a local intervention have a higher M2/total TAM ratio and lower CD8(+) cell count at diagnosis compared to patients who did not develop this outgrowth. We propose that the M2/total TAM ratio and the CD8(+) T-cell amount are potential tools to predict which MPM patients are prone to develop LTO. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Mar 2015 · Lung cancer (Amsterdam, Netherlands)
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    • "Gordon et al. described a four-gene expression ratio test that can predict good prognosis after surgery [6], however this test still has to be validated in a clinical setting. Suzuki et al. found in a patient group with predominantly surgical therapy that chronic inflammation in stroma is an independent predictor of survival [7], while other groups found a subset of immunological cell types to predict for better outcome in patients receiving surgical treatment with a special focus on CD8 tumor infiltrating lymphocytes [8], [9]. The question remains whether these factors are prognostic or predictive for the effect of surgery. "
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    ABSTRACT: Hypothesis The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells. Methods 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment. Results The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r −0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found. Conclusions The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "The prognostic value of NLR was subsequently demonstrated in four independent studies (Kao et al, 2011; Cedres et al, 2012; Pinato et al, 2012; Kao et al, 2013), although there were differences in study populations, and in two studies the NLR cutoffs used were different from the original threshold value of 5. However, in one study of surgically treated patients, the association between NLR and survival was not statistically significant, although this study was underpowered for this analysis (Suzuki et al, 2011). "
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    ABSTRACT: Background: Recent studies proposed neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in malignant pleural mesothelioma (MPM). We examined baseline prognostic variables including NLR and the EORTC and CALGB models as predictors of overall survival (OS) in MPM. Methods: In this retrospective study, 274 consecutive eligible, newly presenting patients with MPM were included. Of these, 159 received chemotherapy, 10 had tri-modality therapy, 2 underwent surgery only and 103 received supportive care alone. Univariate analyses and multivariate Cox models were calculated for OS. Results: In univariate analysis, poor prognostic factors were: age ⩾65 years, nonepithelioid histology, stage III–IV, poor performance status (PS), weight loss, chest pain, low haemoglobin and high platelet count. A baseline NLR⩾5 did not predict worse OS (hazard ratio (HR) 1.25; P=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain and platelet count remained significant. The EORTC and CALGB prognostic groups were validated as predictive for OS (HR 1.62; P<0.001 and HR 1.65; P<0.001, respectively). Conclusion: Our findings validate standard prognostic variables and the existing EORTC and CALGB models, but not NLR, at initial diagnosis of MPM. In guiding patient management at diagnosis, it is important to consider multiple baseline variables that jointly predict survival.
    Full-text · Article · Aug 2013 · British Journal of Cancer
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