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Morphologic and Immunohistochemical Features of the Cynomolgus Macaque CervixDepartment of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA Correspondence: Charles E. Wood, Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157–1040, USA; E-mail:chwood{at}wfubmc.edu.
Female macaques serve as an important model for the study of reproductive diseases in women. Here we summarize characteristics of the macaque cervix, with a particular emphasis on the cynomolgus macaque. Key anatomic features include a stratified squamous exocervix, squamocolumnar junction and transformation zone, and glandular endocervix with prominent colliculi. Endocervical eversion occurs with onset of ovarian cycling and regresses to varying degrees based on age, hormonal status, and individual conformation. The cervical epithelium in macaques is highly responsive to estrogens, which induce marked squamous epithelial maturation and glandular hypertrophy. Progestogen effects include further induction of endocervical secretory activity and release of viscous mucus, which functions in both mucosal immunity and fertility regulation. On immunohistochemistry, the squamous cervix shows strong expression of estrogen receptor  , the proliferation marker Ki67/MIB1, and cytokeratin 14, whereas endocervical epithelium strongly expresses estrogen and progesterone receptors and cytokeratins 18 and 19. These patterns of expression are altered in cervical intraepithelial neoplasia, which is a common spontaneous lesion of the macaque cervix associated with specific types of oncogenic papillomaviruses. This report highlights important similarities with human cervix that should be useful for future studies of genital infection, neoplasia, and immunity in the macaque model. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. The author did not declare any other competing interests.
Key Words: Cervix • histopathology • Macaca • cervical intraepithelial neoplasia • papillomavirus Abbreviations: CIN, cervical intraepithelial neoplasia • CIS, carcinoma in situ • CK, cytokeratin • DES, diethylstilbestrol • E2, estradiol • ER, estrogen receptor alpha • fr, free-ranging • HandE, hematoxylin and eosin • HPV, human papillomavirus • Mf, Macaca fascicularis • MfPV, cynomolgus papillomavirus • Mm, Macaca mulatta • PGR, progesterone receptor • PV, papillomavirus • RhPV, rhesus papillomavirus • SCC, squamous cell carcinoma • SCJ, squamocolumnar junction • T-zone, transformation zone • VIN, vaginal intraepithelial neoplasia
Macaques are a highly successful and diverse genus of Old World anthropoid monkeys with a natural range throughout southern and central Asia. Female macaques have a reproductive physiology highly similar to that of women, including a twenty-eight-day menstrual period and comparable sex steroid profile (Cline and Wood 2005–2006; Corner 1923; Corner 1952; Stute et al. 2004), and for this reason they have been widely used as models for the study of human reproductive biology. The two most common research species are the rhesus macaque (Macaca mulatta) and the smaller but closely related cynomolgus macaque (M. fascicularis) (also called long-tailed or crab-eating macaque). For decades these animals have served as important models for the study of reproductive physiology, sex hormone effects, genital immunity, and sexually transmitted diseases such as simian/human immunodeficiency virus (Cline et al. 2001; Corner 1952; Lackner and Veazey 2007; Lehner et al. 1992; Ramsey et al. 1960; West and Brenner 1985). To aid in future such studies, here we describe anatomic, histopathologic, and immunohistochemical features of the macaque cervix. For simplicity, this review will focus primarily on the cynomolgus macaque with references to pertinent differences among macaque species and comparisons with the human cervix.
The cervix is the proximal portion of the uterus extending from the uterine neck into the posterior vagina. Cynomolgus macaques have a relatively straight vaginal wall, whereas rhesus macaques generally have more infoldings or ridges. The cervix in the adult cynomolgus macaque is about 2.0 cm in length and about 1.5 to 2.0 cm in width, with a convex lower portion protruding about 0.5 to 1.0 cm into the vaginal canal (Figure 1). This latter region, called the exocervix, is divided into a large dorsal shelf and smaller ventral lip (Hertig and MacKey 1973). In the center of the exocervix is the external cervical os, which leads, via the endocervical canal, into the uterine isthmus, past the internal os, and into the uterine corpus. The endocervical canal of cynomolgus macaques follows a curved path lined with prominent glandular colliculi, which collectively form a series of blind pouches. Similar raised folds are present in the cervix of rhesus macaques but not stumptailed macaques (M. arctoides), which have a reasonably straight, and proportionally longer, endocervical canal (Demers et al. 1972). The curvilinear canal and endocervical colliculi in cynomolgus and rhesus macaques are clinically notable because they limit transcervical access to the uterine corpus.
The lower portion of the macaque cervix consists of stratified squamous epithelium overlying a stroma composed mainly of dense connective tissue and smooth muscle. In contrast to the vaginal mucosa, the cervical squamous epithelium lacks prominent rete pegs and often has less superficial keratin. The squamous mucosa is divided into three layers, the germinal basal/parabasal zone, the stratum spinosum of intermediate cells, and the superficial zone of mature keratinocytes. Moving posteriorly, the stratified squamous epithelium abruptly shifts to tall columnar glandular epithelium at a site known as the squamocolumnar junction (SCJ), which varies in location based on age, hormone status, and individual conformation (Figure 1). Prior to puberty, both squamous and glandular epithelial cells are atrophic, cervical shelves and colliculi are rudimentary, and the SCJ is indistinct (Figure 1A). Estrogen exposure following onset of ovarian follicular activity (about two to three years of age in rhesus and cynomolgus macaques) induces a marked increase in vaginal and cervical squamous maturation and keratinization and a moderate increase in endocervical gland hypertrophy. At this early pubertal state (i.e., prior to ovulation) the SCJ typically remains within the endocervical canal near the external os (Figure 1B). Once complete menstrual cycle activity has begun, the glandular cervix becomes more enlarged and typically everts past the external cervical os, shifting the original SCJ to the exocervix as far as the dorsal and ventral fornices (Figure 1C). This degree of eversion (also called ectopy) is more exaggerated than in the human cervix, in which the original SCJ normally does not cross the middle portion of the exocervix (Wright and Ferenczy 2002). During the premenopausal years, the "exposed" exocervical glandular epithelium becomes replaced to varying degrees by metaplastic squamous epithelium called the transformation zone (T-zone) (Figure 1D). By covering pre-existing mucus glands, which often become obstructed and distended by trapped mucus secretion, the endocervical margin of the T-zone effectively forms a second "functional" SCJ. With increasing age, the T-zone expands and glandular eversion lessens, bringing the T-zone (and functional SCJ) back toward the external cervical os (Figure 1E). The loss of ovarian hormones following natural or surgical menopause results in squamous epithelial atrophy, an overall decrease in cervix size, and further regression of the glandular cervix, in some cases drawing the T-zone (and functional SCJ) back into the endocervical canal (Figure 1F). Histologically, the T-zone is composed of an attenuated layer of squamous epithelium lacking superficial maturation and the abundant intracytoplasmic glycogen seen in normal maturing keratinocytes of the spinosum (Figure 2A). Squamous metaplasia of the T-zone is thought to occur in response to a combination of factors, including the lower pH of the vagina, hormonal exposure, local infection and inflammation, and microtrauma (Wright and Ferenczy 2002). In addition to the T-zone, squamous metaplasia is also commonly seen in the basal portion of endocervical glands in actively cycling and estrogen-treated macaques (Figures 2B and 2C), strongly suggesting that estrogen is a key factor in this process. In macaques and women, the metaplastic cells of the T-zone are also the primary target for infection with high-risk oncogenic genital papillomaviruses (PVs) and cervical neoplasia, as discussed below (Wood et al. 2004; Wright et al. 2002). Although not well studied, the dynamic effects of age and ovarian hormones on the morphology of the T-zone and associated glandular epithelial cells likely have an important influence on susceptibility to PVs and other infectious diseases.
The macaque endocervical mucosa is composed of simple columnar epithelial cells, which line the main canal and colliculi and form infolded subsurface glandular structures. In cycling animals columnar cells have oval basal nuclei and clear to pale eosinophilic vacuolated cytoplasm. These glandular epithelial cells overlie reserve cells, which may become crowded and prominent in certain types of glandular hyperplasia. In one histologic study of the endocervix of the cynomolgus macaque, glandular crypts were composed of 23.9% ciliated cells, 76.0% secretory cells, and 0.1% secretory/ciliated cells (David et al. 1975). The primary roles of secretory and ciliated columnar cells are to secrete and distribute mucus, respectively. Secretory activity peaks in the luteal phase, when the apical cytoplasm expands and cells may reach about 50 µm in height (David et al. 1975). Compared to endometrial glands, cervical gland epithelial cells are generally taller, with increased vacuolation and a more defined basement membrane (David et al. 1975).
The cervicovaginal mucosa is a key site of infection for many important pathogens. Mucosal immune function in the vagina and cervix has an important role in the establishment and persistence of these infections. The mucosal immune system in the macaque and human cervix is composed of humoral (IgG), secretory (IgA), and cellular elements and includes CD8+ cytotoxic T lymphocytes, CD4+ helper T lymphocytes, plasma cells, B lymphocytes, and dendritic cells, all of which reside mainly in the lamina propria (Lehner et al. 1992; Lehner et al. 1995; Ma et al. 2001; Wright and Ferenczy 2002). This genital-associated lymphoid tissue ("GenALT") is often apparent on histology as scattered aggregates of submucosal lymphocytes and plasma cells, occasionally organized into lymphoid follicles, and should not be identified as chronic cervicitis unless large numbers of less organized inflammatory cells are present. In recent years a large body of evidence has emerged related to simian immunodeficiency virus (SIV) in rhesus macaques, and this work has led to numerous important insights related to mucosal immune function in the cervix and vagina, mechanisms of viral infection and transmission, and novel interventions for preventing and treating lentiviral infections (Lackner and Veazey 2007; Miller and Lu 2003).
The primate cervix is profoundly influenced by sex hormone exposure. As described above, ovarian hormones induce marked keratinization of squamous epithelial cells in the vagina and adjacent regions of exocervix. These cells are particularly sensitive to estrogen and respond to very low levels of exposure with basal/parabasal cell proliferation, maturation, and desquamation (Graham 1970; Hisaw and Lendrum 1936; Parakkal and Gregoire 1972; Wood et al. 2004). In macaques, the exocervical squamous epithelium approaching the SCJ increases in thickness in response to estrogen but typically does not become keratinized. A characteristic cytologic or ultrastructural feature of this maturation is the accumulation of intracytoplasmic glycogen in cells of the spinosum (King 1983). Superficial keratinization of the macaque vagina is more pronounced than in women and includes formation of verrucous keratin ridges, which may falsely resemble papillomatous or polypoid lesions (Figure 3A). As noted above, estrogens also induce squamous metaplasia of endocervical glands (Graham 1970), which should not be confused with intraepithelial neoplasia. Loss of estrogenic stimulation at menopause leads to diffuse atrophy of squamous epithelium in macaques and women, and this change is rapidly reversed by administration of exogenous estrogens (Figure 3B). Prior studies of the human cervix have reported that progestogens may attenuate this estrogen-induced maturation of the more superficial squamous epithelial layers (Wright and Ferenczy 2002).
Estrogens and progestogens induce marked hypertrophy and mucus secretion of the endocervical glands (Figure 3C–3D). In macaques this effect is seen in early puberty with onset of ovarian hormone production (Figure 1A–1C) and with administration of exogenous estrogen-progestogen combinations to ovariectomized animals, which dramatically increases secretion of viscous mucus (Valerio 1989). Estradiol generally induces a more profuse, watery, and alkaline mucus that facilitates passage of sperm, whereas progesterone induces more viscous and acidic mucus inhibitory to sperm (Iacobelli et al. 1971; Nasir-ud-Din et al. 1979; Nasir-ud-Din et al. 2003). An important model for the study of cervical mucus is the bonnet macaque (M. radiata), which has a complex tortuous endocervix and exaggerated mucus production in response to ovarian hormones (McArthur et al. 1972). Early observations of cervical mucus changes in response to hormones (Parkes and Zuckerman 1931), and subsequent studies of mucus biochemistry and glycoprotein/sperm interactions (Nasir-ud-Din et al. 1979; Nasir-ud-Din et al. 1982; Nasir-ud-Din et al. 2003; Ovadia et al. 1971; Sheth et al. 1975), were conducted in this species. Ovarian hormones may also affect mucosal immune function of the cervix. Studies in rhesus macaques have shown alterations in cervicovaginal CD8+ T cell activity and immunoglobulin secretion at different stages of the menstrual cycle (Lu et al. 1999; Lu et al. 2002; Yang and Schumacher 1979). Similar to women, cervical mucus IgG and IgA concentrations were found to be highest during menstruation and lowest in the periovulatory period (Lu et al. 1999; Yang and Schumacher 1979), suggesting immunization response or infection susceptibility may vary based on hormonal status. However, a separate study found no change in the actual number or distribution of mucosal immune cells across the rhesus macaque menstrual cycle (Ma et al. 2001).
The cervix expresses a variety of marker proteins related to sex steroid response, proliferation, epithelial differentiation, and growth factor signaling. In the macaque cervix, immunolabeling for estrogen receptor alpha (ER) is present in the nuclei of basal, parabasal, and intermediate squamous epithelial cells (Figure 4A) in addition to glandular endocervical cells. This pattern of expression is similar to that reported in the human cervix (Wright and Ferenczy 2002). A previous study found that progesterone may downregulate ER in the cynomolgus macaque cervix, consistent with the antiestrogenic effects of progestogens in the endometrium (West and Brenner 1985). Progesterone receptor (PGR) is less abundant in squamous epithelium and present only sporadically in basal/parabasal cells but strongly present throughout the glandular epithelium (Figure 4B), similar to the human cervix (Flickinger et al. 1977; Ma et al. 2001). Labeling for the proliferation marker Ki67/MIB1 (expressed only in nonquiescent cells) in squamous epithelium is generally restricted to the basal and parabasal cells (Figure 4C) (Wood et al. 2007), suggesting that this layer is the primary zone of cell division.
Expression of different cytokeratins (CKs), which are useful markers for different lineages of epithelial differentiation, varies based on epithelial compartment. In the macaque cervix, CK 14 is found diffusely within the cytoplasm of all squamous cells of the vagina and cervix (Figure 4D), including strong expression in metaplastic squamous epithelium, but absent in glandular endocervical cells. CK 18 exhibits a complementary pattern, with strong cytoplasmic expression in glandular cells but not in squamous epithelial cells. CK 19 labeling shows a mixed labeling pattern, with sporadic cytoplasmic staining in normal basal/parabasal and metaplastic squamous epithelium and diffuse moderate staining within glandular endocervical cells (Figure 4E). In the human cervix, expression of growth factor receptors such as Her2/neu and epidermal growth factor receptor is variably expressed in basal and parabasal cells, whereas the cell survival protein bcl-2 is found only in basal cells (Berchuck et al. 1990; Saegusa et al. 1995).
Neoplasia of the macaque cervix was first described in 1958 in a detailed case report of a metastatic cervical squamous cell carcinoma in an aged rhesus monkey (Hisaw and Hisaw 1958). Three years later a separate report documented a carcinoma in situ of the cervix, also in a rhesus macaque (Sternberg 1961). Since then a number of survey studies of cynomolgus and rhesus macaques have confirmed that cervicovaginal dysplasia, also called cervical/vaginal intraepithelial neoplasia (CIN/VIN), is a common lesion of the macaque genital mucosa, with a reported prevalence ranging from 5% to 19% (Table 1) (DiGiacomo 1977; DiGiacomo and McCann 1970; Hertig et al. 1983; Ostrow et al. 1990; Wood et al. 2004; Wood et al. 2007). Among these surveys, the two studies reporting 19% prevalence both used cytologic (Pap) sampling in addition to histology, which may have provided greater screening sensitivity.
The morphologic hallmarks of human and macaque CIN lesions are nuclear atypia and expansion of the basal epithelium (Figures 5A–5D) (Hertig et al. 1983; Wood et al. 2004; Wood et al. 2007; Wright et al. 2002). This latter change can often be seen subgrossly as increased thickening and invagination of the squamous mucosa, often at the SCJ or T-zone (Sternberg 1961). Human cervical lesions are commonly classified as CIN1, CIN2, or CIN3 for mild, moderate, and severe dysplasia, respectively (Wright et al. 2002), and similar terminology has been adapted to macaque lesions (Wood et al. 2004). Early or low-grade CIN1 lesions often exhibit acanthosis, with large atypical nuclei and perinuclear clearing (called koilocytosis) but limited expansion of the basal epithelium, which is normally one or two cell layers in thickness (Figures 5A and 5B). In CIN2 lesions, basal-type cell layers occupy one third to two thirds of the total epithelial thickness (Figure 5C), whereas CIN3 (carcinoma in situ) lesions are composed almost entirely of basal-type cells with hyperchromatic nuclei and scant cytoplasm (Figure 5D). A subset of CIN3 lesions may progress to invasive squamous cell carcinomas, which can assume keratinizing and nonkeratinizing forms (Figures 5E–5G) (Wood et al. 2004). Intraepithelial neoplasia should be distinguished from mucosal papillomas (condyloma acuminata), which, in contrast to CIN lesions, have an exophytic warty architecture (Cooper and Gabrielson 2007; Wood et al. 2004) and are not considered to be precancerous.
On immunohistochemistry, CIN lesions generally show strong positive nuclear labeling for ER and moderate PGR labeling primarily in basal-type cells (Figures 6A and 6B). In contrast to normal epithelium, Ki67/MIB1 staining is present throughout all epithelial layers (Figure 6C). Macaque CIN lesions also show distinct upregulation of the tumor suppressor protein p16INK4a (Figure 6D), which may be useful in confirming equivocal histologic changes since it is absent in normal squamous mucosa (Wood et al. 2007). Cytoplasmic expression of CK 14 is diffusely present in CIN lesions (Figure 6E), whereas CK 18 is absent and CK 19 is restricted to basal-type cells.
Almost all cases of cervical dysplasia and cancer in women are caused by specific oncogenic types of human papillomavirus (HPV), which are among the most common sexually transmitted agents worldwide. Similarly, macaques carry their own complement of genital papillomaviruses (PVs) (Chan et al. 1997; Wood et al. 2007), which are also highly associated with cervical neoplasia (Ostrow et al. 1990; Wood et al. 2004; Wood et al. 2007). In the original report documenting this association, PV DNA was identified in a metastasis of a primary penile carcinoma in a male rhesus monkey (Ostrow et al. 1990). Later survey of thirty-two female macaques, some of which had known mating contact with the infected male, revealed DNA from this papillomavirus (named RhPV-1) from cervical samples in nineteen of the females and dysplastic or invasive cervical intraepithelial lesions in six of the females (Ostrow et al. 1990). In a more recent study of cynomolgus macaques, cervicovaginal PV infections were found in nineteen of fifty-four older female cynomolgus monkeys with no breeding contact for at least three years (Wood et al. 2007) (Table 2). The four PV types associated with CIN in this study were RhPV-d, RhPV-a, MfPV-a, and one novel MfPV. The most common virus type identified was RhPV-d, which was sequenced from a high-grade CIN lesion and found to be related to the highly oncogenic HPV 16. In this latter report, RhPV-d was also shown to be transmissible and oncogenic based on abnormal cytology and histology in one of four experimentally infected animals after eighteen weeks of infection (Wood et al. 2007).
A variety of spontaneous inflammatory lesions have been described in the macaque cervix and vagina. One of the earlier surveys, conducted in sixty-three female rhesus macaques, reported subacute vaginitis (15/63), subacute to chronic cervicitis (9/63), generalized chronic cervicitis (2/63), and endocervical polyps (2/63) (DiGiacomo and McCann 1970). A subsequent survey in thirty-eight laboratory (lab) and seventeen free-ranging (fr) female cynomolgous macaques reported vaginitis (23/38 lab, 14/17 fr); cervicitis (13/38 lab, 8/18 fr); vaginal adenosis (0/38 lab, 1/17 fr); and one endocervical polyp (1/38 lab, 0/17 fr) (DiGiacomo 1977). On histology, macaque vaginitis/cervicitis may be acute or chronic, typically consisting of lymphocytes, plasma cells, and scattered neutrophils (Cooper and Gabrielson 2007). The most common site for chronic cervicitis is around the SCJ (Figure 7A).
Other common incidental findings include lymphoid follicular hyperplasia of the vaginal and/or cervical submucosa (Figure 7B), mucus-filled cysts (also known as nabothian cysts) often at the original SCJ as the result of endocervical gland obstruction by metaplastic squamous cells (Figure 7C), squamous metaplasia of endocervical glands (Figure 7D), bacteria colonies and associated neutrophils (often within intraluminal mucus), and hyperkeratosis. Two incidental changes of the endocervical epithelium not to be confused with dysplasia are reserve cell hyperplasia and tubal metaplasia. Reserve cell hyperplasia is defined by increased numbers of cells lining the basement membrane of the glandular mucosa (Figure 7E). In the human cervix, this feature is used to help distinguish incidental "microglandular hyperplasia" from endocervical adenocarcinoma in situ. In tubal metaplasia, normal glandular cells become crowded and pseudostratified with prominent cilia (Figure 7F). Less common incidental lesions of the macaque cervix include endometriosis along the serosal surface of the cervix, mucosal papillomas, endocervical polyps, intravaginal foreign bodies (e.g., trichobezoars), and decidual change of the endocervical stroma associated with prior pregnancy or progestogen exposure. Though identified only sporadically, potential infectious diseases of the macaque genital tract (other than PVs) include measles, cercopithecine herpesvirus 1 (herpes B), Candida spp., chlamydias, mycoplasmas, ureaplasmas, and trichomonads, among others (Kebu et al. 2006; Renne et al. 1973; Schoeb et al. 1997).
A limited number of toxicologic lesions have been reported for the macaque cervix. In early studies investigating potential environmental causes of cervical cancer, topical administration of the polycyclic aromatic hydrocarbon methylcholanthrene was shown to induce cervical dysplasia in rhesus macaques (Kaminetzky 1971; Kaminetzky and Swerdlow 1968). Later toxicologic studies evaluated the effects of prenatal exposure to the synthetic estrogen diethylstilbestrol (DES), showing increased incidence of vaginal adenosis, cervical hooding, and squamous metaplasia, but not adenocarcinoma (Hendrickx et al. 1979; Hendrickx et al. 1987–1988). In the human cervix retinoids have been studied as potential therapies for cervical neoplasia (Meyskens et al. 1994; Ruffin et al. 2004). Retinoids act through nuclear receptors and retinoic acid/retinol binding proteins found in the cervical squamous mucosa to induce differentiation of cervical and various other squamous epithelial tissues (Hillemanns et al. 1992).
The author thanks Hermina Borgerink, Jean Gardin, and Lisa O’Donnell for technical assistance with histology and immunohistochemistry for this article.
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Toxicologic Pathology, Vol. 36, No. 7 Suppl,
119S-129S (2008)
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Abstract
Introduction
