Tamoxifen-associated malignant endometrial tumors: pathologic features and expression of hormone receptors estrogen-α, estrogen-β and progesterone; a case controlled study

Abstract

Objective. Expression analysis of estrogen receptor-beta (ER-β) and estrogen receptor-alpha (ER-α) in tamoxifen-associated malignant endometrial tumors (TAMET) has not previously been published. Antiestrogens complexed with ER-β have been reported to result in activation of the activator protein-1 (AP-1) pathway that may result in cell proliferation and tumor growth. In this study, the pathologic features and expression of ER-α, ER-β and progesterone receptor (PR) in TAMET were determined and compared to matched cases of non-tamoxifen-associated endometrial cancers. Methods. TAMET ( n = 33) were evaluated for pathologic features (tumor type, grade, depth of myometrial invasion, lymphvascular space invasion and lymph node status), expression of ER-α, ER-β and PR, and survival data (mean follow-up: 28.7 months). Each case was matched to two control patients with spontaneous endometrial cancers according to tumor type, grade and stage as well as patient age and weight (mean follow-up: 51.5 months). Formalin-fixed paraffin-embedded tissue sections were immunostained with anti-ER-α (1D5, Dako, Carpinteria, CA) and anti-PR (PgR636, Dako). Expression scores were determined as a sum of the product of staining intensity and proportion of cells staining (H-score). Deparaffinized sections of tumor were microdissected followed by RNA isolation. Quantification of ER-β mRNA was performed by real-time quantitative RT-PCR with results expressed as a percentage of β-actin mRNA. Results. Of the 33 cases 20 were endometrioid (8 grade 1, 10 grade 2, 2 grade 3), 9 papillary serous and 4 malignant mullerian mixed tumors. Using a multivariate conditional regression model, TAMET had lower ER-α expression ( P = 0.018), higher PR expression ( P = 0.029), and more frequent expression of ER-β ( P = 0.032) as compared to control cases. Cases with TAMET had more deaths from cancer and significantly worse survival from disease than controls ( P = 0.01 by a log rank test). Conclusion. TAMET are characterized by a lower expression of ER-α, higher expression of PR and more frequent expression of ER-β as compared to spontaneous tumors. Differential expression of ER-α and ER-β may alter the expression of key target genes (such as those induced by AP-1-dependent gene transcription), and contribute to the pathogenesis and clinical behavior of these tumors. Survival from disease was significantly worse for cases with TAMET as compared to controls.