CONGENITAL ANOMALIES :
Congenital anomalies of the cervix reflect only the lower part of the spectrum of congenital anomalies involving the müllerian system. The cervix has 3 types of anomalies: fusion abnormalities, congenital absence, and changes due to in utero exposure to diethylstilbestrol (DES) and other nonsteroidal estrogens.
Fusion anomalies
A failure to fuse or incomplete fusion of the müllerian ducts results in duplication of the vagina, cervix, or uterus. Failure of fusion of the distal müllerian duct can result in any of the anomalies discussed below.
Uterus didelphys results from a complete lack of fusion of the müllerian ducts. Duplication of the vagina, cervix, and/or uterus occurs. A longitudinal vaginal septum is present, with 2 separate cervices and 2 separate endometrial cavities.
With septate cervix, the appearance is that of 1 cervix with 2 separate cervical openings. The septum may be partial. The gross appearance is of 2 separate cervices but 1 endometrial cavity. On the other hand, the septum may extend through the entire length of the uterus, with 2 separate endometrial cavities. Depending on the shape of the uterine fundus, the anomaly is either a septate uterus or an arcuate uterus. Laparoscopy is necessary to distinguish between these 2 anatomic variations.
Congenital absence of the cervix
Congenital absence of the cervix usually occurs as part of the syndrome of müllerian agenesis, also known as Mayer-Rokitansky-Küster-Hauser syndrome. This syndrome occurs in approximately 1 per 4000 female births.
Women with müllerian agenesis typically have a blind vagina and normal ovaries. Approximately one third of patients have urinary tract anomalies, and 12% have skeletal anomalies, usually involving the spine. Imaging of these structures should be part of the evaluation.
In women with partial müllerian agenesis, a uterine bud or fundus may be present without a cervix and proximal vagina. If endometrium is present in this uterine bud, hematometra occurs at puberty, producing cyclic abdominal pain. These patients require excision of the uterine bud. Although vaginal patency has been surgically created in a few patients, pregnancy has not occurred in the absence of a cervix.
In utero exposure to diethylstilbestrol and other nonsteroidal estrogens
Changes associated with in utero exposure to DES and other nonsteroidal estrogens are encountered. The epidemiologic association of in utero exposure to DES with clear cell vaginal adenocarcinoma has been known since 1970. The use of DES, which initially was prescribed for thousands of women to prevent miscarriage, was discontinued at approximately that time. However, unique anomalies of the müllerian system are present in women exposed to DES.
The classic anomaly is a hypoplastic T-shaped uterus, referring to the T shape of the endometrial cavity. Defects limited to the cervix, in addition to hypoplastic cervix, include local interesting gross and colposcopic findings.
In addition to vaginal adenosis, other findings unique to in utero DES exposure include the so-called cockscomb cervix, cervical rings, cervical collars, and cervical hoods. The cockscomb cervix refers to the abnormal stromal development causing the epithelium to be thrown into firm transverse ridges in the anterior vaginal fornix, including the upper ectocervix.
Incompetent cervix with pregnancy wastage is a potential problem in females exposed to DES.
INFLAMMATORY DISEASES :
Inflammation of the cervix is extremely common. Chronic inflammation is present in the cervix of almost every sexually active woman. On a microscopic level, regardless of the etiology, the tissue response of the cervix is limited to inflammation and repair.
Infectious cervicitis
Susceptibility of the cervix to bacterial infection depends on the virulence of the organism, the epithelial integrity, and the vaginal pH. Infections of the endocervical canal include infection with Neisseria gonorrhoeae and Chlamydia trachomatis. Organisms infecting the portio of the cervix can produce either exophytic or ulcerative lesions. These include human papilloma virus (HPV), herpes simplex virus (HSV), Treponema pallidum, Haemophilus ducreyi, and donovanosis.
Infections of the endocervical canal (mucopurulent cervicitis)
Infection with C trachomatis or N gonorrhoeae requires no predisposing factor and primarily depends on the size of the inoculum.
Mucopurulent secretions have been reported in more than 60% of women with cervical chlamydial infections. Mucopurulent discharge is present in 12% of women with no cervical pathology. Yellow mucopus collected from the endocervix and visualized on a white cotton-tipped applicator may correlate with chlamydia, gonorrhea, or HSV infections. It also correlates with the identification of trichomonads in the vagina.
Traditionally, mucopurulent cervicitis has been associated with chlamydial infection and, to a lesser extent, gonorrhea; however, in published studies, the sensitivity, specificity, and positive predictive values have been quite variable. Thus, the color and consistency of the discharge alone is not enough to make a specific diagnosis.
Gram stain findings of gram-negative intracellular diplococci within the cytoplasm of neutrophils are highly specific for gonorrhea but can be identified in only 50-60% of women with gonococcal infections. On occasion, cervical cytology identifies inclusion-containing vacuoles in endocervical or metaplastic cells. The presence of these inclusions correlates well with C trachomatis infection.
The best guide to therapy for endocervicitis is identification of the specific microbiologic agent. This is accomplished best by the isolation of N gonorrhoeae, C trachomatis, HSV, or Trichomonas vaginalis in appropriate culture. DNA amplification and detection methods are gaining in popularity for screening and diagnosing women who are at risk or who are symptomatic.
Infections involving the portio of the cervix
Human papilloma virus
HPV can infect the ectocervix and can cause warty lesions similar to those seen in the vagina or on the vulva; however, the virus on the cervix typically causes flat warts. These are macular or papular lesions that become more visible to the naked eye when swabbed with 3-5% acetic acid. The acetic acid causes cellular dehydration. The resulting increase in nuclear density appears clinically as a white lesion. This phenomenon is transient. The term aceto-white describes this finding. In addition to HPV, squamous metaplasia and cervical intraepithelial neoplasia can appear aceto-white.
HPV lesions tend to have indistinct and feathered borders, and the lesions may appear broken or flocculated. Unlike cervical intraepithelial neoplasia (CIN), satellite lesions may be present, and HPV lesions may be within or outside the transformation zone on the portio of the cervix. Another appearance of HPV may be snow-white, shiny, and raised lesions. Frequently, fine-caliber blood vessels are present.
Lesions suggestive of HPV should be confirmed by performing a biopsy. The hallmark histologic feature is the koilocyte. On both cytologic preparations of cervical biopsy specimens, koilocytes are cells with wrinkled nuclear membranes (like raisins) that frequently are binucleate and occasionally are multinucleate. The nuclei are surrounded by a clear halo, which gives the cells their name. Cytologic and nuclear atypia typically is present. In cervical biopsy specimens, a few normal mitotic figures may be seen in the basal layer of the squamous epithelium, while koilocytes occupy the intermediate and superficial layers.
Currently, more than 60 types of HPV are described, but only a few types cause genital tract lesions. The typical exophytic warts that present on the vulva, vagina, and cervix are type 6 or type 11. Types 16, 18, 31, 33, and 35 are more commonly associated with flat warts and have an epidemiologic link to CIN. Kits are available that classify HPV lesions as either benign (ie, 6 or 11) or at risk (ie, 16, 18, 31, 33, and 35). Currently, for reflex HPV testing of thin layer cervical cytology, 14 different oncogenic HPV types are tested: HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.
A vaccine for HPV (Gardasil) has been recently approved by the FDA. It is a quadrivalent HPV recombinant vaccine containing activity against HPV types 6, 11, 16, and 18. The vaccine is indicated for prevention of HPV-associated dysplasias and neoplasias, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3). The immunization series should be completed in girls and young women aged 9-26 years.
Herpes simplex virus
Of women with their first episode of HSV-2 infection, 70-90% have herpetic cervicitis as part of the manifestation. In recurrent infections, cervicitis is present in 15-20% of women.
Primary herpetic cervicitis frequently is asymptomatic; however, it may present as a purulent or bloody vaginal discharge. Grossly, the cervix may appear diffusely red and friable. At times, ulcerations, which may be extensive, are present on the ectocervix.
Making a clinical diagnosis may be difficult. Colposcopic findings of acute cervicitis are identifiable in two thirds of women with primary herpes cervicitis. Multinucleate cells with typical ground-glass inclusions may be identified on cervical cytology results in 60% of these women.
The differential diagnosis includes the chancre of syphilis. Gonorrhea and chlamydia infection can cause a similar type of discharge, although ulceration in these conditions is uncommon. Syphilis, gonorrhea, and chlamydia infection may coexist with HSV-2 infection. Women with primary genital herpes involving the cervix should be started on antiviral therapy.
The other presentation of herpes involving the cervix is asymptomatic shedding. In these instances, the classic multinucleate cells with ground-glass inclusions may be identified on cervical cytology results as an incidental finding. In a sexually transmitted disease clinic, HSV was isolated from 4% of randomly selected women. Treatment for asymptomatic shedding is not recommended.
T pallidum
The primary lesion of syphilis develops at the site of inoculation 2-6 weeks after infection. The primary lesion begins as a papule and then ulcerates. Typically, the diameter is 0.5-1.5 cm.
In women, besides the labia and posterior fourchette, the cervix is a common site for the primary chancre. Because the primary lesion is asymptomatic and the cervix is not visualized readily, primary lesions in this location frequently remain undiagnosed. If untreated, they heal in 3-6 weeks. The disease then enters the latent period.
The differential diagnosis of these ulcers includes HSV-2 and H ducreyi. Diagnosis is best made using a dark-field microscopic examination of exudate taken from the surface of the lesion. The rapid plasma reagin (RPR) test results may be positive at a relatively low titer (1:16 or less) at this time. If syphilis is strongly considered and both the dark-field examination and the RPR test findings are negative, a repeat RPR test in 2 weeks will have positive results.
Treatment for primary syphilis is benzathine penicillin G at 2.4 million units. If the patient is allergic to penicillin, doxycycline at 100 mg twice daily for 2 weeks by mouth or tetracycline at 500 mg 4 times/d by mouth for 2 weeks is acceptable. If the patient is pregnant, desensitization followed by treatment with penicillin is recommended.
All patients with a diagnosis should be tested for HIV.
H ducreyi (ie, chancroid)
The primary ulcer is typically on the fourchette, labia, or vestibule.
Vaginal wall ulcers can occur and, at times, involve the cervix. Involvement of the cervix alone is very rare.
Donovanosis (ie, granuloma inguinale)
The typical site of infection in women is the labia minora and the fourchette. Lesions of the cervix are uncommon but are easily confused with cervical carcinoma.
Four distinct types of lesions are described; the most common lesion on the cervix is the necrotic, deep, foul-smelling ulcer associated with tissue destruction.
A tissue smear is the mainstay of diagnosis. A Giemsa stain typically is used. The Donovan bodies are identified in monocytes. The characteristic histologic picture is that of chronic inflammation, with plasma cells and polymorphonuclear leukocytes. Rarely, Donovan bodies are identified on cervical cytology.
Treatment is with trimethoprim-sulfamethoxazole double-strength tablets twice daily or doxycycline at 100 mg orally twice daily. Alternative regimens include ciprofloxacin at 750 mg twice daily or erythromycin base at 500 mg 4 times daily. Treatment is for a minimum of 3 weeks.
Actinomyces organisms
Actinomyces organisms are isolated most commonly in women with intrauterine devices (IUDs), but infection can be a result of surgical instrumentation and abortion.
Demonstrating the organism in the center of large abscesses confirms the diagnosis.
Lesions appear yellow and granular to the naked eye, hence the term sulfur granule.
Tuberculosis
When the cervix is involved, the lesion almost always is secondary to tuberculous salpingitis, which is secondary to pulmonary tuberculosis.
The gross appearance can be confused with invasive carcinoma.
Histologically, multiple granulomas or tubercles with central caseation necrosis, epithelioid histiocytes, and multinucleated Langhans giant cells characterize the lesions.
The differential diagnosis includes lymphogranuloma venereum and sarcoidosis. An unequivocal diagnosis requires the identification of acid-fast Mycobacterium tuberculosis.
Protozoal and parasitic cervicitis: These are usually part of a more generalized process.
Schistosomiasis and amebiasis: These are common in certain geographic areas.
Atypia of repair
This is a response to any injury that is characterized by epithelial disorganization and nuclear atypia. In reactive atypia, the nuclei are uniform in shape and size and the chromatin is aggregated in prominent chromocenters. Mitotic figures are normal and confined to the parabasal and basal cells. Maturation occurs in a normal manner. In the endocervix, reparative changes include nuclear enlargement, hyperchromasia, cytoplasmic eosinophilia, and loss of the mucin droplets.
Hyperkeratosis and parakeratosis
This usually involves the portio and may appear as whitish plaques (ie, leukoplakia). When diffuse, the portio is covered by a thickened, white, wrinkled epithelial membrane. The thick keratin layer on the surface is referred to as hyperkeratosis. When pyknotic nuclei are found within the keratin layer, the term parakeratosis is used. Acanthosis (ie, elongation of the rete pegs) is usually present.
Noninfectious cervicitis
This includes chemical irritation (eg, deodorants, douching), local trauma from foreign bodies (eg, tampons, pessaries, IUDs), surgical instrumentation, and therapeutic intervention. Clinically, the cervix is swollen, erythematous, and friable, and an associated purulent discharge may be present. The epithelium may be denuded and ulcerated. In chronic cervicitis, the cervix may be extremely friable and postcoital bleeding is a presenting complaint. Microscopically, lymphocytes, histiocytes, and plasma cells are present, with varying amounts of granulation tissue and stromal fibrosis. Lymphoid follicles with germinal centers are occasionally found beneath the epithelium. Chlamydia infection is isolated in some of these women.
BENIGN TUMORS :
Endocervical polyps
Endocervical polyps are the most common benign neoplasms of the cervix. They are focal hyperplastic protrusions of the endocervical folds, including the epithelium and substantia propria. They are most common in the fourth to sixth decades of life and usually are asymptomatic but may cause profuse leukorrhea or postcoital spotting.
Grossly, they appear as typical polypoid structures protruding from the cervical os. At times, endometrial polyps protrude through the cervical os. They cannot be distinguished from endocervical polyps by gross appearance. Microscopically, a variety of histologic patterns are observed, including (1) typical endocervical mucosal, (2) inflammatory (granulation tissue), (3) fibrous, (4) vascular, (5) pseudodecidual, (6) mixed endocervical and endometrial, and (7) pseudosarcomatous.
Treatment is removal, which can usually be accomplished by twisting the polyp with a dressing forceps if the pedicle is slender. Smaller polyps may be removed with punch biopsy forceps. Polyps with a thick stalk may require surgical removal.
Microglandular hyperplasia
Microglandular hyperplasia refers to a clinically polypoid growth measuring 1-2 cm. It occurs most often in women who are on oral contraceptive therapy or Depo-Provera and in pregnant or postpartum women. It reflects the influence of progesterone.
Microscopically, it consists of tightly packed glandular or tubular units, which vary in size, lined by a flattened-to-cuboidal epithelium with eosinophilic granular cytoplasm containing small quantities of mucin. Nuclei are uniform, and mitotic figures are rare. Squamous metaplasia and reserve cell hyperplasia are common. An atypical form of hyperplasia can be mistaken for clear cell carcinoma. Unlike clear cell carcinoma, it lacks stromal invasion, has scant mitotic activity, and lacks intracellular glycogen
Squamous papilloma
Squamous papilloma is a benign solid tumor typically located on the ectocervix. It arises most commonly as a result of inflammation or trauma.
Grossly, the tumors are usually small, measuring 2-5 mm in diameter. Microscopically, the surface epithelium may show acanthosis, parakeratosis, and hyperkeratosis. The stroma has increased vascularity and a chronic inflammatory infiltrate. Treatment is removal. The squamous papilloma resembles a typical condyloma acuminatum but lacks the koilocytes microscopically.
Smooth muscle tumors (leiomyomas)
These benign neoplasms may originate in the cervix and account for approximately 8% of all uterine smooth muscle tumors. They are similar to tumors in the fundus. When located in the cervix, they usually are small, ie, 5-10 mm in diameter.
Symptoms depend on size and location. Microscopically, leiomyomas resemble the typical smooth muscle tumor found in the uterine corpus. Treatment is required only for those patients who are symptomatic. The cervical leiomyoma is usually part of the spectrum of uterine smooth muscle tumors.
Mesonephric duct remnants
When present, mesonephric duct remnants are typically located at the 3-o'clock and the 9-o'clock positions, deep within the cervical stroma. They usually are incidental findings and are present in approximately 15-20% of serially sectioned cervices. As the name implies, mesonephric duct remnants are vestiges of the mesonephric or Wolffian duct. Usually, they are only a few millimeters in diameter and seldom are grossly visible.
Microscopically, they consist of a proliferation of small round tubules lined by epithelium that is cuboidal to low columnar. The tubules tend to cluster around a central duct. The cells lining the tubules contain no glycogen or mucin, but the center of the tubule may contain a pink material that contains glycogen or mucin.
Endometriosis
When present in the cervix, endometriosis is usually an incidental finding. Grossly, it may appear as a bluish-red or bluish-black lesion, typically 1-3 mm in diameter. Microscopically, the implants are typical endometriosis, consisting of endometrial glands, endometrial stroma, and hemosiderin-laden macrophages. The implants usually gain access to the cervix during childbirth or previous surgery.
Papillary adenofibroma
This neoplasm is uncommon. Grossly, it appears as a polypoid structure. Microscopically, the neoplasm contains branching clefts and papillary excrescences lined by mucinous epithelium with foci of squamous metaplasia. A compact, cellular, fibrous tissue composed of spindle-shaped and stellate fibroblasts supports the epithelium. The stroma is devoid of smooth muscle, and mitoses are rare. Similar growths occur in the endometrium and the fallopian tubes.
Heterologous tissue
Heterologous tissue includes cartilage, glia, and skin with appendages. This type of tumor rarely occurs in the cervix. While they may arise de novo, these tumors probably represent implants of fetal tissue from a previous aborted pregnancy.
Hemangiomas
Hemangiomas in the cervix are rare and are similar to those found elsewhere in the body.