The role and prognostic value of inducible nitric oxide synthase (iNOS) and interleukin-33 (IL-33) in serous and mucinous epithelial ovarian tumours Eman M. Saied a, ⁎, Nour M. El-Etreby b a Department of Pathology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt b Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Alexandria, Egypt abstract article info Available online xxxx Understanding different mechanisms contributing to the aggressive behaviour of epithelial ovarian cancer (EOC) is a large challenge. Interaction between inflammation, immunity and carcinogenesis occurs in different cancers; however, the potential roles of different molecules involved in these processes in relation to ovarian carcinogen- esis were not fully investigated. Inducible nitric oxide synthase (iNOS) and interleukin-33 (IL-33) are implicated in carcinogenesis. iNOS is an NOS isoform that generates nitric oxide, which plays important roles in various stages of carcinogenesis. IL-33 is a cytokine implicated in modulation of anti-tumour immunity and tumour growth. This work aimed at studying the immunohistochemical expression of iNOS and IL-33 in serous and mu- cinous epithelial ovarian tumours to investigate their role and prognostic significance. Immunohistochemical ex- pressions of iNOS and IL-33 were assessed in 90 patients with epithelial ovarian tumours (45 serous and 45 mucinous tumours, categorized as benign, borderline, and malignant tumours). iNOS and IL-33 showed signifi- cantly higher expressions in borderline and malignant serous and mucinous tumours compared to benign ones (p = 0.0001). The differences between borderline and malignant tumours were statistically insignificant (p = 0.2351&0.6321). iNOS showed significantly higher expression with increasing tumour grade in malignant mucin- ous tumours (p = 0.0011). IL-33 showed significantly higher expression with increasing tumour grade in both malignant serous and mucinous tumours (p = 0.0074 and 0.0007). Upregulation of iNOS and IL-33 expression in borderline and malignant epithelial ovarian tumours indicates their involvement in the development and pro- gression of EOC, and their increased expression in less differentiated cancers suggests their association with poor prognosis in this category of tumours. © 2017 Elsevier Inc. All rights reserved. Keywords: iNOS IL-33 Epithelial ovarian tumours Immunohistochemistry Prognosis 1. Introduction Ovarian malignancy is a major health problem as it ranks as the sixth most common cancer in the world [1], the fourth common site of malig- nancy in females [2], and the seventh cause of cancer death in females [3]. Among the different types of ovarian cancers, epithelial ovarian can- cer (EOC) is the most lethal gynecological malignancy, as it accounts for 80–90% of cases, with the serous subtype being the most common and most aggressive [4-6]. This high mortality rate in these tumours is attributed to the absence of specific symptoms, as most tumours are silent [7-8], in addition to the absence of effective screening strategies for this type of cancer [1]. The previous factors resulted in poor prognosis and survival as well as high recurrence rate of EOC, as most cases are first diagnosed with ad- vanced stage even with metastases [9-11]. These data about EOC provided a wide field of research and were considered a true challenge for discovering the different molecular mechanisms involved in this type of cancer that contribute to its aggres- sive growth and metastatic ability [8], as well as an urgent need to de- velop new therapeutic strategies [3]. One of the well-established aetiological factors involved in about 15% of cancers, including EOC, is chronic inflammation [12]. It is regulat- ed by the interaction between a complex network of cytokines that reg- ulate growth, signaling, and differentiation of different types of cells including tumour and stromal cells. These cytokines may have crucial roles in cancer development and progression, as they may produce op- timal growth conditions within the tumour microenvironment, and af- fect the behaviour of malignant cells [13]. Nitric oxide “NO” is a free radical gasotransmitter responsible for various biological functions in the body [14]. Three isoforms of NOS are present: neuronal NO synthase (nNOS, also known as NOS1), induc- ible NO synthase (iNOS or NOS2) and endothelial NO synthase (eNOS or NOS3) [15]. Among the three NOS isoforms, iNOS is considered as the most common one involved in the process of carcinogenesis. It is expressed after cytokine exposure, and modulates different tumour re- lated processes such as malignant transformation, angiogenesis, and metastasis [14]. Annals of Diagnostic Pathology 27 (2017) 62–68 ⁎ Corresponding author. E-mail address: dremansaied@gmail.com (E.M. Saied). http://dx.doi.org/10.1016/j.anndiagpath.2017.01.006 1092-9134/© 2017 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Annals of Diagnostic Pathology