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01-12-2011 | Original article

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

Authors: Kei Suzuki, Kyuichi Kadota, Camelia S. Sima, Michel Sadelain, Valerie W. Rusch, William D. Travis, Prasad S. Adusumilli

Published in: Cancer Immunology, Immunotherapy | Issue 12/2011

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.

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Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc P-H, Trajanoski Z, Fridman W-H, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRef

Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213PubMedCrossRef

Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14:5220–5227PubMedCrossRef

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc P-H, Trajanoski Z, Fridman W-H, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRef

Robinson BWS, Musk AW, Lake RA (2005) Malignant mesothelioma. Lancet 366:397–408PubMedCrossRef

Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ (1999) Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results of 183 patients. J Thorac Cardiovasc Surg 117:54–65PubMedCrossRef

Leigh RA, Webster I (1982) Lymphocytic infiltration of pleural mesothelioma and its significance for survival. S Afr Med J 61:1007–1009PubMed

Anraku M, Cunningham KS, Yun Z, Tsao M-S, Zhang L, Keshavjee S, Johnston MR, de Perrot M (2008) Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 135:823–829PubMedCrossRef

Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T, Nishimura M (2010) CD8 + tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59(10):1543–1549

10.

Alì G, Boldrini L, Lucchi M, Mussi A, Corsi V, Fontanini G (2009) Tryptase mast cells in malignant pleural mesothelioma as an independent favorable prognostic factor. J Thorac Oncol 4:348–354. doi:10.1097/JTO.0b013e3181989ddb PubMedCrossRef

11.

Mudhar HS, Wallace WAH (2002) No relationship between tumour infiltrating lymphocytes and overall survival is seen in malignant mesothelioma of the pleura. Eur J Surg Oncol (EJSO) 28:564–565CrossRef

12.

Kao SCH, Pavlakis N, Harvie R, Vardy JL, Boyer MJ, van Zandwijk N, Clarke SJ (2010) High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res 16:5805–5813PubMedCrossRef

13.

Travis W, Colby T, Corrin B, Shimosato Y, Brambilla E (1999) World health organization international histological classification of tumours: histological subtyping of lung and pleural tumours, 3rd edn. Springer, Berlin

14.

Travis W, Brambilla E, Muller-Hermelink H, Harris C (2004) Pathology and genetics. Tumours of the lung, pleura, thymus, and heart. IARC Press, Lyon

15.

Greene F, Page D, Fleming I, Fritz A, Balch C, Haller D, Morrow M (2002) AJCC cancer staging manual. Springer, New York

16.

Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S, Katoh H (2006) Concurrent infiltration by CD8 + T cells and CD4 + T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94:275–280PubMedCrossRef

17.

Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol Mech Dis 1:119–150CrossRef

18.

Blankenstein T (2005) The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol 17:180–186PubMedCrossRef

19.

Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, Ellis IO, Green AR (2011) Tumor-infiltrating CD8 + lymphocytes predict clinical outcome in breast cancer. J Clinical Oncol 29:1949–1955CrossRef

20.

Hegmans JPJJ, Hemmes A, Hammad H, Boon L, Hoogsteden HC, Lambrecht BN (2006) Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 27:1086–1095PubMedCrossRef

21.

Fridlender ZG, Buchlis G, Kapoor V, Cheng G, Sun J, Singhal S, Crisanti MC, Wang L-CS, Heitjan D, Snyder LA, Albelda SM (2010) CCL2 blockade augments cancer immunotherapy. Cancer Res 70:109–118PubMedCrossRef

22.

de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37PubMedCrossRef

23.

Shigematsu Y, Hanagiri T, Kuroda K, Baba T, Mizukami M, Ichiki Y, Yasuda M, Takenoyama M, Sugio K, Yasumoto K (2009) Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibody titers. Cancer Sci 100:1326–1334PubMedCrossRef

24.

Bouaziz J-D, Yanaba K, Tedder TF (2008) Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev 224:201–214PubMedCrossRef

25.

Johansson M, DeNardo DG, Coussens LM (2008) Polarized immune responses differentially regulate cancer development. Immunol Rev 222:145–154PubMedCrossRef

26.

An X, Ding P-R, Li Y-H, Wang F-H, Shi Y-X, Wang Z-Q, He Y-J, Xu R-H, Jiang W-Q (2010) Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer. Biomarkers 15:516–522PubMedCrossRef

27.

Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ (2005) Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 91:181–184PubMedCrossRef

28.

Sarraf K, Belcher E, Raevsky E, Nicholson A, Goldstraw P, Lim E (2009) Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 137:425–428PubMedCrossRef

Title: Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients
Authors: Kei Suzuki
Kyuichi Kadota
Camelia S. Sima
Michel Sadelain
Valerie W. Rusch
William D. Travis
Prasad S. Adusumilli
Publication date: 01-12-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 12/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1073-8

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