Skip to main content
Top
Published in: Clinical and Translational Oncology 9/2014

01-09-2014 | Research Article

Expression of Wilms’ tumor gene (WT1) is associated with survival in malignant pleural mesothelioma

Authors: S. Cedrés, M. A. Montero, E. Zamora, A. Martínez, P. Martínez, L. Fariñas, A. Navarro, D. Torrejon, A. Gabaldon, S. Ramon y Cajal, E. Felip

Published in: Clinical and Translational Oncology | Issue 9/2014

Login to get access

Abstract

Introduction

Calretinin and Wilms’ tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution.

Materials and methods

Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan–Meier method and Cox regression was used to evaluate the prognostic value of the variables.

Results

Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil–lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively).

Conclusion

In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM.
Literature
1.
go back to reference Martini N, McCormack PM, Bains MS, Kaser LR, Burt ME, Hilaris BS, et al. Pleural mesothelioma. Ann Thorac Surg. 1987;43:113–20.PubMed Martini N, McCormack PM, Bains MS, Kaser LR, Burt ME, Hilaris BS, et al. Pleural mesothelioma. Ann Thorac Surg. 1987;43:113–20.PubMed
2.
go back to reference Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636–44.PubMed Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636–44.PubMed
3.
go back to reference Van Meerbeeck JP, Gaafar R, Manegold C, VanKlaveren R, VanMarck E. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005;23:6881–9.PubMed Van Meerbeeck JP, Gaafar R, Manegold C, VanKlaveren R, VanMarck E. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005;23:6881–9.PubMed
4.
go back to reference Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for research and treatment of Cancer experience. J Clin Oncol. 1998;16(1):145.PubMed Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for research and treatment of Cancer experience. J Clin Oncol. 1998;16(1):145.PubMed
5.
go back to reference Edwards JG, Abrams KR, Leverment JN, Spyt TJ, Waller DA, O’Byrne KJ. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax. 2000;55(9):731.PubMedCentralPubMed Edwards JG, Abrams KR, Leverment JN, Spyt TJ, Waller DA, O’Byrne KJ. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax. 2000;55(9):731.PubMedCentralPubMed
6.
go back to reference Kao S, Pavlakis N, Harvie R, Vardy J, Boyer M, Zandwijk N, et al. High blood neutropil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res. 2010;16:5805–13.PubMed Kao S, Pavlakis N, Harvie R, Vardy J, Boyer M, Zandwijk N, et al. High blood neutropil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res. 2010;16:5805–13.PubMed
7.
go back to reference Marchevsky AM. Application of immunohistochemistry to the diagnosis of malignant mesothelioma. Arch Pathol Lab Med. 2008;232:397–401. Marchevsky AM. Application of immunohistochemistry to the diagnosis of malignant mesothelioma. Arch Pathol Lab Med. 2008;232:397–401.
8.
go back to reference Ordoñez NG. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol. 2007;38:1–16.PubMed Ordoñez NG. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol. 2007;38:1–16.PubMed
9.
go back to reference Kao S, Klebe S, Henderson D, Reid G, Chatfield M, Armstrong NJ, et al. Low calretinin expression and high neutrophil-to-lymphocyte ratio are poor prognostic factors in patients with malignant mesothelioma undergoing extrapleural pneumonectomy. J Thorac Oncol. 2011;6:1923–9.PubMed Kao S, Klebe S, Henderson D, Reid G, Chatfield M, Armstrong NJ, et al. Low calretinin expression and high neutrophil-to-lymphocyte ratio are poor prognostic factors in patients with malignant mesothelioma undergoing extrapleural pneumonectomy. J Thorac Oncol. 2011;6:1923–9.PubMed
10.
go back to reference Pu R, Pang Y, Michael C. Utility of WT-1, p63, MOC31, mesothelin and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma and malignant mesothelioma in effusions. Diagn Cytopathol. 2008;36:20–5.PubMed Pu R, Pang Y, Michael C. Utility of WT-1, p63, MOC31, mesothelin and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma and malignant mesothelioma in effusions. Diagn Cytopathol. 2008;36:20–5.PubMed
11.
go back to reference Scattone A, Serio G, Marzullo A, Nazzaro P, Corsi F, Cocca M, et al. High Wilm′s tumour gene (WT1) expression and low mitotic count are independent predictors of survival im diffuse peritoneal mesothelioma. Histopathology. 2012;60:472–81.PubMed Scattone A, Serio G, Marzullo A, Nazzaro P, Corsi F, Cocca M, et al. High Wilm′s tumour gene (WT1) expression and low mitotic count are independent predictors of survival im diffuse peritoneal mesothelioma. Histopathology. 2012;60:472–81.PubMed
12.
go back to reference Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J, et al. WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell type transition, and prognosis. J Pathol. 1997;181:67–74.PubMed Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J, et al. WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell type transition, and prognosis. J Pathol. 1997;181:67–74.PubMed
13.
go back to reference Kushitani K, Takeshima Y, Amatya V, Furonaka O, Sakatani A, Inai K, et al. Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma. Pathol Int. 2007;57:190–9.PubMed Kushitani K, Takeshima Y, Amatya V, Furonaka O, Sakatani A, Inai K, et al. Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma. Pathol Int. 2007;57:190–9.PubMed
14.
go back to reference O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.PubMedCentralPubMed O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.PubMedCentralPubMed
15.
go back to reference Silberstein GB, Van Horn K, Strickland P, Roberts C, Daniel C. Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA. 1997;94:8132–7.PubMedCentralPubMed Silberstein GB, Van Horn K, Strickland P, Roberts C, Daniel C. Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA. 1997;94:8132–7.PubMedCentralPubMed
16.
go back to reference Carpentieri DF, Nichols K, Chou PM, Mathews M, Pawel B, Huff D, et al. The expression of WT1 in the differentiation of rhabdomyosarcoma from other pediatric small round blue cell tumors. Mod Pathol. 2002;15:1080–6.PubMed Carpentieri DF, Nichols K, Chou PM, Mathews M, Pawel B, Huff D, et al. The expression of WT1 in the differentiation of rhabdomyosarcoma from other pediatric small round blue cell tumors. Mod Pathol. 2002;15:1080–6.PubMed
17.
go back to reference Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, et al. Overexpression of the Wilms’ tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci. 2003;94:712–7.PubMed Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, et al. Overexpression of the Wilms’ tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci. 2003;94:712–7.PubMed
18.
go back to reference Hashiba T, Izumoto S, Kagawa N, Suzuki T, Hashimoto N, Maruno M, et al. Expression of WT1 protein and correlation with cellular proliferation in glial tumors. Neurol Med Chir. 2007;47:165–70. Hashiba T, Izumoto S, Kagawa N, Suzuki T, Hashimoto N, Maruno M, et al. Expression of WT1 protein and correlation with cellular proliferation in glial tumors. Neurol Med Chir. 2007;47:165–70.
19.
go back to reference Ohno S, Dohi S, Ohno Y, Kyo S, Sugiyama H, Suzuki N, et al. Immunohistochemical detection of WT1 protein in endometrial cancer. Anticancer Res. 2009;29:1691–6.PubMed Ohno S, Dohi S, Ohno Y, Kyo S, Sugiyama H, Suzuki N, et al. Immunohistochemical detection of WT1 protein in endometrial cancer. Anticancer Res. 2009;29:1691–6.PubMed
20.
go back to reference Oates J, Edwards C. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma. Histopathology. 2000;36:341–7.PubMed Oates J, Edwards C. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma. Histopathology. 2000;36:341–7.PubMed
21.
go back to reference Foster MR, Johnson JE, Olson SJ, Allred DC. Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesothelioma and primary pulmonary adenocarcinomas. Arch Pathol Lab Med. 2001;125:1316–20.PubMed Foster MR, Johnson JE, Olson SJ, Allred DC. Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesothelioma and primary pulmonary adenocarcinomas. Arch Pathol Lab Med. 2001;125:1316–20.PubMed
22.
go back to reference Ordoñez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27:1031–51.PubMed Ordoñez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27:1031–51.PubMed
23.
go back to reference Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht T. The prioritization of cancer antigens: a national cancer institute project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323–37.PubMed Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht T. The prioritization of cancer antigens: a national cancer institute project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323–37.PubMed
24.
go back to reference May RJ, Dao T, Pinilla-Ibarz J, Korontsvit T, Zakhaleva V, Zhang R, et al. Peptide epitopes from the Wilms’ tumour 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. Clin Cancer Res. 2007;13:4547–55.PubMed May RJ, Dao T, Pinilla-Ibarz J, Korontsvit T, Zakhaleva V, Zhang R, et al. Peptide epitopes from the Wilms’ tumour 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. Clin Cancer Res. 2007;13:4547–55.PubMed
25.
go back to reference Krug LM, Tsao AS, Kass S. Randomized, double-blinded, phase II trial of a WT1 peptide vaccine as adjuvant therapy in patients with malignant pleural mesothelioma (MPM). J Clin Oncol 2011;29(Suppl):abst TPS139. Krug LM, Tsao AS, Kass S. Randomized, double-blinded, phase II trial of a WT1 peptide vaccine as adjuvant therapy in patients with malignant pleural mesothelioma (MPM). J Clin Oncol 2011;29(Suppl):abst TPS139.
26.
go back to reference NCT01265433 randomized study of adjuvant study of adjuvant WT-1 analog peptide vaccine in patients with malignant pleural mesothelioma (MPM) after completion of combined modality therapy. NCT01265433 randomized study of adjuvant study of adjuvant WT-1 analog peptide vaccine in patients with malignant pleural mesothelioma (MPM) after completion of combined modality therapy.
27.
go back to reference NCT01890980 phase II study of adjuvant WT-1 analog peptide vaccine in MPM patients after MSK 10-134. NCT01890980 phase II study of adjuvant WT-1 analog peptide vaccine in MPM patients after MSK 10-134.
28.
go back to reference Cristaudo A, Foddis R, Vivaldi A, Guglielmi G, Dipalma N, Filiberti R, et al. Clinical significance of serum mesothelin in patients with mesothelioma and lung cancer. Clin Cancer Res. 2007;13:5076–81.PubMed Cristaudo A, Foddis R, Vivaldi A, Guglielmi G, Dipalma N, Filiberti R, et al. Clinical significance of serum mesothelin in patients with mesothelioma and lung cancer. Clin Cancer Res. 2007;13:5076–81.PubMed
29.
go back to reference Lopez-Rios F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, Illei P, et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 2006;66:2970–9.PubMed Lopez-Rios F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, Illei P, et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 2006;66:2970–9.PubMed
30.
go back to reference Singhal S, Wiewrodt R, Malden L, Amin K, Matzie K, Friedberg J, et al. Gene expression profiling of malignant mesothelioma. Clin Cancer Res. 2003;9:3080–97.PubMed Singhal S, Wiewrodt R, Malden L, Amin K, Matzie K, Friedberg J, et al. Gene expression profiling of malignant mesothelioma. Clin Cancer Res. 2003;9:3080–97.PubMed
Metadata
Title
Expression of Wilms’ tumor gene (WT1) is associated with survival in malignant pleural mesothelioma
Authors
S. Cedrés
M. A. Montero
E. Zamora
A. Martínez
P. Martínez
L. Fariñas
A. Navarro
D. Torrejon
A. Gabaldon
S. Ramon y Cajal
E. Felip
Publication date
01-09-2014
Publisher
Springer Milan
Published in
Clinical and Translational Oncology / Issue 9/2014
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-013-1146-6

Other articles of this Issue 9/2014

Clinical and Translational Oncology 9/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine