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Uterine Paramesonephric Cysts in Sprague-Dawley Rats from National Toxicology Program Studies

Daven N. Jackson-Humbles, John Curtis Seely, Ronald A. Herbert, David E. Malarkey, Barry S. McIntyre, Paul M. Foster, and Darlene Dixon
Toxicologic Pathology (2018). DOI: https://doi.org/10.1177/0192623318772487 PMID: 29706125


Publication


Abstract

Congenital uterine wall cysts arising from paramesonephric (Müllerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and/or estrogen receptor α (ER-α), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8 and ER-α and/or PR staining. Additionally, 70% of the cysts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct.

Figures


Figure 1. Uterine subserosal cyst from a SD rat.

A shows a 3-mm raised, fluid-filled cyst (arrow) on the left uterine horn (UtH).
B is a low-magnification image of the cyst that is present between the serosa and the outer myometrial layer and not associated with uterine cavity. The inset shows the cyst lined by a single layer of flattened cuboidal epithelium (arrowhead). Note, lightly basophilic staining flocculent intraluminal material. SD = Sprague-Dawley, UtB = fused uterus and cervix, V = vagina.

Figure 2. Uterine cyst from a SD rat.

Low-magnification images of a second cyst filled with basophilic flocculent material located beneath the serosa and compressing the outer myometrial layer (A and B). C to F are higher magnifications of the cyst that is lined by flattened to cuboidal epithelium that has moderate eosinophilic cytoplasm and large oval nuclei with 1 to 2 prominent nucleoli. Endometrial cavity is not associated with the cyst (C, H&E). The wall is composed of scant to moderate blue staining of collagen and abundant red staining of muscle (D, Masson’s trichrome). E and F show positive immunostaining for SMA with moderate brown staining of muscle fibers (E) and intense brown cytoplasmic staining for CK-18 in cyst epithelial cells (F). CK-18 = cytokeratin 18, H&E = hematoxylin and eosin, SD = Sprague-Dawley, SMA = smooth muscle actin.

Figure 3. Uterine cyst in SD rat.

Low-magnification images of a third cyst show similar features of the previous cysts in Figures 1 and 2 (A and B). The higher magnification inset in B demonstrates the differences of the tall columnar endometrial epithelium (adjacent to asterisk) and the flattened cuboidal cyst epithelium (arrowhead). C to F are high-magnification images of the cyst and are representative of immunohistochemical staining patterns of the cyst. Brown staining indicates positive reaction to the indicated antibody. Cyst epithelium (arrowhead) has multifocal weak to moderate nuclear and weak cytoplasmic staining for PR, while endometrial epithelium (adjacent to asterisk) has negative to weak staining (C). Nuclear staining for ER-α was weak to intense in both cyst and endometrial epithelium (D). There is diffuse moderate to intense nuclear staining in the epithelium and endometrium for PAX8 and negative staining for GATA3 (E and F, respectively). ER-α = estrogen receptor α, PAX8 = paired box 8, PR = progesterone receptor, SD = Sprague-Dawley.

Figure 4. The overall average quickscores of immunohistochemical markers.

The overall average quickscores of immunohistochemical markers evaluated in uterine subserosal cyst epithelium or wall were categorized as 0 to 1 = negative, 2 to 6 = weak, 7 to 12 = moderate, and 13 to 18 = strong. Overall, cyst walls displayed moderate positive staining for SMA; and epithelia were strongly positive for CK-18 and PAX8, moderate for ER-α, weak for PR, and negative for GATA3. Data are expressed as mean + standard error of mean. CK-18 = cytokeratin 18, ER-α = estrogen receptor α, PAX8 = paired box 8; PR = progesterone receptor, SMA = smooth muscle actin.

Tables


Table 1. Immunohistochemical Stains.

Table 2. Animal Information.

Table 3. Gross Appearance and Localization of Uterine Cysts in Sprague-Dawley Rats.

Table 4. Estrous Cycle Stage and Immunohistochemical Staining Intensity of Uterine Cysts in Sprague-Dawley rats.