Suppressed expression of type 2 3alpha/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma

Abstract

The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3alpha-/type 5 17beta-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.

Keywords: Aldo-keto reductase; endomtrial cancer; estrogen; progesterone; prostaglandin.

Figure 1

Expression of AKR1C3 in normal and hyperplastic endometrium. (A) Normal proliferative endometrial glands and blood vessels (arrow) are uniformly immunoreactive for AKR1C3 but endometrial stromal cells are negative. (B) Both nuclear and cytoplasmic immunoreactivity are noted in both endometrial glands and endothelial cells of blood vessels (arrow). (C) In this case of complex hyperplasia with atypia, only about 30% of the hyperplastic glands are immunoreactive for AKR1C3. Both positive (arrow) and negative areas are included here. (D) In some areas of this case, weak immunoreactivity limited to scant cells is demonstrated (arrow). (E) In this case of complex hyperplasia with atypia, there is immunoreactivity in practically in all of the hyperplastic cells. Note that a strip of residual normal endometrium is present (arrow) and shows stronger immunoreactivity than the hyperplastic cells. (F) Both cytoplasmic and nuclear immunoreactivity are noted in the hyperplastical glands. Stromal cells are largely negative. (Original magnification for panel A, C, and E is 10×, for panel B, D, and F is 60×).

Figure 2

Expression of AKR1C3 in endometrial adenocarcinoma of endometrial type. (A) In this case of adenocarcinoma, there is no immumoreactiv-ity for AKR1C3 in the carcinomatous cells but enodothelial cells of blood vessels are immunoreactive (arrow). (B) Both nuclear and cytoplasmic immunoreactivity are demonostrated in blood vessels (arrow). (C) In this case of adenocarcinoma, there is widespread positive immunoreactivity with small clusters of non-immunoreactive area (arrow). (D) Small clusters of non-immunoreactive cells are present among positive cells. (E) In this case of adenocarcinoma, practically all carcinomatous cells are immunoreactive. (F) Both nuclear and cytoplasmic immunoreactivity are demonstrated. (Original magnification for panel A, C, and E is 10×, for panel B, D, and F is 60×).