Benign Cervical Lesions

In early development, prior to 8 weeks, the wolffian (ie, mesonephric) and the m悤lerian (ie, paramesonephric) ducts are present. Fusion of the distal portions of the m悤lerian ducts gives rise to the uterine fundus, the cervix, and the upper vagina. In a female fetus, the m悤lerian duct persists, while the wolffian duct disappears except for nonfunctional vestiges. The m悤lerian duct is lined by a columnar epithelium. This includes the entire cervix and upper vagina to the vaginal plate (ie, sinovaginal bulb). Through a process of squamous metaplasia, the vagina and a variable portion of the ectocervix become covered with squamous epithelium. This process is complete by the fifth month of pregnancy.

ANATOMY

The cervix (Latin for neck) is the inferior part of the uterus protruding into the vagina.

Gross anatomy

The cervix measures 2.5-3 cm in diameter and 3-5 cm in length. The normal anatomic position of the cervix is angulated slightly downward and backward. Inferiorly, the cervix projects into the vagina as the portio vaginalis. The anterior and posterior fornices delimit the portio (exocervix). The cervical canal measures approximately 8 mm wide and contains longitudinal ridges. The area between the endocervical and endometrial cavity is called the isthmus or lower uterine segment.

The lymphatic drainage of the cervix is first to the parametrial nodes, then to the obturator, internal iliac, and external iliac nodes. Secondary drainage is to the presacral, common iliac, and para-aortic lymph nodes.

The innervation of the cervix is from the Frankenh酳ser plexus, a terminal part of the presacral plexus. The nerves enter the lower uterine segment and upper cervix on either side and form 2 lateral semicircular plexuses. The major blood supply is from the descending branch of the uterine artery. Also contributing is the cervical branch of the vaginal artery. The venous return mirrors the arterial blood supply.

Microscopic anatomy

Microscopically, the cervical stroma is composed of an admixture of fibrous, muscular (15%), and elastic tissue. The epithelium is squamous on the ectocervix and columnar in the endocervix. The exposed (ie, vaginal) portion of the cervix is lined by nonkeratinizing-stratified squamous epithelium that becomes continuous with the vaginal epithelium. This is referred to as the native portio epithelium. The native portio epithelium is replaced every 4-5 days, is sensitive to estrogen and progesterone, and contains glycogen. In postmenopausal women, the squamous epithelium is atrophic with little or no glycogen, and the cellular alterations can be confused with cervical intraepithelial neoplasia.

The mucosa of the cervical canal (endocervix) is composed of a single layer of mucin-secreting columnar epithelium, which lines both the surface and the underlying glandular crypts. Isolated neuroendocrine epithelial cells of argentaffin type or argyrophil type are admixed with the normal endocervical cells. Under normal conditions, mitotic figures rarely are identified in endocervical epithelium. True lymphoid follicles, with or without germinal centers, are encountered in the stroma of both the ectocervix and endocervix. During pregnancy, there is a marked increase in the vascularity and edema within the cervical stroma and an inflammatory infiltrate

Squamocolumnar junction

The squamocolumnar junction is the border between the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix. Just distal to the squamocolumnar junction, an area of immature squamous metaplastic epithelium is present. Trauma, chronic irritation, and cervical infections play a role in the development and maturation of the squamous epithelium of the cervix. Immature squamous metaplasia shares biochemical and immunohistochemical features of both mature squamous epithelium and columnar mucinous epithelium.

The transformation zone

The transformation zone is a dynamic area, usually located on the ectocervix. At times, the distal edge of the transformation zone extends onto the upper vagina. The transformation zone, by definition, is the area between the original squamocolumnar junction and today𠏋 squamocolumnar junction. The transformation zone is that portion of the cervix that originally was columnar epithelium and now is squamous epithelium. Squamous metaplasia occurs continuously; however, this process is most active during fetal development, around the time of menarche, and during pregnancy. Local hormonal changes, as reflected by vaginal pH, influence this process.

In young females, the endocervical tissue tends to roll out from the cervical os; this is called cervical eversion and corresponds to the original squamocolumnar junction. In a normal transformation, one can find remnants of gland openings and nabothian cysts. On the other hand, in postmenopausal women, the squamocolumnar junction frequently is located within the cervical canal. In this position, it is not visualized through speculum examination. Understanding the transformation is of utmost importance because cervical cancer and its precursors typically begin within the transformation zone.

PHYSIOLOGY

Cervical mucus responds to hormonal stimulation. Under the influence of estrogen, the cervical mucus is profuse, watery, and alkaline. The rich concentration of sodium chloride and potassium are responsible for ferning. The degree of ferning reflects estrogen levels. After ovulation, the cervical mucus is thick, scant, acidic, and contains numerous leukocytes. In pregnancy, the cervical mucus is even thicker and more tenacious. It is rich in leukocytes and forms a mucus plug that obliterates the cervical canal. During pregnancy, during the postpartum state, and in women who are on progestin therapy, microglandular hyperplasia may occur. This is discussed in detail in microglandular hyperplasia. Decidual changes within the cervical stroma also can occur during pregnancy and high-dose progestin therapy.

CONGENITAL ANOMALIES

Congenital anomalies of the cervix reflect only the lower part of the spectrum of congenital anomalies involving the m悤lerian 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 m悤lerian ducts results in duplication of the vagina, cervix, or uterus. Failure of fusion of the distal m悤lerian duct can result in any of the anomalies outlined below.

Uterus didelphys: This results from complete lack of fusion of the m悤lerian 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.
　
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 m悤lerian agenesis, also known as Mayer-Rokitansky-Kuster-Hauser syndrome. This syndrome occurs in approximately 1 per 4,000 female births.

Women with m悤lerian 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 m悤lerian 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, there are unique anomalies of the m悤lerian system that are present in these DES-exposed women.

The classic anomaly is the 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 T vaginalis in appropriate culture. DNA amplification/detection methods are gaining in popularity for screening and diagnosing women who are at risk or symptomatic.
　
Treatment for mucopurulent cervicitis after identifying the causative organism is outlined in Table. The Centers for Disease Control and Prevention (CDC) do not recommend a test of cure in uncomplicated gonorrhea or chlamydial infection when treated with any of the outlined regimens, unless symptoms persist. Pregnant women should not be treated with quinolones or tetracyclines.

Treatment for Mucopurulent Cervicitis


Diagnosis	Primary treatment	Alternative treatment
Chlamydia trachomatis	Azithromycin 1 g PO or Doxycycline 100 mg PO bid for 7 days	Erythromycin base 500 mg PO qid for 7 days or Erythromycin ethylsuccinate 800 mg PO qid for 7 days or Ofloxacin 300 mg PO bid for 7 days
Neisseria gonorrhoeae	Cefixime 400 mg PO or Ceftriaxone 125 mg IM or Ciprofloxacin 500 mg PO or Ofloxacin 400 mg PO or Azithromycin 1 g PO or Doxycycline 100 mg PO bid for 7 days	Spectinomycin 2 g IM or Ceftizoxime 500 mg IM or Cefotaxime 500 mg IM or Cefotetan 1 g IM or Cefoxitin 2 g + Probenecid 1 g PO or Enoxacin 400 mg PO or Lomefloxacin 400 mg PO or Norfloxacin 800 mg PO
HSV	Acyclovir 400 mg PO tid for 7-10 days or Acyclovir 200 mg PO 5 times daily for 7-10 days or Famciclovir 250 mg PO tid for 7-10 day or Valacyclovir 1 g PO bid for 7-10 days
Trichomonas vaginalis	Metronidazole 2 g PO or Metronidazole 500 mg bid for 7 days

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 exist, 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 more commonly are 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).
  　
　
Herpes simplex virus
- Of women with their first episode of herpes simplex virus 2 (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 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. 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 as an incidental finding. In a sexually transmitted disease (STD) clinic, HSV was isolated from 4% of randomly selected women. Treatment for asymptomatic shedding is not recommended.
　
Treponema 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 made best using a darkfield microscopic examination of exudate taken from the surface of the lesion. The rapid plasma reagin (RPR) may be positive at a relatively low titer (1/16 or less) at this time. If syphilis is suspected strongly and both the darkfield examination and the RPR findings are negative, a repeat RPR in 2 weeks will be positive.
  　
- Treatment for primary syphilis is benzathine penicillin G 2.4 million units. If the patient is allergic to penicillin, doxycycline 100 mg twice daily for 2 weeks by mouth or tetracycline 500 mg 4 times daily 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.
　
Haemophilus ducreyi (ie, chancroid): The primary ulcer typically is 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 confused easily with cervical carcinoma.
  　
- Four distinct types of lesions exist; 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 trimethoprim-sulfamethoxazole double-strength (DS) tablets twice daily or doxycycline 100 mg orally twice daily. Alternative regimens include ciprofloxacin 750 mg twice daily or erythromycin base 500 mg 4 times daily. Treatment is for a minimum of 3 weeks.
　
Actinomyces organisms
- Actinomyces organisms most commonly are isolated 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 (LGV) and sarcoidosis. An unequivocal diagnosis requires the identification of acid-fast Mycobacterium tuberculosis.
　
Protozoal and parasitic cervicitis usually is part of a more generalized process.
　
Schistosomiasis and amebiasis 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) usually is 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 there may be an associated purulent discharge. 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 occasionally are 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 the following: (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 usually can 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 in size. It most often occurs in women who are on oral contraceptive therapy or Depo-Provera and in pregnant or postpartum women and 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 usually are 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, between 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 who are symptomatic. The cervical leiomyoma usually is part of the spectrum of uterine smooth muscle tumors.

Mesonephric duct remnants

When present, mesonephric duct remnants typically are located at the 3-o𠸍lock and the 9-o𠸍lock 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 visible grossly.

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 usually is 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.

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