Elsevier

Human Pathology

Volume 81, November 2018, Pages 138-147
Human Pathology

Original contribution
IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma,☆☆

https://doi.org/10.1016/j.humpath.2018.07.003Get rights and content

Highlights

  • Malignant peritoneal mesothelioma (MPeM) is an incurable cancer with poor prognosis.

  • Significant perioperative risks necessitate consideration of prognostic markers.

  • Clinicopathological data have different prognostic effects in different studies.

  • IMP3, with treatment, is a powerful prognosticator for overall survival in MPeM.

Summary

Malignant peritoneal mesothelioma (MPeM) is an incurable cancer with poor prognosis, and several biomarkers have been suggested for screening of MPeM. The aim of our study was to evaluate the prognostic significances of IMP3 and Fli-1 in MPeM. Diagnostic biopsies of 44 MPeM patients were centrally collected and were immunohistochemically analyzed for expression of IMP3, Fli-1, and Ki-67. Labeling was assessed by 2 pathologists. Complete clinical information and follow-up were obtained from patients' records. Carcinomas expressed Fli-1 in 42 (95.5%) of 44 specimens, and IMP3 in 23 (52.3%) of 44 specimens. Spearman ρ analysis revealed that Fli-1 expression was related to both histologic type and Ki-67 labeling index (Ki-67LI; r = −0.500, P < .05; r = 0.358, P < .05), and IMP3 expression was related to Ki-67LI (r = 0.401, P < .05). A Kaplan-Meier analysis and univariate Cox regression analysis showed that tumor-directed treatment, a lower peritoneal carcinomatosis index, stage I, lower Ki-67LI, and lower level of IMP3 expression had a statistically significantly positive effect on overall survival; Fli-1 did not affect overall survival in the univariate analysis (hazard ratio [HR], 1.026; P = .904). A Kaplan-Meier analysis showed the correlation between IMP3–Fli-1 and overall survival, whereas univariate and multivariate Cox regression analyses did not confirm the correlation. Cox regression analysis revealed that IMP3 expression (HR, 2.311 [95% confidence interval, 1.190-4.486]; P = .013) and no tumor-directed treatment (HR, 0.189 [95% confidence interval, 0.086-0.416]; P = .000) retained independent prognostic significance, both with negative effect on OS. IMP3, along with tumor-directed treatment protocols, is a powerful prognosticator in patients with MPeM.

Introduction

Mesothelioma is a very rare malignancy of serosal membranes, with malignant peritoneal mesothelioma (MPeM) accounting for 7% to 30% of cases [1]. The epidemiologic data on malignant mesothelioma vary widely across countries, and the incidence is 4.5 cases per million in East China. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis with a median survival of less than 12 months from diagnosis. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for patients with MPeM have resulted in improved disease control and increased survival [2], [3]. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection [4]. Radiological markers of treatment response and prognostication in malignant peritoneal mesothelioma have limitations due to the morphology of the disease, whereas biomarkers, such as glucose transporter 1 (GLUT1) [5], and pre-operative CA-125 [6] et al, that could act as an adjunct to radiological assessment would be of significant value.

Ki-67 is a nuclear protein that is detectable in every phase of the cell cycle of proliferating cells but is absent in G0 cells [7]. It is therefore widely used as a proliferation marker in breast cancer, gastric cancer, and many other malignancies [8], [9]. Ki-67 staining on cytological preparations from pleural effusions has been studied as a potential diagnostic marker to discriminate between reactive mesothelial cells and mesothelioma [10]. Ki-67 was found to be prognostic in mesothelioma in many studies [11], [12].

The insulin-like growth factor mRNA-binding protein 3 (IMP3) is a member of an evolutionarily conserved mRNA-binding protein family that regulates mRNA transport, translation and turn over [13]. IMP3 is ubiquitously expressed during the early stages of embryogenesis, with only limited expression in postembryonic stages. IMP3 is also expressed by a variety of malignant tumors, and strong expression of this protein has been correlated with a poor prognosis, whereas negative or weak expression is thought to indicate benign or low-grade lesions [14].

Friend leukemia integration 1 transcription factor (Fli-1), also known as transcription factor ERGB, is encoded by the Fli-1 gene, a proto-oncogene, and features a 98-amino-acid DNA-binding domain [15]. Fli-1, as a member of the ETS transcription factor family, regulates the expression of oncogenes, tumor suppressor genes, and other genes related to vessel formation, invasion, and metastasis, and expression of these factors often correlates with poor survival [16]. Findings from the pleural counterpart would suggest a significant increase in IMP3 [17], [18]. Fli-1 affects cellular proliferation and tumorigenesis in Ewing sarcoma and ovarian carcinoma [16], [19], but there is no report on the expression of Fli-1 in mesothelioma. Moreover, no study has reported the immunohistochemical expression of IMP3 and Fli-1 that could assess the prognosis of MPeM.

The aims of the present study were therefore to evaluate the possible prognostic value of IMP3 and Fli-1 expression for MPeM patients and to elucidate the correlation between IMP3 and Fli-1 expression levels and proliferative activity.

Section snippets

Patients and tumor tissue samples

A total of 44 patients diagnosed as having MPeM over approximately a 4-year period (August 2013–October 2017) at the Cangzhou Central Hospital were included in the study. Clinical information on patient demographics, asbestos exposure, treatments, follow-up, and outcome was retrieved from patient medical records. The histopathologic diagnosis criteria for MPeM were established according to the guidelines [20]. The stage of MPeM was evaluated by a novel “TNM” staging system proposed in 2011 by

Patients

In total, 44 patients were evaluated in the study, 15 of them were male and 29 were female. The median patient age at diagnosis was 61.5 years (range, 42-84 years). Asbestos exposure was documented for 93% of patients, and 66% had been exposed professionally and 27% environmentally. Thirty cases were epithelioid (68.2%), and 14 cases were nonepithelioid (31.8%). The mean PCI was 25.3 (range, 3-39). According to the novel “TNM” staging system, 3 patients (6.8%) were stage I, 23 patients (52.3%)

Discussion

Because of the rarity of MPeM, there have been no randomized controlled trials on the best treatment strategies. It is necessary to take prognostic markers into consideration during patient selection because of significant perioperative risks associated with CRS-HIPEC.

Some of the predictive factors for OS in patient with MPeM have been identified as histologic type and grade, completeness of cytoreduction, PCI, age, involvement of lymph nodes, and the use of cisplatin as one of the agents

Conclusions

In conclusion, we found a high level of Fli-1 expression in MPeM patients. Although Fli-1 expression was not an independent indicator for OS, it may be a possible therapeutic approach to induce tumor suppression or a potential diagnostic or differential diagnosis factor for MPeM. IMP3 expression was an independent indicator for OS, and a higher level of IMP3 expression correlated significantly with poorer OS. This result warrants further prospective studies on IMP3 as a predictive marker in

Acknowledgements

The authors wish to thank the Department of Pathology, Cangzhou Central Hospital, for immunohistochemical staining of the slides.

Author contributions: Song Hui and Zheng Guo-Qi designed the study and wrote the manuscript. Guo Xiao-Zhong and Liu Chun-Rong performed immunohistochemistry and examined the immunostained sections. Yang Dong-Liang and Liang Yu-Fei analyzed statistical data. All authors read and approved the final manuscript.

References (35)

  • N.P. Schaub et al.

    A novel nomogram for peritoneal mesothelioma predicts survival

    Ann Surg Oncol

    (2013)
  • J. Gerdes et al.

    Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67

    Am J Pathol

    (1991)
  • S.H. Sim et al.

    CKAP2 (cytoskeleton-associated protein2) is a new prognostic marker in HER2-negative luminal type breast cancer

    PLoS One

    (2017)
  • Y. Nagasako et al.

    Evaluation of malignancy using Ki-67 labeling index for gastric stromal tumor

    Gastric Cancer

    (2003)
  • F. Hasteh et al.

    The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions

    Cancer Cytopathol

    (2010)
  • T.C. Chua et al.

    Differential expression of Ki-67 and sex steroid hormone receptors between genders in peritoneal mesothelioma

    Pathol Oncol Res

    (2009)
  • B. Ghanim et al.

    Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study

    Br J Cancer

    (2015)
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    Competing interests: The authors declare that they have no actual or potential conflict of interest in relation to the present article.

    ☆☆

    Funding/Support: The present study was funded by Cang Zhou Finance Bureau.

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