Inflammatory Cervical Lesions
Acute cervicitis is a common condition characterized by erythema, swelling, neutrophilic infiltration, and focal epithelial ulceration. The endocervix is more frequently involved than the ectocervix.
Acute cervicitis is usually a sexually transmitted infection, commonly with gonococci, Chlamydia trachomatis, Candida albicans, Trichomonas vaginalis, and herpes simplex (see Chapter 54: Sexually Transmitted Infections). Non-sexually transmitted agents such as Escherichia coli and staphylococci may also be isolated from acutely inflamed cervices, but their role is not clear. Acute cervicitis also follows the trauma of childbirth and surgical instrumentation.
Clinically, there is a purulent vaginal discharge and pain. The severity of symptoms does not correlate well with the degree of inflammation.
Moderate numbers of lymphocytes, plasma cells, and histiocytes are present in the cervix in all females. Chronic cervicitis is therefore difficult to define pathologically. The presence of detectable cervical abnormalities such as granularity and thickening along with increased numbers of chronic inflammatory cells in a biopsy specimen is considered necessary to warrant a diagnosis of chronic cervicitis.
Chronic cervicitis is most commonly seen at the external os and endocervical canal. It may be associated with fibrous stenosis of gland ducts, leading to retention (nabothian) cysts. When lymphoid follicles are present on microscopic examination, the term follicular cervicitis is sometimes used.
Clinically, chronic cervicitis is often an incidental finding. However, it may produce a vaginal discharge, and in a few cases associated fibrosis of the endocervical canal may cause stenosis, leading to infertility.
Nonneoplastic Cervical Proliferations
Squamous metaplasia of the endocervical epithelium is common, probably representing a response to irritation.
Microglandular hyperplasia is an unusual proliferation of endocervical glands that has been associated with the use of oral contraceptive agents. It presents grossly as a polypoid lesion that protrudes into the endocervical canal. Microscopically, it is characterized by an abnormal mass of endocervical glands lined by a flattened cuboidal epithelium. It has no malignant potential.
Polyps are common lesions of the endocervical canal, usually occurring at about the time of menopause. When large, a polyp may protrude out of the external os. Microscopically, endocervical polyps contain hyperplastic endocervical glands and a highly vascular stroma and may show marked chronic inflammation. The surface epithelium of a polyp commonly shows squamous metaplasia. Endocervical polyps are benign, with no increased incidence of neoplasia.
Rarely, decidualization of the cervical stroma in pregnancy may produce polypoid lesions clinically resembling neoplasm. These are called decidual polyps.
Condyloma acuminatum is a common lesion of the cervix caused by the human papillomavirus, which is transmitted by sexual contact. It occurs in two forms: (1) as a wart-like papillomatous lesion that resembles condylomata in other sites; and (2) as elevated flat areas in the epithelium with no papillomatous growth.
Condyloma acuminatum is characterized by hyperplasia of the squamous epithelium with marked cytoplasmic vacuolation (koilocytosis) and nuclear chromatin condensation. Nuclear atypia is often present. Immunoperoxidase studies using antibodies against human papillomavirus are positive (Figure 53-15). A large number of different types of papillomavirus have been identified in condylomas; some of these, particularly types 16, 18, 31, and 33, which cause mainly flat condylomas, are also associated with cervical squamous carcinoma. Human papillomavirus types 6 and 11, which are commonly associated with wart-like condylomas, are very rarely found in cervical cancers.
Flat condyloma acuminatum of the cervix, showing marked vacuolation of the cytoplasm and nuclear pyknosis (koilocytosis). This slide has been stained by the immunoperoxidase technique for papillomavirus and shows positive nuclear staining in many of the cells.
Cervical squamous carcinoma is common, causing 7000 deaths annually in the United States. It ranks sixth as a cause of cancer deaths in women. The mortality rate from cervical carcinoma has been falling, partly due to early detection of premalignant epithelial dysplasia by routine cytologic screening of cervical smears (Pap smears); many cases are detected and treated in the preinvasive stage.
In contrast to carcinoma, dysplasia of the cervical epithelium remains common and appears to be occurring in younger women.
Considerable evidence suggests that carcinoma of the cervix is caused by a sexually transmitted carcinogenic agent, probably viral (Table 53-3). The risk of developing carcinoma increases with early onset of sexual activity, frequency of coitus, and greater number of sexual partners. It is common in multiparous women who have married early and in prostitutes but vanishingly rare in nuns. In general, cervical carcinoma tends to affect the lower socioeconomic stratum of society.
Cervical carcinoma is uncommon in Jewish and Moslem women, leading to a theory that male circumcision reduces the incidence of cervical cancer in women. It has been shown recently that there is a threefold increase in the incidence of cervical cancer among the sexual partners of men who have been married previously to women with carcinoma of the cervix.
Two viruses are suspected of having an etiologic role in cancer of the cervix:
Herpes simplex virus type 2 (HSV-2): HSV-2 antibodies are present in a high percentage of patients with cervical carcinoma when compared with controls. Although entire viral particles have not been demonstrated in the cells of cervical carcinoma, HSV-2 viral deoxyribonucleic acid (DNA), messenger ribonucleic acid (RNA), and viral proteins have been found in some cases. The incidence of cervical carcinoma in patients infected with HSV-2 virus is, however, low, indicating that carcinogenic potential of the virus is not great. If HSV-2 is involved, it is thought to play only a minor promoting role.
Human papillomavirus—particularly serologic types 16 and 18, which cause atypical flat condyloma acuminatum—has been found in both squamous carcinoma and dysplastic lesions of the cervix. This is presently considered to be an important etiologic agent. Recent studies show that the presence of human papillomavirus, as demonstrated by immunologic or molecular techniques in cervical smears or vaginal fluid, is associated with a 20-fold increase in the risk for cervical carcinoma (see also Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia).
Dysplasia of the Cervix (Cervical Intraepithelial Neoplasia; Squamous Intraepithelial Lesion)
Squamous epithelial dysplasia and carcinoma of the cervix, showing criteria used to grade dysplasia. Dysplasia commonly occurs at the squamocolumnar junction. CIN = cervical intraepithelial neoplasia; SIL = squamous intraepithelial lesion.
Most cervical carcinomas arise in a stratified squamous epithelium that shows precancerous change (dysplasia; see Chapter 16: Disorders of Cellular Growth, Differentiation, & Maturation). Dysplasia commonly involves the region of the squamocolumnar junction and the endocervical canal that has undergone squamous metaplasia. Dysplasia is recognized by the presence of cytologic abnormalities in a cervical (Pap) smear (Table 53-2) and confirmed by cervical biopsy (Figure 53-17). The cytologic changes include increased nuclear size, increased nuclear:cytoplasmic ratio, hyperchromatism, abnormal chromatin distribution, and nuclear membrane abnormalities. The extent of these changes permits classification (in order of increasing severity) as mild, moderate, or severe dysplasia and carcinoma in situ (Figure 53-16). These cytologic changes on a Pap smear correlate accurately with the degree of abnormal maturation of the epithelium in a subsequent cervical biopsy specimen. In carcinoma in situ, biopsy reveals that maturation is totally lacking, and most of the cytologic changes of carcinoma are present except invasion through the basement membrane.
Moderate to severe dysplasia (CIN III, high-grade SIL) of the cervical squamous epithelium, showing disordered maturation, increased nuclear:cytoplasmic ratio, hyperchromasia, chromatin clumping, and mitotic figures in the upper part of the epithelium.
Dysplasias are reversible lesions, but the more severe the degree of dysplasia the less the tendency to reverse. The time span for progression of dysplasia is variable. The median time for carcinoma to develop is 7 years for mild dysplasia and 1 year for severe dysplasia. This observation has led to the recommendation that routine cervical Pap smears should be performed in all women at least once every 3 years after two initial examinations 1 year apart have proved negative.
The term cervical intraepithelial neoplasia cervical intraepithelial lesion (CIN) has the same denotation as dysplasia. CIN I is equivalent to minimal dysplasia, CIN II to moderate dysplasia, and CIN III includes severe dysplasia and carcinoma in situ. More recently, dysplasias are classified as low- and high-grade squamous intraepithelial lesions (SIL).
Dysplasia affects cervical surface epithelium as well as extending down into endocervical glands (gland duct involvement). The significance of gland duct involvement is the same as that of dysplasia of the surface epithelium.
Dysplasia and carcinoma in situ produce no symptoms. Changes in the mucosa on inspection are minimal, but some lesions may be recognized by means of the magnified image provided at colposcopy (eg, abnormal vascular pattern, thickening, and white coloration). Colposcopy and biopsy should be performed in all patients in whom dysplasia of any grade is found on routine cervical cytologic examination (see Table 53-2). The Schiller test, which consists of painting the cervix with aqueous iodine, is helpful in locating areas of dysplasia, since dysplastic epithelium lacks glycogen and will appear as a pale area whereas normal epithelium stains dark brown with iodine.
The treatment of dysplasia is local and conservative. Cryosurgery, electrocoagulation, laser coagulation, and conization—removal of a cone of cervical tissue, including the entire squamocolumnar junction—are all effective.
Microinvasive Carcinoma (Stage IA)
Microinvasive carcinoma of the cervix is defined as cervical carcinoma in which the total depth of invasion is less than 5 mm from the basement membrane (Table 53-5). Microinvasive carcinoma so defined is rarely associated with metastases, and local surgical excision is curative. It should be recognized that the submucosa of the cervix within this 5-mm zone below the basement membrane does contain lymphatics and blood vessels, and metastases are a hypothetical possibility. Nonetheless, the rarity of metastases is a statistical fact.
Clinical Staging of Cervical Carcinoma.
Clinical Staging of Cervical Carcinoma.
Carcinoma in situ (100%).
Microinvasive carcinoma; invasion to a depth <5 mm from the basement membrane (>95%).
Invasive carcinoma, infiltrating to a depth >5 mm but confined to the cervix (90%).
Extension of tumor beyond the cervix to involve the endometrium, vagina (but not the lower third), or paracervical soft tissue (but has not extended to the pelvic side wall) (75%).
Extension to the pelvic side wall or involvement of the lower third of the vagina or the presence of hydronephrosis from ureteral involvement (35%).
Extension beyond the pelvis or clinical involvement of bladder or rectal mucosa (10%).
Invasive Squamous Carcinoma (Stage IB & More Extensive)
Invasive carcinoma is defined as carcinoma infiltrating to a depth of greater than 5 mm from the basement membrane. It occurs most frequently in the age group from 30 to 50 years.
Invasive carcinoma may present grossly as an exophytic, fungating, necrotic mass (Figure 53-18), the most common appearance; as a malignant ulcer; or as a diffusely infiltrative lesion with only minimal surface ulceration or nodularity (uncommon). Microscopically, there are three different types: (1) large cell, nonkeratinizing squamous carcinoma—the most common type, with the best prognosis; (2) keratinizing squamous carcinoma—next most common, with an intermediate prognosis; and (3) small cell carcinoma—rare, with a poor prognosis.
Squamous carcinoma of the cervix involving the squamocolumnar junction and most of the endocervical canal. The tumor is mainly to the left of the displaced endocervical canal in this figure.
Invasive cervical carcinoma is manifested as abnormal uterine bleeding (commonly irregular and excessive menstrual bleeding or postmenopausal bleeding) or vaginal discharge. Obstruction of the cervical canal may cause blood to accumulate in the uterine cavity and result in infection (pyometron). Colposcopy permits direct visualization and biopsy to make a definitive histologic diagnosis. Cervical carcinoma is staged according to the degree of spread (Table 53-5).
Treatment is a combination of surgery and radiation therapy, depending on the extent of disease. The prognosis depends primarily on the clinical stage of the disease. The histologic type is a lesser prognostic factor.
Endocervical adenocarcinoma accounts for 10–15% of cervical cancers. It arises in the endocervical glands, presenting as a mass in the endocervical canal. It frequently obstructs the endocervical canal, predisposing to pyometron.
Microscopically, endocervical adenocarcinoma is usually a well-differentiated lesion, often with a papillary appearance. It may show squamous differentiation (adenoacanthoma, adenosquamous carcinoma). The prognosis is less favorable than that of squamous carcinoma. Adenosquamous carcinoma behaves in a highly malignant fashion.