Treatment Guidelines

Treatment of Precancers

According to the ASCCP Guidelines for the Management of Women with CIN, treatment of CIN should be based on the histologic results stemming from colposcopy with biopsy. Since most CIN 1 lesions regress spontaneously, conservative management with close observational follow-up is a reasonable option, with treatment reserved for those that persist. For CIN 2/3 lesions, surgical ablative or excisional treatments such as cone biopsy or loop electrosurgical excision procedure (LEEP) are recommended [Wright, 2003].

Figure 47. Management of Histologic Abnormalities after Colposcopy with Biopsy

Women with Biopsy-Confirmed CIN 1

The natural history of CIN 1 is characterized by high rates of spontaneous regression and low rates of progression to invasive cancer. Primary management consists of follow-up with either repeat cytology at 6 and 12 months or HPV DNA testing at 12 months. Another acceptable approach is a combination of repeat cytology and colposcopy at 12 months.

Women with Biopsy-Confirmed CIN 2/3

Unlike CIN 1, a histologic diagnosis of CIN 2/3 is more likely to persist or progress than regress. Surgical excision/ablation procedures are acceptable modalities in patients with CIN 2/3.

Following excisional or ablative procedures for CIN 2/3, cytology should be performed at 4 to 6 months until three consecutive negative cytologies are obtained; then annual cytologic screening can be resumed. Alternatively, HPV DNA testing can be performed 6 months after treatment. If the results are positive for high-risk HPV types, colposcopy is recommended; if the results are negative, the patient can return to annual cytologic screening.

With adolescents, a more conservative approach may be taken since HPV-related lesions are common but invasive cervical cancer is rare in this population. Therefore, observation may be appropriate for adolescents with biopsy-con-firmed CIN 2 who are considered to be reliable for follow-up. In contrast, there is a high rate of recurrence/persistence of CIN 2/3 in women infected with HIV, in whom the level of immunosuppression correlates with the level of risk.

Figure 48. Histology of CIN 1,CIN 2, and CIN 3

Correlation between Cytologic and Histologic Findings

It is important to note that a particular cytologic result is not necessarily a reliable predictor of the CIN grade found on colposcopy. For example, Table 15 illustrates the relationship between different cytologic results and histologic findings of CIN 2/3 on colposcopy with biopsy. Even among expert cytologists, the interpretation of cervical cytology results is not always reproducible. In the 2001 consensus guidelines for the management of women with cervical cytological abnormalities it was reported that a woman with ASC by cervical cytology had a 5% to 17% chance of having CIN 2/3 confirmed by biopsy. Similarly, cytological grade is a relatively poor predictor in women with LSIL or HSIL; 15-30% of women with LSIL on cervical cytology and 70-75% of women with HSIL on cervical cytology will have CIN 2 or 3 identified on cervical biopsy [Wright, 2002]. These results summarized in Table 15 below stress the necessity of additional testing for an abnormal result.

Table 15. Cytologic Results Associated with Percent of CIN 2/3 Found on Colposcopy

In summary, Figure 49 provides a general comparison of the Bethesda Classification, CIN grades, and the corresponding histology. It is important to bear in mind that this representation is not intended to provide an exact (that is 1:1) correspondence between all cytologic and histologic grades, but rather to illustrate common relationships between categories.

Figure 49. Comparison of the Bethesda Classification, CIN grade, and Corresponding History for Squamous Intraepithelial Lesions

Treatment of CIN and CIS

Current procedures performed when managing CIN and CIS include surgical ablative and surgical excisional procedures. Ablative procedures destroy abnormal tissue and thus do not produce a tissue specimen for additional histological examination; surgical excisional procedures cut out the abnormal area preserving it for additional histological evaluation. Both types of procedures are normally performed on an outpatient basis. Following these therapeutic procedures, lesions recur at a rate of up to 10% because latently infected cells may persist. Therefore, it is necessary to perform cytologic follow-up at approximately three-month intervals for one year.

Surgical Ablative Procedures

Before cervical ablation can be performed, the following criteria have to be met: a satisfactory colposcopic examination, an agreement in pathologic and colposcopic diagnosis, no endocervical canal neoplasia, and the exclusion of cervical cancer. For cryosurgery, the cure rates of premalignant lesions are related more to lesion grade (CIN 1 or 2) than lesion size.

Surgical Excisional Procedures

Surgical procedures such as LEEP, conization, and hysterectomy may be used in patients with CIN. LEEP has advantages over laser therapy including reduced cost, shorter treatment time, and less discomfort. Consequently, LEEP has become the procedure of choice for CIN 2/3. Indications for conization are: a lack of correlation between cytologic, colposcopic, and histologic findings; a positive endocervical curettage; any portion of lesion in the endocervical canal; cytology or colposcopic biopsy that indicates AIS; microinvasive squamous cell carcinoma noted on colposcopic biopsy; or an invasive carcinoma suggested by cytology or colposcopy but not proven by colposcopy-directed biopsy.

In some cases, a hysterectomy may be warranted in the treatment of CIN when CIN 3 is seen at the limits of the conization specimen, when there is microinvasion, when there is poor compliance by the patient with regard to follow-up, or when there are other gynecologic problems that require a hysterectomy (such as fibroids, endometriosis, and pelvic inflammatory disease).

Treatment of Cervical Cancer

A woman’s course of treatment and prognosis are determined by the histological type, stage and size of the tumor; the overall physical health and age of the woman; potential complications from surgery or treatment (radiation/chemotherapy); and the woman’s preference for fertility-sparing treatments.

The type and stage of cervical cancer are the most important factors associated with a woman’s chances of survival. Unfortunately, when left untreated or if treatment fails, 95% of women do not survive 2 years after diagnosis.

Several different types of treatment are available for patients with cervical cancer. The National Cancer Institute has developed guidelines for cervical cancer treatment based on the stage of cancer at diagnosis which are listed in Table 16 [Natl Cancer Inst, Available at: http://www.nci.nih.gov/cancertopics/pdq/treatment/cervical/Patient/page5].

Table 16. National Cancer Institute Recommended Treatment Options for Cervical Cancer

Surgery

In the earliest stages of disease, cervical cancer is highly curable by removing (excision) or destroying (ablation) the cancerous tissue. Treatment options that avoid significant damage to the cervix and uterus are often selected to preserve a woman’s ability to have children. These fertility-sparing procedures, also used in the treatment of CIN, include cryosurgery, carbon dioxide laser beam, LEEP (loop electrosurgical excision procedure), and conization. Additionally, when cancer has spread beyond the cervix to adjacent pelvic tissues, a hysterectomy may be required [Hatch & Berek, 2002].

Ablative Procedures

Cryosurgery

With cryosurgery (also referred to as cryotherapy), the abnormal epithelium and 5 to 7 mm of surrounding tissue are frozen with a supercooled probe (cryoprobe). Gases such as nitrous oxide and carbon dioxide are most commonly used to cool the probe to -20 to -30°C. Normally, a single freeze of such tissue does not induce adequate necrosis so the area is thawed and the procedure is repeated. Advantages of this procedure are its relatively low cost, widespread availability and low complication rate. A disadvantage is a heavy, odorous discharge lasting several weeks.

Carbon Dioxide Laser Beam

Carbon dioxide laser beam appears to be as effective as cryosurgery. In this procedure, a laser beam is used to make bloodless cuts in tissue or to remove a surface lesion. As with cryosurgery, laser surgery should destroy tissue to a depth of 5 to 7 mm. It may be particularly applicable to larger lesions that cannot be adequately covered by the cryoprobe and lesions in areas difficult to access. Carbon dioxide laser beam is costly and the technique is more difficult to learn than the other surgical procedures.

Excisional Procedures

LEEP (loop electrosurgical excision procedure)

In LEEP, also known as loop diathermy, the transformation zone and distal endocervical canal is excised (not burned) with an electrically-charged wire (an electrical current passed through a thin wire loop). The benefit of this procedure is that the excised tissue is preserved for histologic examination to confirm the lesion was completely removed (by examining the tissue margin) and invasive cancer excluded; this procedure performs both a therapeutic and diagnostic function.

Conization

Conization (also called excisional cone biopsy or cone biopsy) is therapeutic in that it removes a cone-shaped piece of abnormal tissue from the cervix and cervical canal and diagnostic in that the tissue can be examined to rule out invasive cancer. Conization is used to manage CIN and microinvasive cancers <3 mm in size. The primary complications of the procedure are perioperative and postoperative bleeding; symptomatic cervical stenosis and uterine perforation can also occur.

Hysterectomy

A hysterectomy, the surgical removal of the uterus and cervix, is often performed when the cancer has spread beyond the cervix into the uterus or ovaries. A hysterectomy may be performed through an abdominal incision (abdominal hysterectomy), a vaginal incision (vaginal hysterectomy), or through small laparoscopic incisions into the abdomen (laparoscopic hysterectomy). A woman’s uterus may be completely or partially removed and, if necessary, her ovaries and fallopian tubes may also be removed as part of this procedure. Complete removal of the uterus and cervix is called a total hysterectomy, whereas further removal of surrounding tissues and the upper part of the vagina is known as a radical hysterectomy.

Exenteration

When a hysterectomy and radiation/chemotherapy are unsuccessful, a pelvic exenteration may be performed for cancers involving multiple pelvic tissues and organs. In women, pelvic exenteration involves removal of the cervix, vagina, ovaries, and surrounding lymph nodes, as well as the lower colon, rectum, and bladder, with creation of stomata through which urine and stool can be passed from the body.

Radiation Therapy

Cancer that has spread to surrounding pelvic tissues may be managed with radiation therapy targeted to the primary tumor and potential areas of local invasion. External radiation therapy uses a machine outside the body to send radiation toward the cancer, often from multiple different directions. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that is inserted directly into a tumor or placed near the cancerous tissue.

Radiation may be used in early stage cancers to eradicate or control the disease. It is often used prior to surgery to reduce tumor size or after surgery to prevent the cancer from returning. In some cases it may be used along with surgery and/or chemotherapy.

Chemotherapy

Chemotherapeutic agents stop the growth of cancer by either preventing further rapid division or multiplication of cells or by completely destroying the cells. The method of administering chemotherapy is determined by the type and stage of the cancer being treated.

Potential Complications

Despite treatment, some types of cervical cancer that are less responsive to treatment may persist. Cancer may also recur, particularly in women who are treated with methods that preserve the uterus and fertility. Finally, some women may experience reduced sexual function and altered bowel and bladder function as a result of surgery and/or radiation.

Treatment of Anogenital Warts

Genital warts spontaneously regress over a four-month period in approximately 30% of patients; however, in those that do not regress, the primary goals of treatment are to limit any symptoms and to remove the warts [Lacey, 2005]. It is unclear whether treatment of external genital warts is able to eradicate the virus. Treatment modalities for genital warts fall into three categories:

• chemical and physical destruction
• surgical excision
• patient- or physician-applied topical drugs

Currently, there is no standard treatment for genital warts; each patient responds differently to each treatment modality. Overall response rates vary from 5 to 65% and recurrences occur in approximately 25% of patients over a three-month period [Lacey, 2005]. The choice of therapy is determined by the number, location, morphology and size of the warts as well as patient preference. Table 17 below summarizes the various treatment options.

Table 17. Treatment Options for External Genital Warts

Surgical excision of warts involves the removal of the wart at the dermal-epidermal junction. This process can leave some scarring, but is the preferred method of choice when there is a large area affected or when there are numerous warts. The benefit of this option is that the patient can be wart-free after only one visit. However, since only the visible lesion is removed and not the under-lying infected keratinocytes, recurrences average approximately 20%.

Cryotherapy, a form of physical destruction, uses extreme cold to remove warts. Liquid nitrogen is applied to the tissue surrounding the wart, and the wart is removed when the surrounding tissue sloughs off. This method works optimally when the number of warts is small, and can be used for either dry or moist warts. Another mechanism of physical destruction is the use of carbon dioxide lasers. This is the best method for intraurethral or extensive vaginal warts. Specialized training and equipment is required with this method. Generally, this is the most expensive method of wart removal.

Location of the warts is an important consideration when deciding on whether to use topical agents. Generally, the drier the surface, the less likely topical treatments will be effective. Patients often require more than one course of topical agents for their warts. The use of topical agents for the treatment of genital warts can be divided into two groups: patient-applied and physician-applied.

Patient-applied treatments

The two most commonly used patient-applied treatments are podofilox (podophyllotoxin) and imiquimod cream [Gunter, 2003]. Podofilox is an antimitotic agent which is capable of preventing proper cell division, inducing blood vessel damage within warts and stimulating cytokine production. This treatment is not recommended for warts found on the vagina or anus, and should not be used during pregnancy.

Imiquimod is supplied as a 5% cream which is topically applied to warts at night, then washed off in the morning. The cream does not directly inhibit HPV, but works by stimulating both the innate and adaptive immune responses. Imiquimod has a higher wart clearance rate in women than men, but even in those patients that do not clear their warts completely, many have a reduction in wart area.

Physician-applied treatments

Podophyllin resin is an antimitotic agent that is applied in the physician’s office. Because it is neurotoxic, its use is limited to small areas, and it is unsuitable for mucosal surfaces or during pregnancy. The varying degree of effectiveness seen with this compound is a result of its instability.

Trichloroacetic acid (TCA) is applied directly to the surface of warts. It can be used on vaginal, cervical, periurethral, and anal warts, and can be used during pregnancy. Frequent applications during multiple physician office visits are often required.

References

Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003;189(3S):S3-S11.

Hatch KD, Berek JS. Intraepithelial Disease of the Cervix, Vagina, and Vulva. In:Berek JS, ed. Novak’s Gynecology, 13th ed. Philadelphia, PA: Lippincott Williams &Wilkins;2002:471-505.

Lacey C. Therapy for genital human papillomavirus-related disease. J Clin Virol.2005;32S:S82-S90.

National Cancer Institute. http://www.nci.nih.gov/cancertopics/pdq/treatment/cervical/Patient/page5

Wright, TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

Wright, TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120-2129.

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