Cervical Dysplasia

• Cervical dysplasia is precancerous change in the lining cells of the cervix of the uterus.
• Cervical dysplasia is caused by infection with the human papillomavirus (HPV), but other factors also play a role.
• HPV infection is common in the general population. It is unclear why some women develop dysplasia and cervical cancer related to HPV infection while others do not.
• Typically, cervical dysplasia does not produce any signs or symptoms.
• Cervical dysplasia is diagnosed by tissue biopsy from the cervix, vagina, or vulva.
• Treatment, when necessary, involves ablation (destruction) or resection (removal) of the abnormal area.
• A vaccine is available against nine common HPV types associated with the development of dysplasia and cervical cancer

Cervical dysplasia refers to the presence of precancerous changes of the cells that make up the surface of the cervix, the opening to the womb (uterus). The term dysplasia refers to the abnormal appearance of the cells when viewed under the microscope. The degree and extent of abnormality seen on a tissue sample biopsy was formerly referred to as mild, moderate, or severe dysplasia. In recent years, this nomenclature has been replaced by a newer system. These systems are based upon changes in the appearance of cells visualized when smears of individual cells (cytological changes) or tissue biopsies (histological changes) are reviewed under a microscope. Pap smears obtain samples of the surface cells to determine if they are normal or abnormal and do not provide a diagnosis, which can only be done by a tissue biopsy.

1. Pap smears are described according to the degree of abnormality: ASCUS (atypical squamous cells of uncertain significance), LSIL (low grade squamous intraepithelial lesion) and HSIL (high grade squamous intraepithelial lesion. Cells from glandular rather than squamous epithelium may also be described.
2. Cervical intraepithelial neoplasia (CIN) is cervical dysplasia that is a pathological diagnosis based on a cervical biopsy or surgically removed cervix. This is indicated by CIN1 (mild), CIN2 (moderate), CIN III (severe). These are all precancerous conditions.

These classification systems will be further discussed below.

Cervical dysplasia generally develops after infection of the cervix with the human papillomavirus (HPV). Although there are over 100 HPV types, a subgroup of HPVs have been found to infect the lining cells of the genital tract in women. HPV is a very common infection and is transmitted most often through sexual contact. Most infections occur in young women, do not produce symptoms, and resolve spontaneously without any long-term consequences. The average length of new HPV infections in young women is 8-13 months. However, it is possible to become re-infected with a different HPV type.

Some HPV infections persist over time rather than resolve, and the reason why the infection persists in these women is not fully understood. Factors that may influence persistence of the infection include:

• advancing age,
• duration of the infection, and
• being infected with a "high-risk" HPV type (see below).

Persistent HPV infection has been shown to play a causal role in the development of genital warts and precancerous changes (dysplasia) of the uterine cervix as well as cervical cancer. Even though HPV infection appears to be necessary for the development of cervical dysplasia and cancer, not all women who have HPV infection develop dysplasia or cancer of the cervix. Additional, yet uncharacterized, factors must also be important in causing cervical dysplasia and cancer. Since HPV infections are transmitted primarily by sexual intimacy, the risk of infection increases as the number of sexual partners increases.

Among the HPVs that infect the genital tract, certain types typically cause warts or mild dysplasia ("low-risk" types; HPV-6, HPV-11), while other types (known as "high-risk" HPV types) are more strongly associated with severe dysplasia and cervical cancer (HPV-16, HPV-18). Cigarette smoking and suppression of the immune system (such as with concurrent HIV infection) have been shown to increase the risk for HPV-induced dysplasia and cancer of the cervix.

The HPV types that cause cervical cancer also have been linked with both anal and penile cancer in men as well as a subgroup of head and neck cancers in both women and men.

Typically, cervical dysplasia does not produce any signs or symptoms. So regular Pap smear screening is important for early diagnosis and treatment.

Screening for cervical dysplasia

Cervical dysplasia and cervical cancer generally develop over a period of years, so regular screening is essential to detect and treat early precancerous changes and prevent cervical cancer. Historically, the Papanicolaou test (Pap test or Pap smear) was the screening method of choice. To perform the Pap smear, the health care practitioner removes a swab or brush sample of cells from the outside of the cervix during a pelvic examination using a speculum in the vagina for visualization. The cells are smeared onto a glass slide, stained, and observed under the microscope for any evidence of abnormal cells.

Newer, liquid-based systems to screen samples of cervical cells became much more common and are effective screening tools for detection of abnormal cells. The samples for this test are obtained the same way as for the conventional Pap smear, but the sample is placed in a vial of liquid that is later used to prepare a microscope slide for examination as with the Pap smear.

HPV testing to detect human papillomavirus infection has replaced the Pap smear as an accepted or preferred form of screening. According the American Cancer Society, "Those aged 25 to 65 should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Papanicolaou (Pap) test every 5 years or a Pap test alone every 3 years."

Further, the ACS recommends that women over age 65 who have had regular screening in the past 10 years with normal results and no history of CIN2 or more serious diagnosis within the past 25 years stop cervical cancer screening.

The U.S. Preventive Services Task Force (USPSTF) recommends "screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years. For women aged 30 to 65 years, the USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with high-risk human papillomavirus (hrHPV) testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting)."

Further testing

For women whose initial screening result is unclear or abnormal, other diagnostic tests are used:

• Colposcopy is a gynecological procedure that illuminates and magnifies the vulva, vaginal walls, and uterine cervix in order to detect and examine abnormalities of these structures. A colposcope is a microscope that resembles a pair of binoculars. The instrument has a range of magnification lenses. It also has color filters that allow the physician to detect surface abnormalities of the cervix, vagina and vulva.
• A Biopsy is a tissue sample obtained for examination under the microscope. A biopsy is taken from suspicious surface areas seen during colposcopy. A diagnosis can only be made from a tissue biopsy.

Cytologic analysis (screening tests)

Pap smear reports are based on a medical terminology system called The Bethesda System that was developed at the National Institutes of Health (NIH) in Bethesda, Maryland in 1988 and modified in 2001. The major categories for abnormal Pap smears reported in the Bethesda Systems are as follows:

1. ASC-US: This abbreviation stands for atypical squamous cells of undetermined significance. The word "squamous" describes the thin, flat cells that lie on the surface of the cervix. One of two choices are added at the end of ASC: ASC-US, which means undetermined significance, or ASC-H, which means cannot exclude HSIL (see below).
2. LSIL: This abbreviation stands for low-grade squamous intraepithelial lesion. This means changes characteristic of mild dysplasia are observed in the cervical cells.
3. HSIL: This abbreviation stands for high-grade squamous intraepithelial lesion. And refers to the fact that cells with a moderate to severe degree of dysplasia are seen.

Histologic analysis (cervical biopsies)

When precancerous changes are seen in tissue biopsies of the cervix, the term cervical intraepithelial neoplasia (CIN) is used. "Intraepithelial" refers to the fact that the abnormal cells are present within the lining, or epithelial, tissue of the cervix. "Neoplasia" refers to the abnormal growth of cells.

CIN is classified according to the extent to which the abnormal, or dysplastic, cells are seen in the cervical lining tissue:

• CIN 1 refers to the presence of dysplasia confined to the basal third of the cervical lining, or epithelium (formerly called mild dysplasia). This is considered to be a low-grade lesion.
• CIN 2 is considered to be a high-grade lesion. It refers to dysplastic cellular changes confined to the basal two-thirds of the lining tissue (formerly called moderate dysplasia).
• CIN 3 is also a high grade lesion. It refers to precancerous changes in the cells encompassing greater than two-thirds of the cervical lining thickness, including full-thickness lesions that were formerly referred to as severe dysplasia and carcinoma in situ.

(These treatments are for CIN precancerous conditions only and are not appropriate for invasive cancer conditions.)

Most women with low grade (mild) dysplasia (CIN1 when the diagnosis is confirmed and all abnormal areas have been visualized), will frequently undergo spontaneous regression of the mild dysplasia without treatment. In others, it will persist, and in some, it will progress. Therefore, monitoring without specific treatment is often indicated in this group. Treatment is appropriate for women diagnosed with high-grade cervical dysplasia (CIN II and CIN III).

Treatments for cervical dysplasia fall into two general categories: destruction (ablation) of the abnormal area and removal (resection). Both types of treatment are equally effective.

The destruction (ablation) procedures are carbon dioxide laser, electrocautery, and cryotherapy. The removal (resection) procedures are loop electrosurgical excision procedure (LEEP), cold knife conization, and hysterectomy. Treatment is not done at the time of the initial colposcopy, since the treatment depends on the subsequent diagnosis of the biopsies obtained.

This procedure, which is also known as CO2 laser, uses an invisible beam of coherent light to vaporize the abnormal area. A local anesthetic may be given to numb the area prior to the laser treatment. A clear vaginal discharge and spotting of blood may occur for a few weeks after the procedure. The complication rate of this procedure is very low. The most common complications are narrowing (stenosis) of the cervical opening and delayed bleeding. This treatment destroys the abnormal area.

Like the laser treatment, cryotherapy is an ablation therapy. It uses nitrous oxide to freeze the abnormal area. This technique, however, is not optimal for large areas or areas where abnormalities are already advanced or severe. After the procedure, women may experience a significant watery vaginal discharge for several weeks. As with laser ablation, significant complications of this procedure are rare. They include narrowing (stenosis) of the cervix and delayed bleeding. Cryotherapy also destroys the abnormal area and is generally felt to be inappropriate for women with advanced cervical disease.

Loop electrosurgical excision procedure, also known as LEEP, is an inexpensive, simple technique that uses a radio-frequency current to remove abnormal areas. It is similar, but less extensive than a cone biopsy. It has an advantage over the destructive techniques in that an intact tissue sample for analysis can be obtained for pathologic study. Vaginal discharge and spotting may occur after this procedure. Complications rarely occur in women undergoing LEEP, and include cervical narrowing (stenosis) that may interfere with fertility and potentially cause premature labor in a subsequent pregnancy.

Cone biopsy (conization) was once the primary procedure used to treat cervical dysplasia, but the other methods have now replaced it for this purpose. However, when a physician cannot view the entire area that needs to be seen during colposcopy, a cone biopsy is typically recommended. It is also recommended if additional tissue sampling is needed to obtain more information regarding the diagnosis. This technique allows the size and shape of the sample to be tailored to the condition. Cone biopsy has a slightly higher risk of cervical complications than the other treatments, which can include postoperative bleeding and cervical narrowing (stenosis) that may interfere with fertility and also premature labor.

Hysterectomy is the surgical removal of the uterus. Hysterectomy may be used if dysplasia recurs after any of the other treatment procedures.

Low-grade cervical dysplasia (CIN1) often spontaneously resolves without treatment, but careful monitoring and follow-up testing is required. Both ablation and resection of cervical dysplasia are effective for a majority of women with dysplasia. However, there is a chance of recurrence in some women after treatment, requiring additional treatment. Therefore, monitoring is necessary. When untreated, high grade cervical dysplasia may progress to cervical cancer over time.

A vaccine is available against nine common HPV types associated with the development of dysplasia and cervical cancer. This vaccine (Gardasil 9) has received FDA approval for use in women between 9 and 26 years of age and confers immunity against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Abstinence from sexual activity can prevent the spread of HPVs that are transmitted via sexual contact. HPV infection can be transmitted from the mother to infant in the birth canal, since some studies have identified genital HPV infection in populations of young children. Hand-genital and oral-genital transmission of HPV has also been documented and is another means of transmission.

HPV is transmitted by direct genital or skin contact. The virus is not found in or spread by bodily fluids, and HPV is not found in blood or organs harvested for transplantation. Condom use seems to decrease the risk of transmission of HPV during sexual activity but does not completely prevent HPV infection. Spermicides and hormonal birth control methods do not prevent the spread of HPV infection.