Macrophages, inflammation and risk of cervical intraepithelial neoplasia (CIN) progression—Clinicopathological correlation Luciano S. Hammes a,b, ⁎ , Rajeshwar Rao Tekmal b , Paulo Naud a , Maria Isabel Edelweiss c , Nameer Kirma b , Philip T. Valente d , Kari J. Syrjänen e , João Sabino Cunha-Filho a a Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil b Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA c Department of Pathology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil d Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA e Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland Received 28 August 2006 Available online 16 January 2007 Abstract Objective. To evaluate the population of macrophages during the cervical malignant transformation and its influence in CIN outcome. Methods. Biopsies from 26 normal cervix, 28 low-grade (LSIL), 30 high grade squamous intraepithelial lesions (HSIL) and 28 squamous cell carcinomas (SCC) were stained by H&E to assess inflammation and by immunohistochemistry with anti-CD68 to detect macrophages. The macrophage count was corrected for the epithelial and stromal compartments using appropriate software. Clinical and prospective follow-up data were also available. Results. We identified that macrophage count increased linearly with disease progression (median count per case at ×200 magnification: normal, 5.1; LSIL, 5.5; HSIL, 9.9; SCC, 14.5; P < 0.001), that inflammation also increased (moderate–intense inflammation present in 25%, 46.1%, 58.4% and 89.3% of normal, LSIL, HSIL and SCC, respectively; P < 0.001) and that macrophage count was independently associated with the lesion grade (P < 0.001). Moreover, macrophages showed an increasing migration into the epithelium along with the progression of CIN to invasive cancer. Of the 24 LSIL cases with information available, followed-up for 805 ± 140 days, 16 regressed, 6 persisted and 2 progressed. Age, high-risk HPV or inflammation were not risk factors for persistent/progressed LSIL in our cohort. However, LSIL that persisted or progressed showed a higher macrophage count (median of 10.8) than lesions that regressed (7; P = 0.031). Conclusions. The study on macrophages offers a potential approach for cervical cancer treatment, since macrophages are closely related to progression of CIN, and can be used as an applicable marker of such a risk. © 2006 Elsevier Inc. All rights reserved. Keywords: Macrophages; Monocytes; CD68 protien; Immunohistochemistry; Inflammation; Cervical intraepithelial neoplasia; Cervical cancer; Disease progression Introduction Malignant tumors are complex structures that for purposes of growth and invasiveness must interact with the surrounding environment. The ultimate goal of this interaction is to promote blood supply, block negative growth signals, increase positive growth signals, create resistance to apoptosis and promote unlimited cell replication [1–3]. Convincing data has emerged in recent years that inflamma- tion plays an important role in this process. Epidemiological studies have demonstrated that the use of anti-inflammatory drugs is associated with a reduced risk of cancer as well as with a decrease of precancer lesions. Among the inflammatory cells, tumor-associated macrophages (TAM) have been identified as important components not only in terms of their number but also with regard to their function [2,4,5]. Macrophages are derived from bone marrow monocytes that adopt different phenotypes when entering the circulatory Gynecologic Oncology 105 (2007) 157 – 165 www.elsevier.com/locate/ygyno ⁎ Corresponding author. Department of Obstetrics and Gynecology, Uni- versity of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Fax: +1 210 567 4958. E-mail address: hammes@cpovo.net (L.S. Hammes). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.11.023