Differential expression patterns and clinical significance of estrogen receptor-α and β in papillary thyroid carcinoma

Abstract

Background: The incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.

Methods: Immunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n =89) and nodular thyroid goiter (NTG; n =30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.

Results: The positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18-45 years old; n =50) than age-matched female NTG patients (n =30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n =39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.

Conclusions: The differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.

Figure 1

Immunohistochemical staining of ERα and ERβ1 in PTC lesions and NTG tissue (400×). ERα and ERβ1 expression was analyzed by immunohistochemical staining of formalin-fixed and paraffin-embedded thyroid tissue sections from patients with papillary thyroid cancer (PTC) and those with nodular thyroid goiter (NTG) using specific antibodies and the Elivision™ plus two-step system. (A) NTG tissue with negative ERα staining; (B) NTG tissue with positive nuclear ERα staining (total score 6); (C) PTC tissue with negative ERα staining; (D) PTC tissue with positive nuclear ERα staining (total score 8); (E) PTC tissue with positive nuclear and cytoplasmic ERα staining (total score 7); (F) NTG tissue with negative ERβ1 staining; (G) NTG tissue with positive nuclear ERβ1 staining (total score 8); (H) NTG tissue with positive nuclear and cytoplasmic ERβ1 staining (total score 7); (I) PTC tissue with negative ERβ1 staining; (J) PTC tissue with positive nuclear ER β1 staining (total score 6); (K) PTC tissue with positive nuclear and cytoplasmic ERβ1 staining (total score 7); (L) PTC tissue with positive cytoplasmic ERβ1 staining (total score 5).

Figure 2

Detection of Ki-67, mutant P53 and VEGF expression in PTC lesions by immunohistochemical staining (400×). Formalin-fixed and paraffin-embedded PTC tissue sections were stained with the Elivision™ plus two-step system and specific antibodies against Ki-67, mutant P53 and VEGF. (A) PTC tissue stained with normal rabbit IgG instead of a specific primary antibody (negative control); (B) PTC tissue with positive Ki-67 staining (nuclear expression, total score 5); (C) PTC tissue with positive mutant P53 staining (combined nuclear and cytoplasmic expression, total score 7); (D) PTC tissue with positive VEGF staining (cytoplasmic expression, total score 7).