Carbonic anhydrase isozymes II, IX, and XII in uterine tumors PIRITTA HYNNINEN, 1,2 SEPPO PARKKILA, 3 HEINI HUHTALA, 4 SILVIA PASTOREKOVA, 5,6 JAROMIR PASTOREK, 6 ABDUL WAHEED 7 , WILLIAM S. SLY 7 and EIJA TOMAS 1 1 Departments of Obstetrics and Gynecology, University of Tampere, Tampere, Finland; 2 Departments of Obstetrics and Gynecology, Kanta-Ha¨ me CentralHospital, Ha¨ meenlinna, Finland; 3 Institute of Medical Technology and School of Medicine, University of Tampere, Tampere, Finland; 4 School of Public Health, University of Tampere, Tampere, Finland; 5 Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland; 6 Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic; and 7 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA Hynninen P, Parkkila S, Huhtala H, Pastorekova S, Pastorek J, Waheed A, Sly WS, Tomas E. Carbonic anhydrase isozymes II, IX, and XII in uterine tumors. APMIS 2012; 120: 117–29. Histopathological diagnostics of gynecological malignancies continues to be challenging despite the well established criteria. For example, the morphological distinction of uterine leiomyosarcoma from certain variants of benign leiomyoma can be difficult. Herein, we investigated the expression of Carbonic anhydrase (CA) II, IX, and XII in the normal endometrium, leiomyomas, uterine sarcomas, and endometrial adenocarcinomas using immunohistochemistry. These isozymes are considered prom- ising diagnostic markers and therapeutic targets. The normal endometrium showed high CA XII expression, whereas the signals were lower in endometrial adenocarcinoma (p < 0.004). Only sporadic CA IX staining was found in the normal endometrium, whereas the enzyme was overexpressed in most cases of endometrial adenocarcinoma (p < 0.005). CA II expression was slightly weaker in the normal endometrium than that in the adenocarcinomas (p < 0.008). Positive immunostaining reactions for CAs were observed in the uterine sarcomas, whereas all leiomyomas were negative for CA II and XII. A comparison between leiomyomas and sarcomas showed statistically significant differences for all studied isozymes (p < 0.001). Our study shows that CA isozymes could together serve as histopatho- logical biomarkers for differential diagnosis between uterine leiomyosarcoma and leiomyoma. In addi- tion to being found in leiomyosarcomas, CA II and IX were overexpressed in endometrial adenocarcinoma, where they might regulate the pH of the tumor microenvironment. Key words: Adenocarcinoma; carbonic anhydrase; immunohistochemistry; mesenchymal tumor; sarcoma; uterine cancer. Piritta Hynninen, Departments of Obstetrics and Gynecology, University of Tampere, Tampere University Hospital, Box 2000, 33521 Tampere, Finland. e-mail: piritta.hynninen@pshp.fi Endometrial carcinoma is a very common gyne- cological malignancy type in the Western world (1, 2). The National Cancer Institute estimated 40 470 new cases in the USA in 2011 (http:// www.cancer.gov). Even though the 5-year survival rates for all the stages are all about 80%, an estimated 9000 women in Europe die from endometrial cancer each year (3). In con- trast to endometrial carcinoma, uterine leio- myosarcoma is rare (incidence: 0.64 per 100 000 women), accounting for 0.2–6% of all smooth muscle tumors of the uterus (4). Independent of the stage, these tumors are aggressive and have Received 25 November 2010. Accepted 23 September 2011 APMIS 120: 117–129 Ó 2011 The Authors APMIS Ó 2011 APMIS DOI 10.1111/j.1600-0463.2011.02820.x 117