ORIGINAL ARTICLE ER-alpha and ER-beta expression in differentiated thyroid cancer: relation with tumor phenotype across the TNM staging and peri-tumor inflammation Flavia Magri • Valentina Capelli • Margherita Gaiti • Laura Villani • Francesca Zerbini • Luigi La Manna • Mario Rotondi • Luca Chiovato Received: 6 August 2014 / Accepted: 13 October 2014 Ó Springer Science+Business Media New York 2014 Abstract Thyroid cancer may express estrogen receptors (ERs) and various grades of peri-tumor inflammation. The aim of the study was to evaluate the expression of ERs in relation to the TNM stage and peri-tumor inflammatory infiltrate in differentiated thyroid cancers. 127 patients (109 females, 18 males) with differentiated thyroid cancer (T1 = 91, T2 = 18, T3 = 11, T4 = 7) were evaluated. In tumors and in the correspondent extra-tumor parenchyma, ERs expression was evaluated by immunohistochemistry. In 114 tumors and correspondent peri-tumor tissues, the pre- sence of inflammatory infiltration was also recorded. ER- alpha expression was higher in clinical than in incidental tumors of the T1 subgroup (p = 0.037), and was associated with capsular invasion in T2 tumors (p \ 0.0001). ER-beta expression was negatively associated with vascular invasion in T1 (p = 0.005) and T2 tumors (p = 0.015). No signifi- cant relationship between ERs expression and tumor phe- notype emerged in T3 and T4 subgroups. Tumors without inflammatory cell infiltrate showed a higher expression of both ER-alpha (p = 0.035) and ER-beta (p = 0.026) than the ones with inflammatory infiltrate. The relationship between tumor phenotype and ERs expression did not vary in the presence or absence of peri-tumor inflammatory infiltration. ER-alpha positivity and ER-beta negativity are associated with a more aggressive phenotype in both T1 and T2 thyroid cancers, suggesting that tumor biology may be more relevant than tumor size for cancer risk assessment. Inflammatory status is also associated with ERs expression, but not with tumor growth or phenotype. Keywords Estrogen receptor Á Tumoral inflammation Á Thyroid cancer Á Risk assessment Introduction Since 1996, it was recognized that estrogen receptors (ERs) were expressed in normal and malignant thyroid cells [1]. Although investigated in several studies [1–6], the role of ERs (both alpha and beta subtypes) in thyroid physiology and carcinogenesis is still debated. ERs are expressed at different levels in normal and neoplastic thyroid tissue and in thyroid tumors of different histotype [4, 5]. Differences also exist in the ER-alpha/ER-beta expression ratio; indeed, when compared to normal parenchyma, ER-alpha expres- sion is usually increased in thyroid tumors, while ER-beta expression is decreased [2, 3]. A recent study showed that ER-beta expression is significantly higher in follicular adenomas than in carcinomas, and a low ER-beta expres- sion is associated with poor survival of patients with fol- licular thyroid carcinomas [6]. Thyroid stem and progenitor cells express both ER-alpha and ER-beta, but the expres- sion levels of ER-alpha mRNA are eight times higher than in differentiated thyroid cells. Estradiol (E2) stimulates the growth of thyroid stem and progenitor cells, but inhibits their TSH-induced differentiation, and in particular the expression of the sodium iodide symporter [7]. In line with these data, in vitro experiments demonstrated that E2 F. Magri Á V. Capelli Á M. Gaiti Á F. Zerbini Á M. Rotondi Á L. Chiovato (&) Unit of Internal Medicine and Endocrinology, Fondazione S. Maugeri, IRCCS, University of Pavia, Pavia, Italy e-mail: luca.chiovato@fsm.it L. Villani Unit of Pathology and Cytology, Fondazione S. Maugeri, Pavia, Italy L. La Manna Department of General and Mininvasive Surgery, Fondazione S. Maugeri, Pavia, Italy 123 Endocrine DOI 10.1007/s12020-014-0457-x