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Selected Background Findings and Interpretation of Common Lesions in the Female Reproductive System in Macaques
1 Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA Correspondence: J. Mark Cline, DVM, PhD, DACVP, Professor of Pathology/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040; e-mail:jmcline{at}wfubmc.edu.
The authors describe a selection of normal findings and common naturally occurring lesions in the reproductive system of female macaques, including changes in the ovaries, uterus, cervix, vagina, and mammary glands. Normal features of immature ovaries, uteri, and mammary glands are described. Common non-neoplastic lesions in the ovaries include cortical mineralization, polyovular follicles, cysts, ovarian surface epithelial hyperplasia, and ectopic ovarian tissue. Ovarian neoplasms include granulosa cell tumors, teratomas, and ovarian surface epithelial tumors. Common non-neoplastic uterine findings include loss of features of normal cyclicity, abnormal bleeding, adenomyosis, endometriosis, epithelial plaques, and pregnancy-associated vascular remodeling. Hyperplastic and neoplastic lesions of the uterus include endometrial polyps, leiomyomas, and rarely endometrial hyperplasia and endometrial adenocarcinoma. Vaginitis is common. Cervical lesions include endocervical squamous metaplasia, polyps, and papillomavirus-associated lesions. Lesions in the mammary gland are most often proliferative and range from ductal hyperplasia to invasive carcinoma. Challenges to interpretation include the normal or pathologic absence of menstrual cyclicity and the potential misinterpretation of sporadic lesions, such as epithelial plaques or papillomavirus-associated lesions. Interpretation of normal and pathologic findings is best accomplished with knowledge of the life stage, reproductive history, and hormonal status of the animal. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. Gerhard F. Weinbauer and Eberhard Buse are employed by Covance Inc. Eveline P. C. T. de Rijk and Eric Van Esch are employed by Schering-Plough. No other competing interests were declared.
Key Words: primate pathology • female reproductive pathology • uterus • ovary • mammary gland Abbreviations: PCOS, polycystic ovary syndrome • CIN, cervical intraepithelial neoplasia • PV, papillomavirus
This review is intended to provide the reader with a brief descriptive and photographic reference to a few of the more common spontaneous lesions in the reproductive tract, pituitary gland, and mammary gland of female macaques. For further discussion of reproductive pathology in female nonhuman primates, the reader is also referred to the recent work of Cooper and Gabrielson (2007) and other articles on the subject (DiGiacomo 1977; Wilkinson et al. 2008). Neoplasms of the reproductive system in macaques have been the subject of several reviews (e.g., Beniashvilli 1989). The few reference books on the spontaneous pathology of nonhuman primates also include information on neoplasms and background findings in the reproductive tract (Benirschke, Garner, and Jones 1978; Takayama, Fukushima, and Thorgeirsson 2000). Two types of change are of greater importance and pose difficulty in interpretation for the toxicologic pathologist, namely, those that relate to abnormalities of the menstrual cycle and potentially treatment-related hyperplastic lesions of the endometrium that have relevance to cancer risk. Accordingly, we have emphasized those two areas. Tissues presented in this review have been collected from animals in breeding colonies and control and treated groups from Wake Forest University, the California National Primate Research Center, Covance Laboratories, Schering-Plough (formerly Organon), and GlaxoSmithKline. Because the age and reproductive status of populations at each site differ substantially, estimates of lesion incidence are not included. Furthermore, some of the "findings" reported here are normal but are included because they create challenges to interpretation. All procedures involving animals at each institution were conducted in compliance with applicable regulations, including Institutional Animal Care and Use Committee oversight.
Pituitary Adenomas Pituitary adenomas are the most common neoplasm in older cynomolgus macaques (Remick et al. 2006) and have also been reported to be common in rhesus macaques (Chalifoux, MacKey, and King 1983). These benign neoplasms are generally clinically silent and found incidentally at necropsy. These neoplasms are most commonly immunoreactive for prolactin or adrenocorticotropic hormone (Figures 1A, 1B), but multihormonal neoplasms are common. Prolactin-staining neoplasms are occasionally associated with galactorrhea (Daviau and Trupkiewicz 2001). In these characteristics, they are similar to those pituitary adenomas seen most commonly in human beings and also may be similarly associated with type 2 diabetes (Remick et al. 2006).
Hypertrophy of Gonadotrophs We have noted the presence of hypertrophied gonadotroph cells in the pituitary of cynomolgus monkeys after ovariectomy, similar to the so-called gonadectomy cells seen in ovariectomized rats. These cells occur diffusely within the pars distalis of ovariectomized animals and stain positively using immunohistochemistry with antibodies directed against follicle stimulating hormone (Figures 1C, 1D).
Immaturity Because female macaques have high individual variability for pubertal onset between the ages of 2.5 and 4, a critical assessment of ovarian morphology is essential to the correct interpretation of changes elsewhere in the reproductive system. Both ovaries of young animals should be examined grossly and histologically for the presence of corpora lutea or remnants, indicating prior ovulation. The ovaries of immature animals are not completely quiescent but typically contain follicles in a range of maturation stages, including antral follicles, which may produce estradiol in early preovulatory animals (Wood, Hester, and Cline 2007). However, these early pubertal ovaries lack the corpora lutea typical of late-pubertal or adult-cycling animals. Immaturity and states of hypothalamo-pituitary-gonadal axis dysfunction are discussed further under the section titled "Uterus" below.
Non-neoplastic Lesions
Ectopic Ovarian Tissue In macaques, ectopic ovarian tissue can occasionally be observed within the broad ligament, on the serosal surface of the uterus, or within the myometrium (Figure 2B). Recently, Kuwamura et al. (2006) reported the presence of ectopic uterine ovarian tissue in 9 out of 118 (7.6%) cynomolgus monkeys ranging from 3 to 7 years of age. Generally such lesions are not grossly visible and are found only incidentally during microscopic investigation of the uterus. The anomaly consists of ovarian stromal tissue with varying appearance of primordial, primary, and/or atretic follicles. Since no signs of trauma or inflammatory changes are generally observed in relation to this lesion, the presence of uterine ovarian tissue is considered to have a congenital background (Payan and Gilbert 1987). The parametrial location of this anomaly supports the hypothesis of its embryologic origin. When using ovariectomized macaques as an experimental model, care must be taken to confirm completeness of the ovariectomy using postsurgical serum estradiol, progesterone, and/or gonadotropin concentrations (Cline, Register, and Clarkson 2002A).
Cortical Mineralization
Polyovular Follicles
Hyperplasia of the Ovarian Surface Epithelium
Endometriosis
Ovarian Smooth Muscle Metaplasia
Ovarian "Deciduosis"
Ovarian Neoplasms
Teratomas Mature teratomas are by far the most common germ cell tumors in women. In nonhuman primates, ovarian teratomas have been reported in rhesus monkeys (Chalifoux 1993), the cynomolgus monkey (Kaspareit et al. 2007; Toyosawa et al. 2000), and other species. For cynomolgus monkeys, the incidence of this neoplasm is estimated at <0.1% (Toyosawa et al. 2000). In our collection, we have encountered unilateral mature benign teratomas in the ovaries of sexually mature cynomolgus monkeys as young as four years of age. In these cases, the affected ovary was enlarged by a cystic mass filled with caseous material (Figures 3D–3F). Microscopically, tumors are situated within the ovary, surrounded by normal ovarian tissue (follicles, corpora lutea, and stroma). In one case, a young corpus luteum was noted next to the tumor, suggesting normal ovarian cyclicity of the tumor-bearing ovary in this animal. Histologically these tumors consist of one or more cysts lined by epithelium, most often keratinized. In the wall of the cyst, skin adnexa, such as sebaceous glands, hair shafts, sweat glands, and a variety of other mature tissue elements, are present. Structures from other germ cell layers have been identified, such as adipose tissue, smooth and skeletal muscle, cartilage, bone, and epithelium with goblet cells.
Ovarian Surface Epithelial Tumors
Non-neoplastic Lesions Disorders of Cycle Regulation Irregular Uterine Bleeding Varying degrees of irregular endometrial bleeding are a common occurrence in macaques, as in women. Recent large observational studies in women have indicated that regular monthly menstrual cycles throughout life are the exception rather than the rule (Gorrindo et al. 2007); thus, observers should not be surprised to see high interindividual variation in menstrual patterns in macaques. In particular, irregular patterns of endometrial bleeding are common in the adolescent macaques typically used in toxicology studies (Resko et al. 1982 and our unpublished observations). These animals are typically at or around menarche and display long, irregular anovulatory cycles; in this regard, they are similar to adolescent human beings (Strickland and Wall 2003). In macaques, this type of uterine bleeding is usually observed only histologically and is characterized by the presence of hemorrhage in the endometrium or uterine lumen, with the endometrium displaying varying degrees of a proliferative phase pattern (Figures 4A–4C). This is similar to the glandular and stromal breakdown with hemorrhage that is commonly observed during anovulatory cycles around menarche in humans (Strickland and Wall 2003). It may be distinguished from normal menstruation by the lack of a secretory phase endometrium, the presence of mitoses in the endometrial glands and stroma, and absence of full endometrial shedding. In addition, there is a lack of a regressing corpus luteum, and often the ovary will display one or more small to medium-sized variably atretic tertiary follicles, as is common in early pubertal or perimenarchal macaques (Van Wagenen and Simpson 1973; Vidal, unpublished observation).
Anovulatory Cycles A great challenge in the interpretation of the primate endometrium is the common occurrence of menstrual cycle irregularity or suppression. Anovulatory cycles occur in both young macaques as well as in mature cycling adults. The cycles following menarche are often irregular and prolonged and lack a distinct luteal phase, suggesting a lack of ovulation. In one study, only 15% of rhesus macaques ovulated in the first five cycles following menarche (Resko et al. 1982). In the wild, macaques are highly social animals living in troops, in which social stressors normally lead to reproductive suppression of subordinate females. In a controlled laboratory setting of small social groups, Adams, Kaplan, and Koritnik (1985) demonstrated that this interactive social stress caused a much higher proportion of anovulatory cycles in subordinate animals, such that only 54% of subordinates had normal ovulatory cycles relative to 88% of dominant animals. Accordingly, when evaluating the uteri of any cohort of macaques, some proportion of the endometria will lack distinct features of any particular stage of the menstrual cycle, or they may incompletely express a follicular-phase or luteal-phase morphology (Figures 4D–4F). This is especially common in non-clinical toxicology safety testing, as the animals are often young and may have only recently reached menarche. A reasonable approach to characterizing such tissues is to describe them as "inactive" with further comment regarding any features of the menstrual cycle that may be present. Although this is a common developmental feature, it may still be considered noteworthy. Because suppression of ovarian function is stress induced through the hypothalamo-pituitary-gonadal axis, a higher proportion of inactive uteri within a given treatment group might indicate treatment-associated stress or illness.
Polycystic Ovary Syndrome
Endometriosis
Statistically significant risk factors for endometriosis in a case-control study in rhesus macaques included hysterotomy (ten-fold risk) and long-term estrogen treatment (six-fold risk) (Hadfield et al. 1997). Whole-body irradiation has also been associated with a higher incidence of endometriosis (Fanton and Golden 1991). In the late 1990s, an intriguing observation was made of a possible link between dioxin exposure and endometriosis (Rier 2002; Rier, Coe, et al. 2001; Rier et al. 1993, Rier, Turner, et al. 2001); also, treatment with dioxin facilitates the successful growth of endometrial explants (Yang, Agarwal, and Foster 2000). However, the causative link in this regard has recently been called into question (Guo 2004). More recently, other intriguing possibilities have emerged, including a strong association with developmental lead exposure (Krugner-Higby et al. 2003) and altered intestinal microflora in animals with endometriosis (Bailey and Coe 2002). Endometriosis in the macaque may have a similar biochemical basis to the disease in man, where it has been postulated that a polymorphism in the expression of N-acetyltransferase may influence risk (Fakis et al. 2007).
Adenomyosis
Pregnancy-associated Vascular Remodeling
The Epithelial Plaque Macaques have a uniquely florid epithelial proliferative response of the endometrial surface in early implantation, not occurring in human beings or other laboratory animal species. This change consists of distinctive plaque-like structures on facing walls of the endometrium, which efface the normal simple columnar surface epithelium and extend into the superficial endometrial stroma. When related to pregnancy, this localized epithelial proliferation is only temporary, and the structure regresses after a few weeks, mainly by apoptosis. This proliferative change, known as the epithelial plaque, is of most interest when it occurs occasionally during the luteal phase in the absence of an embryo (Kaspareit et al. 2004). The epithelial plaque response can be induced experimentally by combined estrogen and progestogen treatment accompanied by trauma to the endometrium and has been used as a model of early implantation (Ghosh, Bell, and Sengupta 2004; Ghosh and Sengupta 1989). The epithelial cells composing the plaques are generally large, pleomorphic, and polygonal, with anaplastic nuclear features resembling a carcinoma. Features distinguishing this change from endometrial carcinoma are often its simultaneous but noncontiguous presence on opposing walls of the endometrium and the distinctive surface orientation of the epithelial proliferative change without invasion into the deeper endometrium (Figure 7).
Hyperplastic and Neoplastic Changes of the Uterus Leiomyomas Uterine leiomyomas or "fibroids" are common, benign neoplasms in adult and aging macaques (Kaspareit et al. 2007; McClure 1973; Seibold and Wolf 1973). They may be solitary or multiple (Figures 8A–8C) and consist of a well-demarcated, expansile mass of smooth muscle cells with varying amounts of dense collagenous matrix. A malignant variant (leiomyosarcoma) has been reported (Cook, Rogers, and Sowers 2004), but in general, these neoplasms are benign. Like the normal myometrium, these neoplasms express estrogen and progesterone receptors and are hormone responsive. They may result in abnormal uterine bleeding or interfere with fertility, as in women.
Endometrial Polyps Endometrial polyps occur in approximately one out of four women over the age of forty (Sherman, Mazur, and Kurman 2002), and they also occur spontaneously in female macaques. The prevalence of polyps is increased in animals treated with estrogens or tamoxifen. Spontaneous endometrial polyps have been observed in both rhesus and cynomolgus macaques at the California National Primate Research Center and often present clinically with irregular and occasionally persistent bleeding (unpublished observations, Vidal and Tarara). In our experience, endometrial polyps in cynomolgus macaques occur at a relatively young age (approximately nine to ten years old, with a range of six to thirteen years), and a similar finding has been reported by other investigators (Kaspareit et al. 2007). This is in contrast to our observations in the rhesus in which polyps have been observed in older, often postmenopausal animals (approximately twenty-five years with a range of eleven to thirty-two years). Macroscopically, endometrial polyps often distend the uterine lumen and may be sessile or pedunculated with one or more polyps occurring in an individual uterus (Figures 8D–8I). These polyps have abundant stroma consisting of a well-vascularized to fibrotic core resembling normal endometrial stroma with varying numbers of glands scattered throughout and generally a single layer of columnar to cuboidal epithelium. Hyperplastic, metaplastic, or malignant changes may occur rarely within a polyp. In some cases in rhesus macaques, ovarian findings (granulosa cell tumor, variably luteinized follicular cyst) may have been a source of estrogenic stimulus for development of the polyp.
Uterine Hemangiomas
Endometrial Hyperplasia In the evaluation of the abnormally thickened human endometrium, the histologic appearance has historically been classified as simple hyperplasia (Figures 9B and 9E) or complex hyperplasia (Figures 9C, 9F, and 10A–10D) (Ronnett and Kurman 2002). Both simple and complex hyperplasia have an increased gland-to-stroma ratio, disordered architecture, glandular epithelial pseudostratification, and increased numbers of glandular epithelial mitoses. Either may also be associated with epithelial atypia, consisting of loss of epithelial cell polarity, increased nucleus-to-cytoplasm ratio, nuclear clearing with clumping of chromatin at the membrane, and a round to irregular nuclear contour. Complex hyperplasia with atypia has the strongest association with endometrial cancer risk in women (Kurman, Kaminski, and Norris 1985). A more recent system of evaluating hyperplastic lesions in the endometrium replaces the category of complex hyperplasia with atypia with endometrial intraepithelial neoplasia (EIN) (Mutter et al. 2007).
In light of the evolving classification of endometrial hyperplasias in human beings, it is incumbent upon the toxicologic pathologist to carefully describe and correctly interpret endometrial changes in laboratory animals. When extrapolating findings in macaques in a regulatory setting to likely outcomes in human beings, there is a tendency for regulators to regard any use of the term hyperplasia as representing complex hyperplasia with atypia, when this may not be the case. There are also differences in the traditional lexicon of MD pathologists and veterinary pathologists, for example, in the case of cystic atrophy and cystic endometrial hyperplasia, respectively, for a lesion in which the endometrium is thickened by cystic dilatation of the glands without marked glandular proliferation. When evaluating proliferative changes, we recommend the use of normal endometrium, follicular phase for endometrial proliferation with features of the normal follicular phase, such as parallel straight or tortuous glands with zonal edema of the functionalis (Figure 9A); simple hyperplasia for disorganized endometrial proliferation without glandular crowding (Figure 9B); and complex hyperplasia for endometrial proliferation with glandular crowding (Figure 9C). Atypia should be indicated when present. We recommend the use of cystic change (evident in Figures 9B and 9C) to avoid the implication of risk that might be associated with the term cystic hyperplasia.
Endometrial Adenocarcinoma
Trophoblastic Neoplasms
Other Incidental Uterine Findings
Vaginitis and Cervicitis The vagina of macaques normally contains lymphoid aggregates and follicles, which have been the subject of extensive study because of their relevance to defense against simian immunodeficiency virus transmission (Miller and Lu 2003). Thus, the presence of lymphoid aggregates in the vagina is not an abnormal finding, and the distinction between normal and inflamed vaginal tissue is somewhat subjective (Figures 12A–12D). Furthermore, some animals are conformationally or behaviorally predisposed to contamination of the vagina by feces, hair, or other foreign material. Therefore, gross evaluation of the vaginal lumen for foreign material and gross lesions is an important part of the necropsy examination, as it may inform later histologic observations.
Endocervical Polyps As described elsewhere in this volume, the cervical os of macaques normally has a protruding anterior shelf, as in women, which should not be misinterpreted as a polyp. However, both endocervical and endometrial polyps are commonly found in the endocervical channel and may protrude into the vagina.
Endocervical Squamous Metaplasia
Papillomavirus-induced Lesions
Sex Skin Rhesus and cynomolgus macaques have species-specific patterns of perineal sex skin swelling and erythema (Baulu 1976; Duran-Reynals, Bunting, and Wagenen 1950). Among rhesus macaques, there is seasonal variability in the prominence of sex skin swelling, with more regular cyclicity in fall and winter (Ghosh and Sengupta 1992). Among cynomolgus macaques, there is pronounced individual and regional variation in sex skin prominence in subpopulations from the widely dispersed island habitats in Southeast Asia. In many cynomolgus macaques, ovulation is "cryptic," with little external evidence of reproductive status (Engelhardt et al. 2005). In other individual animals, there is clear correlation of external sex skin swelling and erythema with ovarian features and hormonal profiles. In still other animals, there is persistent perineal swelling that is present continuously without reference to menstrual cycle or hormonal features. Thus measurement of sex skin features is not generally useful in assessing cycle stage, particularly in cynomolgus macaques.
Papillomas
Clitoromegaly
Immaturity The rapidly occurring, but highly variable, proliferative changes in the macaque mammary gland described elsewhere in this monograph are a source of much confusion in the interpretation of studies using young animals. The growing margin of the glandular tissue in young animals contains terminal end buds (solid epithelial structures approximately 200 microns in diameter, often surrounded by loose connective tissue) and immature ductal and lobuloalveolar units (small branching arrays of tubular structures). The terminal end buds in particular may resemble focal ductal hyperplasias or carcinoma in situ lesions. These normal structures may be distinguished from abnormal proliferative lesions by their location at the margin of the gland and by the lack of surrounding well-differentiated lobular structures (Wood, Hester, and Cline 2007).
Cystic Change
Focal Lobular Hyperplasia Focal hyperplasia of mammary lobules occurs commonly in macaques and consists of one or more rounded, enlarged, expansile lobules against a background of atrophic lobules (Cameron and Faulkin 1974; Warner 1979). These enlarged lobules may be numerous in individual animals (Figure 13B) and are also present in nonatrophic glands but are less conspicuous than in atrophic glands. We have also used the term focal lobular proliferation to name this lesion in order to avoid confusion with risk-associated lesions in women that have a different morphology (Cline 2007); however, we believe that the term focal lobular hyperplasia should be used, because it is the most clearly descriptive of the change. These lesions have elevated expression of proliferation markers relative to adjacent tissue but also have relatively normal lobular architecture and cellular phenotypes, including myoepithelial cells, and they continue to express sex steroid receptors. The behavior of these lesions is unknown, but in our experience, they do not progress to neoplasia. Focal lobular hyperplasia should also be distinguished from atypical lobular hyperplasia, which consists of irregularly enlarged acini with at least two layers of luminal epithelial cells and variable cystic dilation by secretory material. This latter lesion may represent a precursor to lobular carcinoma in situ, which includes both architectural and cytologic atypia.
Ductal Hyperplasia
Mammary Gland Cancers
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Toxicologic Pathology, Vol. 36, No. 7 Suppl,
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Abstract
Introduction
