Benign Diseases of the Cervix
This chapter begins with a brief review of the gross anatomy of the cervix including its blood supply and lymphatic drainage. It then discusses the normal histology and physiology of the cervix including a description of the immunohistochemical staining patterns of the different cell types. The size and configuration of the cervix, as well as the localization of specific types of epithelial cells on the mucosal surface and their degree of differentiation, change during a woman’s lifetime. These changes play a fundamental role in the development of several pathological conditions including cervical cancer. An important anatomical landmark is the squamocolumnar junction. This is the dividing line between the native squamous epithelium of the outer portion of the cervix and the mucus secreting columnar epithelium of the endocervical canal. The location of the squamocolumnar junction migrates during a woman’s lifetime. The squamocolumnar junction is important because it contains specialized epithelial cells that appear to be the cell of origin of invasive squamous cell carcinomas. The majority cervical precancers involve this region. Benign changes that occur in the cervical epithelium include metaplastic changes including tubal metaplasia and transitional cell metaplasia, responses to high levels of hormones resulting in the Arias-Stella reaction and pseudodecidual reactions, inflammatory conditions and infections, as well as pseudoneoplastic glandular conditions. Pseudoneoplastic glandular lesions such as florid mesonephric hyperplasia and lobular endocervical glandular hyperplasia are particularly challenging since they are relatively uncommon and can be mistaken for endocervical adenocarcinoma. The chapter concludes with a description of a number of benign tumors, cysts, and tumor-like conditions that the practicing surgical pathologist can encounter.
Histology and Physiology
The cervix is composed of an admixture of fibrous, muscular, and elastic tissue and is lined by columnar and squamous epithelium. Fibrous connective tissue is the predominant component. Smooth muscle comprises 15% of the substance and is located mainly in the endocervix, the portio vaginalis being nearly devoid of smooth muscle fibers. In contrast, at the isthmus, 50–60% of the supportive tissue consists of concentrically arranged smooth muscle which acts as a sphincter.
Immunohistochemical staining patterns of normal cervical tissues
Cells of Stratified Squamous Epithelium
Reserve Cells/Squamous Metaplasia
Endocervical Columnar cells
Her 2/neu (Raju 1994)
EGF receptor (Raju 1994)
Cell cycle proteins
Cyclin B1 (Novotny et al. 1992)
Cyclin D1 (Cho et al. 1997)
CD44 (Zhang et al. 2007)
The midzone is occupied by cells that are undergoing maturation, characterized by a gradual increase in the volume of the cytoplasm. Nuclear size, however, remains stable up to the most superficial cell level. These cells are referred to as intermediate cells. They do not divide. Intermediate cells have abundant periodic-acid Schiff (PAS)-positive, diatase-labile intracellular glycogen, which is responsible for the clear, vacuolated appearance of their cytoplasm.
The squamous epithelium of the portio is supported by fibrous connective tissue, devoid of endocervical glands. It has occasional finger-like extensions into the epithelium, the stromal papillae (Fig. 3). The penetrating vessels within the papillae supply the epithelial cells with nutrients and oxygen. Occasional free nerve endings are seen entering the stromal papilla.
Effect of Estrogen and Progesterone
The epithelium of the exocervix is remodeled by proliferation, maturation, and desquamation during the reproductive period. The epithelium is completely replaced by a new population of cells every 4–5 days; the process of squamous epithelial maturation can be accelerated to 3 days by the administration of estrogenic compounds (Koss 1992). Estrogen receptors have been localized to nuclei in the basal, parabasal, and intermediate cell layers (Kanai et al. 1998; Konishi et al. 1991). Compared to the endometrium, in the cervix only a small increase of estrogen receptor levels occurs during the follicular phase as compared to the luteal phase. In atrophic and highly inflamed exocervical epithelium, the amount of estrogen receptor is reduced. No, or only low levels, of progesterone receptors are detected immunohistochemically in the exocervical epithelium during the follicular phase of the menstrual cycle, whereas during the luteal phase and during pregnancy, progesterone receptors appear in the parabasal cell layer (Konishi et al. 1991; Nikolaou et al. 2014). Both estrogen and progesterone receptors can be detected in stromal fibroblasts of the exocervix throughout the menstrual cycle.
In general, estradiol-17ß stimulates epithelial proliferation, maturation, and desquamation, whereas progesterone inhibits maturation at the upper midzone level of the epithelium. Accordingly, the portio epithelium during the postnatal period is fully mature and contains large amounts of glycogen as a result of maternal estrogen stimulation. Maturation ceases and glycogen rapidly disappears as the serum hormone levels fall. The epithelium remains atrophic during childhood until menarche when, under the stimulatory effect of ovarian hormones, maturation occurs again and glycogen reappears. During pregnancy, when progesterone levels are elevated, superficial cell maturation is absent.
Mitoses in the normal columnar epithelium are very rarely observed. It is not known whether regeneration occurs from the underlying subcolumnar reserve cells, which under normal circumstances are seldom seen even at the ultrastructural level, or from the persisting mature endocervical cells (Gould et al. 1979). Unlike the attenuated vascular stromal papillae of the original squamous portio epithelium, the subepithelial capillary network in the endocervical mucosa is well developed.
The stroma of the endocervix is comparatively better innervated than that of the exocervix. Fibers run parallel to muscle bundles, but sensory free endings have not been clearly demonstrated. True lymphoid follicles, with or without germinal centers, are encountered in the subepithelial stroma of both the exocervix and the endocervix.
Effects of Estrogen and Progesterone
The cervical mucus is subject to profound cyclic changes. Under estrogenic stimulation, the endocervical secretions are profuse, watery, and alkaline, facilitating sperm penetration. During the postovulatory phase, secretions are scant, thick, and acid, containing numerous leukocytes, and act as a barrier to sperm penetration. Endocervical secretory activity operates by both the apocrine and the merocrine type of expulsion of secretory products (Ferenczy and Richard 1974). In the former, a portion of apical cytoplasm packed with secretory granules is detached, whereas in the latter, secretory products are released from apical granules through pore-like openings of the surface cytoplasmic membrane.
Langerhans Cells and Lymphoid-Derived Cells
Mucosal immunity is an important component of the host’s defense mechanism against viral and bacterial pathogens. Components of the secretory (IgA antibody-mediated), humoral (IgG antibody-mediated), as well as the cellular immune systems are present in the cervix. A variety of lymphocyte and dendritic macrophage subsets are present in both the epithelium of the exo- and endocervix as well as the subepithelial stroma (Manickam et al. 2007). Dendritic cells include both mature and immature forms. They are primarily responsible for antigen recognition and the earliest stage of cellular immune response.
The Transformation Zone
Over time, the columnar epithelium that composes the cervical ectopy is remodeled and replaced by metaplastic squamous epithelium. As this occurs, the histological squamocolumnar junction moves toward the exocervical os. This newly formed squamocolumnar junction is called the physiologic, functional, or new squamocolumnar junction. While the original squamocolumnar junction is usually quite abrupt, the junction between the columnar and squamous epithelium at the physiologic or functional squamocolumnar junction can be either abrupt or gradual (Fig. 12). The region between the original squamocolumnar junction and the post-pubertal functional squamocolumnar junction is termed the transformation zone. The transformation zone is histologically characterized by the presence of metaplastic epithelium (see section “Squamous Metaplasia”).
The concept of the transformation zone is extremely important for understanding the pathogenesis of squamous cell carcinomas of the cervix and its precursors, since virtually all cervical squamous neoplasia begins at the new squamocolumnar junction and because the extension and limits of cervical cancer precursors coincide with the distribution of the transformation zone. It is also important to remember that during the childbearing years and during pregnancy the transformation zone is located, in almost all instances, on the exposed portion of the cervix. Consequently, the vast majority of cervical neoplasias can be sampled for histologic diagnosis by punch biopsy. Movement of the functional squamocolumnar junction continues throughout the reproductive years. Therefore, in older and postmenopausal women, the functional squamocolumnar junction is nearly always located within the external os (Fig. 12).
Cervical high-grade squamous intraepithelial lesions (HSIL) that are high-risk human papillomavirus (HPV) positive and invasive cervical cancers have been shown to have the SC junctional cell immunophenotype, whereas ectocervical low-grade squamous intraepithelial lesions (LSIL) and vulvar and vaginal SILs of both grades do not (Herfs et al. 2012). Therefore, it is thought that the SC junctional cells are the target cells for high-risk HPV infections that can progress to cervical HSIL or invasive cervical cancer.
Pregnancy and Puerperium
The morphologic alterations that occur in the antepartum or postpartum cervix are not pathognomonic of pregnancy or parturition but are seen more commonly at these times than in the nonpregnant postpartum state. They are related to the stimulatory effects of elevated steroid hormones. The spongy enlargement of the pregnant cervix is caused by increased vascularity and edema of the stroma accompanied by acute inflammation. The massive destruction of collagen fibers and accumulation of extracellular glycoprotein ground substance before labor result in cervical softening and effacement, facilitating dilation of the cervix to about 10 cm during labor. Gestational cervical mucus is thick, tenacious, rich in leukocytes, and forms a mucous plug that obliterates the cervical canal, sealing the endometrial cavity from the vagina and thus preventing bacterial invasion. Squamous metaplasia and lobules of tightly-packed, small endocervical glandular units forming polypoid protrusions into the canal are often seen.
The Arias-Stella reaction can occasionally be mistaken for clear cell carcinoma or adenocarcinoma in situ of the cervix. Differentiation from clear cell carcinoma is made by the lack of a mass lesion and clear cut stromal invasion as well as by the absence of the classic tubular and papillary areas typical of clear cell carcinoma. The cells in adenocarcinoma in situ have more uniform nuclei and less cytoplasmic vacuolization. The Arias-Stella reaction lacks mitotic activity whereas both clear cell carcinoma and adenocarcinoma in situ are mitotically active. Because of the possibility of confusing Arias-Stella reaction with clear cell carcinoma or adenocarcinoma in situ, the diagnosis of the later two entities should be made with caution in the pregnant patient.
Tubal metaplasia can be quite extensive and can occasionally be mistaken for endocervical glandular neoplasia. However, the bland cytological features, lack of mitotic activity, and prominent cilia seen at the apical surfaces of tubal metaplasia usually allow it to be differentiated from a neoplastic lesion. Other features that can aid in distinguishing between tubal metaplasia and glandular neoplasia are the location and shape of the glands and the surrounding stroma. Glands demonstrating tubal metaplasia are typically confined to the superficial third of the cervical wall (i.e., they extend less than 7 mm into the cervical stroma) and typically show only slight variation in size and shape. Moreover, the stroma surrounding glands involved by tubal metaplasia is usually normal appearing and is neither desmoplastic nor edematous appearing. Cases of tubal metaplasia demonstrating glandular architectural abnormalities or hypercellularity of the adjacent stroma can present diagnostic difficulties (Oliva et al. 1995).
Transitional Cell Metaplasia
The controversy surrounding transitional cell metaplasia revolves around whether it represents a unique histopathological entity that has a specific biology or whether it simply represents a biologically insignificant histological variation of other well described histological entities. Almost all of the reported examples of transitional cell metaplasia have been identified in postmenopausal women. In the two largest series, the mean ages of women with the lesion were 60 and 67.8 years (Egan and Russell 1997; Weir et al. 1997). Some of these women have had previous abnormal Papanicolaou smears, and it has been suggested that some of the cases may represent atrophic high-grade SIL (Koss 1998). In addition to arising in the transformation zone, transitional cell metaplasia can also be identified in the exocervix and the vagina (Weir et al. 1997). This suggests that in some cases, transitional cell metaplasia may simply represent a histological variant of atrophy, either of the original squamous epithelium or of a fully mature metaplastic squamous epithelium, in which the number of cell layers is not reduced. Immunohistochemical studies using cytokeratin antibodies have shown that foci of transitional cell metaplasia express cytokeratins 13, 17, and 18, which are expressed in normal urothelium, but do not express cytokeratin 20 and the asymmetric unit membrane that are related to urothelial differentiation (Harnden et al. 1999). Lack of diffuse p16 positivity helps to differentiate transitional cell metaplasia from HSIL.
Cervicitis can be divided into two categories, based on whether the etiology of the disorder is noninfectious or infectious. Whatever the etiology, the tissue response of the cervix to injury is limited and reflects the basic mechanisms of inflammation and repair. Two types of morphologic changes, however, that are often encountered in association with a variety of inflammatory diseases deserve specific attention. These are atypia of repair and hyperkeratosis and parakeratosis.
Atypia of Repair
Treatment of the cervix with therapeutic levels of radiation can cause morphological changes in both the squamous and glandular epithelium. The atypical squamous cells that develop post radiation have nuclear enlargement and can be multinucleated. The cells can have abundant amounts of vacuolated cytoplasm and are usually detected in cervical cytological preparations. Radiation-induced changes in the endocervical glandular epithelium include cellular enlargement, a loss of polarity of nuclei, and dense eosinophilic, enlarged nucleoli that can be multiple (Mohan et al. 1999). The stroma in women who have received therapeutic radiation is frequently fibrotic, often with hyalinization. Blood vessels often have intimal hyaline thickening and can be totally occluded. Atypical fibroblasts that are sometimes referred to as “radiation fibroblasts” are usually not present (Lesack et al. 1996). These morphological changes can exist for many years after radiation therapy.
Hyperkeratosis and Parakeratosis
Hyperkeratosis and parakeratosis can be detected cytologically in up to 8% of all women undergoing routine Pap smear screening (Johnson et al. 1991). Both hyperkeratosis and parakeratosis have the gross appearance of a thickened, white epithelium and can be either focal or diffuse. When diffuse, the entire portio is covered by a thickened, white, and wrinkled epithelial membrane. When focal, a slightly raised white plaque is present. The etiology of cervical hyperkeratosis is poorly understood, but in some cases, it appears to be related to chronic irritation. For example, most patients with diffuse hyperkeratosis have prolapsed uteri. Focal areas of hyperkeratosis can be associated with a local chronic irritation, such as seen in women who wear a diaphragm or pessary, and in women with cervical neoplasia. However, in most cases, there is no known cause.
Although there is neither morphological nor clinical evidence that hyperkeratosis and parakeratosis represent precursor lesions to cervical neoplasia, both of these can occur in association with HSIL and invasive cervical cancer. Because of this association, some experts have suggested that all women with otherwise negative Pap smears but demonstrating these findings need colposcopy. However, several studies have reported that less than 4% of women with hyperkeratosis or parakeratosis without nuclear atypia on an otherwise negative Pap smear had HSIL and that in all instances with a squamous intraepithelial lesion it was low-grade. This suggests that routine colposcopic evaluation is unnecessary in such women (Johnson et al. 1991). It should be emphasized, however, that since hyperkeratosis may occasionally overlie HSIL and invasive carcinomas, all grossly visible white plaques on the portio vaginalis or vaginal epithelium should be biopsied.
Noninfectious cervicitis is, for the most part, chemical or mechanical in nature, and the inflammatory response is nonspecific. Common causes include chemical irritation secondary to douching or local trauma produced by foreign bodies, including tampons, diaphragms, pessaries, and intrauterine contraceptive devices. Surgical instrumentation and therapeutic intervention are common iatrogenic causes of cervical tissue injury and inflammation. Stromal edema, vascular congestion, and neutrophilic infiltration of the stroma and epithelium characterize acute cervicitis. Clinically, the cervix appears swollen, erythematous, and friable, and there may be an associated purulent endocervical discharge. Prolonged or severe acute inflammation eventually leads to degenerative changes in the epithelial surface, loss of endocervical secretory activity, and ulceration.
Microorganisms causing infectious cervicitis
Bacteria, chlamydia, mycobacteria, Polymicrobial, endogenous vaginal aerobes, and anaerobes
Group B Streptococcus
Herpes simplex virus
Protozoa and parasites
Infectious cervicitis can affect either the endocervical-type columnar epithelium producing endocervicitis (mucopurulent cervicitis) or affect the stratified squamous epithelium of the exocervix producing exocervicitis (Holmes and Stamm 1999). The infectious agents that cause endo- and exocervicitis tend to differ, although some agents can cause both.
Bacterial and Chlamydial Cervicitis
Bacterial and chlamydial infections of the cervix are the most common cause of infectious cervicitis and are associated with a nonspecific inflammatory response. The columnar epithelium of the endocervix is much more susceptible to bacterial and chlamydial infections than is the surrounding squamous epithelium, and endocervicitis is characteristic. The infectious agents that most commonly cause clinically significant endocervicitis are Chlamydia trachomatis and Neisseria gonorrhoea. Infection with either of these two agents requires no predisposing factors and is primarily dependent on exposure and size of the inoculum.
Histologically, follicular cervicitis is frequently found in patients with chlamydia trachomatis infection and chlamydia trachomatis is now presumed to be a major cause of this condition in younger women. Chlamydia trachomatis cervicitis has also been associated with a dense, diffuse inflammatory exudate as well as reactive squamous and endocervical atypia (Crum et al. 1984).
Actinomyces israelii is a frequent commensual organism found in the female lower genital tract. Culture and immunofluorescence studies of cervical and vaginal secretions indicate that 3–27% of asymptomatic women without obvious risk factors are infected with actinomyces israelii (Lippes 1999). Aggregates of bacteria with the morphological appearance of actinomyces have been reported to occur in approximately 0.13% of all Papanicolaou smears (Petitti et al. 1983). The organism is more commonly identified in women wearing intrauterine devices (IUDs) than in women in the general population, and detection is related to the length of time that the IUD has been in place (Lippes 1999; Petitti et al. 1983; Curtis and Pine 1981). Structures resembling the “sulfur granules” observed in Actinomyces israelii infections are sometimes identified in endocervical curettings of asymptomatic women. In the majority of cases, these are “pseudoactinomycotic radiate granules” which are nonspecific collections of bacteria or foreign material (e.g., fragments from nylon strings of IUD), glycoproteins, and lipids rather than actual collections of Actinomyces israelii (Bhagavan et al. 1982). The pseudoactinomycotic radiate granules can be distinguished histologically from actinomycotic granules. On H&E stained sections, the actinomycotic granules appear as distinct granules with basophilic peripheral radiating filaments and a dense central esoinophil core. In contrast, on H&E, the pseudoactinomycotic radiate granules have refractile granules with irregular club-like peripheral projections and no central dense core. The filaments of actinomycotic granules are Gram positive and stain with Gomori methenamine silver stain (GMS). In contrast, the pseudoactinomycotic radiate granules show negative or nonspecific staining with Gram and GMS (Pritt et al. 2006). However, cases that include both pseudoactinomycotic radiate granules as well as true actinomycotic granules have been reported (Boyle and McCluggage 2009).
The identification of Actinomyces israelii in asymptomatic women has little clinical significance and does not warrant antibiotic therapy (Lippes 1999). Rarely, Actinomyces israelii can be associated with pelvic abscesses.
Tuberculosis of the cervix is almost invariably secondary to tuberculous salpingitis and endometritis and is typically associated with pulmonary tuberculosis (see chapters “Benign Diseases of Endometrium” and “Diseases of Fallopian Tube”). The prevalence of cervical tuberculosis is difficult to know since it is usually incidentally diagnosed in women undergoing infertility workup. In women, genital tuberculosis represents about 5–10% of nonpulmonary cases and most of these involve either the endometrium or fallopian tubes (Pintos-Pascual et al. 2017). Cervical involvement only occurs in about 5–15% of cases of genital tuberculosis which means it is diagnosed in only 0.1–0.65% of women with tuberculosis (Sharma 2015). Macroscopically, the cervix may appear normal and inflamed or simulates invasive carcinoma (Pintos-Pascual et al. 2017). Histologically, tuberculous infection of the cervix is recognized by the presence of multiple granulomas or tubercles characterized by central caseous necrosis, epithelioid histiocytes, and multinucleated Langhans giant cells. Granulomas typically disappear after successful antitubercular therapy (Agarwal and Gupta 1993). Tuberculous cervicitis may appear as a noncaseating, granulomatous lesion. Since caseating, nontuberculous granulomas due to lymphogranuloma venereum or sarcoidosis may be encountered in the cervix, the unequivocal diagnosis of tuberculous cervicitis requires demonstration of acid-fast Mycobacterium tuberculosis, a straight, rod-shaped bacillus, by Ziehl-Neelsen-stained sections, or by culture (Evans et al. 1984). Because culture yields far better results than staining of tissue sections, unfixed biopsy material should be obtained for microbiologic testing whenever tuberculosis is suspected. The most common granulomatous lesions to be distinguished from tuberculous cervicitis include foreign body giant cell granulomas secondary to sutures, crystals, or cotton, lymphogranuloma venereum, schistosomiasis, and sarcoidosis. Cervical granuloma may occasionally develop after a biopsy or operation as a reaction to local tissue necrosis (Evans et al. 1984).
Other Granulomatous Infections
Certain venereally-transmitted diseases commonly encountered in the vulva may also involve the cervix (see chapter “Diseases of the Vulva”). These include syphilis, either as the primary chancre, secondary mucous patches, or tertiary gumma, lymphogranuloma venereum, granuloma inguinale, and chancroid. All these conditions may resemble carcinoma clinically. This is particularly a problem with granuloma inguinale that is endemic in areas of Africa that have high prevalence of invasive cervical cancer. Up to 50% of women with granuloma inguinale may be initially misdiagnosed as having carcinoma of the cervix. Many of these women are thought to have high-stage tumors because of spread of the infection to the parametrial tissue (Hoosen et al. 1990). In addition to characteristic morphologic features, specific bacteriologic and immunologic techniques are available for identifying each of these diseases.
In contrast to bacterial infections of the cervix, the most common cervical viral infections – human papillomavirus (HPV) and herpes simplex virus (HSV) – have a predilection for the squamous epithelium and produce characteristic morphologic changes. Cytomegalovirus, although often isolated from cervical secretions, is not typically associated with cervicitis, and its role in cervical infection is poorly understood.
Herpesvirus Infection (HSV)
Vesicular and bullous lesions of the cervical squamous mucous membrane, other than herpetic cervicitis, have been reported (Burd and Easterly 1971). Pemphigus vulgaris of the cervix is a common finding in women with generalized disease (Kaufman et al. 1969). Microscopically, there are multiple intraepithelial bullae in a suprabasal location containing the characteristic acantholytic Tzanck cells.
Human Papillomavirus (HPV)
The natural history of exophytic LSIL (condyloma) is one of spontaneous regression, good response to conservative therapy, unpredictable recurrence, and sometimes persistence. Lesion regression or apparent cure following biopsy is fairly common. The natural history of exophytic LSIL (condyloma) in general may be modified by host factors, notably immunosuppression and steroid hormone levels.
Cervical fungal infection by Candida albicans usually occurs as part of a generalized lower genital tract infection involving the vagina and vulva. Antibiotic therapy, poorly controlled diabetes mellitus, and immunosuppression all favor fungal overgrowth (Sobel 1997). Cervical candidal infections can be associated with increased numbers of polymorpholeukocytes present in the upper layers of the epithelium and fungal hyphae that can be identified by periodic acid-Schiff (PAS) stains both at the surface of the epithelium and within the superficial layers of the epithelium.
Protozoal and Parasitic Diseases
Cervical infestation by trichomonas vaginalis is quite frequent and most often associated with concurrent trichomonal vaginitis. Acute trichomonal cervicitis may provoke an intense inflammatory response with prominent reparative atypia in exfoliated squamous and endocervical cells, with corresponding gross and colposcopic abnormalities.
Multiple, blue-gray, subepithelial cysts of the portio vaginalis and vagina characterize this unusual disease (Gardner and Fernet 1964). In rare cases, the cysts have been misdiagnosed as an invasive cervical cancer (Akang et al. 1997). The cause of this condition is unknown, but it is often associated with trichomoniasis (Gardner and Fernet 1964). Gas-forming bacteria have never been identified within the cysts. The cysts are dilated connective tissue spaces without lining epithelium that contain air and carbon dioxide. Multinucleated foreign body giant cells surround some of the cysts, and often the subepithelial veins and lymphatics are dilated.
Gynecologic vasculitides are rare conditions occurring in between 0.04% and 0.1% of surgically removed gynecologic specimens. Most are isolated, single-organ disease and the cervix is the most frequently involved organ (Hernandez-Rodriguez et al. 2009). Single-organ vasculitis or “isolated” arteritis of the cervix, is histologically identical but clinically unrelated to polyarteritis nodosa (Laurtizen and Meinecke 1987; Gozukucuk et al. 2016; Ganesan et al. 2000). In most cases, medium-sized arteries contain nongranulomatous vasculitis which is usually asymptomatic and identified as an incidental finding in surgical specimens. Occasionally, it may be associated with bleeding and a few cases have clinically resembled cancer. The etiology of this condition is unknown. A literature review done in 2007 identified 118 cases of single organ vasculitis of the cervix and found that 99.1% were nonprogressive to systemic disease and that excision of the tissue appeared to be curative (Hoppe et al. 2007). Therefore, if no systemic disease is identified, no further therapy is indicated.
Pseudoneoplastic Glandular Conditions (Hyperplasias) and Endometriosis
Microglandular Endocervical Hyperplasia
Microglandular endocervical hyperplasia is a benign proliferation of endocervical glands. Microglandular hyperplasia is frequently detected as an incidental finding on a cervical biopsy, cone biopsy, or a hysterectomy specimen. It has been detected in up to 27% of cone biopsies or hystereectomy specimens (Brown and Wells 1986). It appears to arise from reserve cells derived from columnar cells (Witkiewicz et al. 2005). If clinically apparent, it most often resembles a cervical polyp measuring 1–2 cm in size. Patients may complain of postcoital bleeding or spotting. Microglandular hyperplasia is most common in women of reproductive ages although some cases (<10%) occur in postmenopausal women (Nucci 2014). Early studies reported that microglandular hyperplasia typically occurs in patients with a history of recent progesterone exposure, either as a result of oral contraceptive use or pregnancy, and concluded that it represents a progestin-induced lesion. However, a number of cases have been reported in which there is no associated hormonal history, and a comprehensive study did not find a relationship between microglandular hyperplasia and progestin exposure (Greeley et al. 1995). Therefore, the role of progestin exposure in the pathogenesis of this lesion is currently unclear.
The immunohistochemical profile of microglandular hyperplasia includes p63 positivity in the associated squamous metaplasia and reserve cell component (Chekmareva et al. 2008; Houghton and McCluggage 2009). Microglandular hyperplasia is usually positive for ER and PR and may show luminal positivity for CEA (Qiu and Mittal 2003). It is usually vimentin negative which may be useful for distinguishing microglandular hyperplasia from an endometrial carcinoma (Qiu and Mittal 2003). Carcinoma and Other Tumors of the Cervix discusses the use of immunohistochemistry in the differential diagnosis of endocervical and endometrial lesions.
Mesonephric Hyperplasia and Remnants
Mesonephric hyperplasia is almost always asymptomatic and is detected on either cervical biopsy, cone biopsy, or hysterectomy specimens. Histological differentiation between mesonephric hyperplasia and mesonephric remnants is quite arbitrary, and of little clinical importance. Mesonephric hyperplasia is a benign condition that is of pathological significance because it can be misinterpreted as a minimal deviation adenocarcinoma of the endocervix (see chapter “Cervical Carcinoma”). Mesonephric hyperplasia is usually distinguished from the rare mesonephric adenocarcinoma by lack of a complex glandular pattern, mitosis, intracellular mucin, and periglandular stromal edema; however, some florid forms of hyperplasia can be problematic to distinguish from carcinoma. The most useful immunohistochemical markers for distinction of mesonephric hyperplasia (and adenocarcinoma) from endocervical and endometrial adenocarcinomas depend on the specific type of adenocarcinoma that is being considered. Mesonephric lesions lack diffuse p16 expression and also hormone receptor expression (ER/PR) but have a high frequency of GATA-3 expression. Thus all these markers are useful for distinction of mesonephric lesions from endometrial endometrioid carcinomas but only p16 and GATA-3 are useful for distinction from high-risk HPV-related endocervical adenocarcinomas and only GATA-3 is useful for distinction from gastric-type (non-HPV) endocervical adenocarcinomas (Roma et al. 2015; Howitt et al. 2015).
Lobular Endocervical Glandular Hyperplasia (LEGH)
Diffuse Laminar Endocervical Glandular Hyperplasia (DLEGH)
The mechanism responsible for the development of endometriosis is unknown, but it is clear that cervical endometriosis frequently develops following cervical trauma. Cervical endometriosis is encountered in 5%–43% of patients who have had cervical cautery or cold-knife cone biopsy or loop excisional procedures (Gardner 1966). This association has been interpreted by some investigators as evidence supporting the implantation theory of endometriosis. According to this theory, endometrial tissue is implanted into the cervical mucosa or submucosa following postmenstrual cauterization or during delivery. However, the frequent occurrence of posttraumatic endometriosis could also be interpreted as supporting the view that cervical endometriosis represents a reparative/metaplastic process. Support for the concept that cervical endometriosis develops as a metaplastic process as opposed to direct implantation also comes from the frequent demonstration of glands with either tubo-endometrioid or pure tubal metaplasia in posttraumatic cervices.
Differential clinical diagnosis of polypoid lesions of the cervix
Microglandular endocervical hyperplasia
Squamous cell carcinoma
Sarcoma, primary or secondary
High-grade SIL, carcinoma, either in situ or invasive (adeno- or squamous), arising in cervical polyps is extremely rare. Endocervical polyps with adenocarcinomatous changes must be differentiated from polypoid adenocarcinoma of the endocervix and from endocervical polyps that are secondarily involved by adjacent adenocarcinoma. The most useful criterion for differentiating between the two is to determine whether or not the base of the pedicle of the polyp is involved by carcinoma. The base of a polyp that harbors a primary tumor is free of disease and the carcinoma usually has a focal distribution within an otherwise benign polyp. In a polypoid carcinoma, the entire mass is malignant, including its base and neighboring areas. It is not clear whether a focus of carcinoma in a cervical polyp without involvement of its base but associated with similar carcinoma in the adjacent regions is the primary focus with non-contiguous spread to the non-polyp region or vice versa.
Mesodermal Stromal Polyp
Superficial Cervicovaginal Myofibroblastoma
Superficial cervicovaginal myofibroblastoma is an uncommon mesenchymal tumor that is histologically distinguishable from a mesodermal stromal polyp and can be found in the cervix and vagina of adult women (Laskin et al. 2001). They arise from the lamina propria and are located in the subepithelial region. They are well circumscribed and range in size from 1 to 6.5 cm in diameter. Superficial cervicovaginal myofibroblastomas are moderately to highly cellular and composed of bland spindle shaped mesenchymal cells that are surrounded by a collagenous stroma that can have myxoid and edematous foci. Characteristically, they have a multipatterned architecture that can consist of a lacelike/sievelike growth pattern of the mesenchymal cells in areas with more stroma and a fasicular growth pattern in the more cellular regions. Mitotic activity is minimal (Laskin et al. 2001). The cells stain positively for vimentin, ER and PR, desmin and CD 34. Some cases stain for smooth muscle actin and muscle-specific actin.
Placental Site Trophoblastic Nodule
Cervical leiomyomas are much less common than uterine leiomyomata. They usually occur singly and produce unilateral enlargement of the cervical portio. At times, the lesion may protrude from the canal, resembling an endocervical polyp, and in pregnancy may produce dystocia. Cervical leiomyomas are similar grossly to those observed in the myometrium; microscopically, they tend to be more vascularized than those of the uterus, a variety of histological patterns may be encountered, including atypical leiomyoma which contains cells with bizarre nuclei, (see chapter “Mesenchymal Tumors of the Uterus”).
Adenomyoma and Papillary Adenofibroma
These neoplasms are rare and are composed of an admixture of fibroconnective tissue and smooth muscle elements intermingling with glands lined by a predominately endocervical type epithelium. The tumors typically measure 1.3–8.0 cm in diameter and usually present as asymptomatic cervical polyps (Gilks et al. 1996). The epithelial component is typically composed of irregular, large glands that may be accompanied by smaller glands in a lobular arrangement. These tumors can be distinguished from endocervical adenocarcinomas by the lack of invasion of the stromal component by the epithelial component, lack of nuclear atypia, and minimal mitotic activity. Adenomyomas can persist or recur, but there are no reported instances of extracervical spread or metastasis (Gilks et al. 1996).
Hemangiomas are rarely found in the cervix. They may be of capillary or cavernous type (Gudson 1965; Busca and Parra-Herran 2016). A single instance of cervical lymphangioma has been reported and several cases of lipoma of the cervix are on record (Stout 1943). Neoplasms of neurogenic derivation arising in the cervix are extremely rare and include neurofibroma and ganglioneuroma. Benign blue nevi of the endocervix, indistinguishable from those arising in the dermis, are seen occasionally (Patel and Bhagavan 1985). They are composed of melanin-containing fusiform cells with dendritic cytoplasmic processes, located in the stroma of the endocervix. Cervical melanosis is an uncommon finding characterized by hyperpigmentation of the cervical basal epithelium. It is reported to occur either with or without accompanying basal melanocytes (Yilmaz et al. 1999).
Endocervical tunnel clusters are benign collections of endocervical glands that are usually located close to the surface epithelium of the cervix. Tunnel clusters are quite common and become more prevalent with increasing age. In Fluhmann’s original description of this condition, they were detected in 8% of all adult women and 13% of the postmenopausal women (Fluhmann 1961b). They appear to be more common in pregnant women. These lesions are asymptomatic and are detected as incidental findings in either hysterectomy specimens or cone biopsies obtained for unrelated reasons (Segal and Hart 1990).
Traumatic inclusion cysts are a form of epidermal inclusion cysts that commonly occur in the vagina at sites of surgical repair of episiotomies or vaginal intrapartum lacerations (see chapter “Vagina”). They are thought to develop from viable fragments of epithelium which become entrapped within the stroma at the time of obstetrical trauma or subsequent surgical repair. Inclusion cysts are uncommonly found on the cervix. Grossly, they present as unilocular cystic structures measuring 1–2 cm in diameter beneath the native portio epithelium (Nikolaou et al. 2014). Microscopically, traumatic inclusion cysts are lined by a stratified squamous epithelium similar to that of the vaginal mucosa but usually somewhat thinner. The epithelium shows normal maturation with the basal cells oriented away from the cyst cavity that is filled with desquamated epithelial cells. The cyst contents are identical to those of epidermal inclusion cysts at other sites and are thick, white and cheesy.
The gross appearance of the pseudodecidual change that can occur during pregnancy depends on the site. If the change occurs on the exocervix, it frequently presents as a raised plaque or pseudopolyp that can be mistaken for invasive carcinoma both colposcopically and microscopically. During gestation, cervical polyps may also contain focal stromal pseudodecidual changes and rarely massive decidualization of endocervical stroma occurs producing a polypoid protrusion from the endocervix. Clinically, decidualized polyps need to be differentiated from extruded fragments of decidua that may indicate an impeding miscarriage. Distinction is made by identifying a stalk for the decidualized polyp, whereas expulsed fragments of decidua lack a stalk. Areas of pseudodecidualization are microscopically differentiated from invasive nonkeratinizing squamous cell carcinoma by the lack of significant nuclear atypia, as well as lack of mitotic figures, a coexisting squamous intraepithelial lesion (SIL) and continuity with the surface epithelium. In difficult cases, immunohistochemistry using antibodies against cytokeratin proteins can be used to differentiate cytokeratin negative decidual reactions from cytokeratin positive nonkeratinizing squamous cell carcinoma.
Postoperative Spindle Cell Nodule and Inflammatory Pseudotumor
Postoperative spindle cell nodules of the cervix are clinically and histologically identical to their more common counterparts of the vulva and vagina (Kay and Schneider 1985; Proppe et al. 1984). These lesions may develop after either a cervical biopsy or some other form of trauma. They resemble nodular fasciitis and are composed of actively proliferative spindle cells with oval nuclei arranged in interlacing bundles (see Fig. 19 in chapter “Diseases of the Vagina”). The cells may vary slightly in size and mitotic figures are often present. A characteristic feature is the presence of neutrophils and erythrocytes in the lesion, giving it the appearance of granulation tissue.
Inflammatory pseudotumor refers to a closely related lesion to postoperative spindle cell nodule that occurs in the absence of a known history of trauma (Abenoza et al. 1994). Inflammatory pseudotumor is a proliferative process of unknown etiology with a polymorphic appearance. The lesions contain two cellular components; a fibrohistiocytic component consisting of fibroblasts, myofibroblasts, and histiocytes; and a polymorphous inflammatory component consisting of lymphocytes and plasma cells. The lesion can be differentiated from other neoplastic processes by the lack of atypia and mitoses and the presence of a polymorphous inflammatory infiltrate.
Lymphoma-like lesions (pseudolymphomas) are marked inflammatory lesions of the cervix, extensive enough to cause confusion with a lymphoproliferative lesion (Young et al. 1985). Lymphoma-like lesions are composed of a superficial band of large lymphoid cells admixed with mature lymphocytes and plasma cells. The lymphoid infiltrates commonly include macrophages and germinal centers which help to distinguish them from lymphomas (Fig. 32). Another feature, which helps to distinguish lymphoma-like lesions from lymphomas, is the superficial localization of the infiltrate. Lymphoma-like lesions rarely infiltrate deeper than 3 mm from the surface epithelium whereas lymphomas of the cervix usually extend beyond the depth of the endocervical glands (see chapter “Carcinoma and Other Malignant Tumors of the Cervix”).
There are 15 recorded cases of neuroglial tissue in the cervix or the endometrium (see chapter “Benign Disease of Endometrium”) (Slavutin 1979). Although the term glioma is used for this condition, the high degree of differentiation of the glial tissue, the absence of mitoses, and the absence of recurrence are against the lesion being neoplastic. The lesion should not be confused with a pure heterologous sarcoma or a teratoma. The neural tissue is believed to represent either implantation of fetal cerebral glia at the time of instrumentation of the gravid uterus or heterotopic maldevelopment during embryogenesis. When the cervix is involved, the lesion usually appears as a polyp that bleeds readily.
Among the pathologic curiosities of the cervix are cases of true epidermidization of the cervical mucosa. In these rare instances, sebaceous glands, hair, sweat glands and occasionally mantle structure are found. These ectodermal structures are usually either attached to the basal layer of the squamous epithelium or are isolated in the cervical stroma. The squamous epithelium overlying the ectodermal structures often shows hyperkeratosis (Brady and McCluggage 2013). The presence of these ectodermal structures, which are normally appendages of the epidermis, on a mucous membrane of mesodermal derivation is difficult to explain. One theory is that the ectodermal structures represent misplaced embryonal tissue. It is conceivable, however, that stratified squamous epithelium under certain circumstances, such as long-standing chronic inflammation can form ectodermal structures by a metaplastic process (Brady and McCluggage 2013; Kazakov et al. 2009).
Four cases of heterotopic mature cartilage in the cervix are on record (Roth and Taylor 1966). The finding of these structures alone has no clinical significance. They should not be confused with a malignant mesodermal mixed tumor.
By immunohistochemistry, the squamous component is usually diffusely positive for GATA3 whereas the glandular component is negative (Fig. 53b). The glandular component frequently stains positively for prostatic acid phosphatase (PrAP) and prostate-specific antigen (PSA) (Kelly et al. 2011). Recently, it has been reported that the glandular component stains with NKX3 (Fig. 53c) which is an androgen-regulated, prostate-specific transcription factor that plays a role in prostate development and tumor suppression (Roma 2016).
The origin of ectopic prostatic tissue in the cervix is unclear. Although it may represent a form of metaplasia, given its usual location on the ectocervix and the fact that histologically it closely resembles tubulosquamous polyps of the vagina, it more likely represents a developmental anomaly in which the periurethral Skene’s glands are misplaced during embryonic development (Kelly et al. 2011; Nucci et al. 2000; Roma 2016). This lesion is sometimes confused with adenoid basal tumor/epithelioma. p16 is useful for distinguishing these lesions, as ectopic prostatic tissue is negative or focally positive for p16 whereas adenoid basal tumors are diffusely positive due to the presence of high-risk HPV.
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