Section 4. Colposcopy

A 21-year-old woman presents for her well-woman examination. She has been followed by her physician for many years and has no complaints. She has been sexually active for a little more than 2 years with one mutually monogamous partner. She does not smoke, has never had a sexually transmitted disease (STD), and uses oral contraceptive pills for contraception. On speculum examination, her cervix appears normal (Figure 88-1) and a Papanicolaou (Pap) test is performed.

The colposcope is an optical instrument using light and magnification that helps distinguish dysplasia and cervical cancer from benign cervical findings (Figure 88-2). Colposcopy (colpo: vagina; scope: to look) literally means to look into the vagina. Primary indications for colposcopy include certain abnormal Pap results or an abnormal appearing cervix. Colposcopically directed biopsies have a higher yield than biopsies done without the benefit of a colposcope, thereby decreasing the risk of false-negative biopsies.

Nabothian cysts are also called mucinous retention cysts or epithelial cysts.

An ectropion is also known as a persistent juvenile transformation zone or cervical erosion.

• The Papanicolaou smear (Pap smear, Pap test) is a commonly employed screening test for dysplasia and cancer of the uterine cervix. More than 50 million Pap smears are performed each year in the United States.1 The Pap test is a cytologic examination of cells taken from the cervical transformation zone (Figures 88-3 and 88-4). Colposcopy is the diagnostic test to evaluate patients with an abnormal cervical cytologic smear or abnormal-appearing cervix.
• Nabothian cysts are common and benign and are considered a normal feature of the adult cervix. They may occur singly or multiple cysts may be found simultaneously (Figure 88-4).2
• Infections of the lower female genital tract are common and can produce a number of cervical epithelial changes (Figure 88-5).
• Cervical epithelial atrophy may occur in hypoestrogenic states and cause the cervix to appear pale and the squamocolumnar junction to retract into the cervical os (Figure 88-6).
• Endocervical polyps are the most common benign neoplasms of the uterine cervix (Figures 88-6 and 88-7) and are most commonly found incidentally during pelvic examination. They are most common in the fourth to sixth decades of life and usually are asymptomatic, but may cause vaginal discharge or postcoital spotting.3 Most polyps are benign with the incidence of malignancy being approximately 1 in 1000.4

• Colposcopy entails the use of a field microscope to examine the cervix. The cervix and vagina are examined under magnification, and all abnormal areas are identified.
• If the colposcopy is satisfactory, the entire transformation zone (TZ) is examined and the extent of all lesions is seen (Figure 88-3). Directed biopsies of the most abnormal areas are performed to obtain a tissue diagnosis.
• Colposcopy begins after visualization of the cervix prior to application of acetic acid to look for leukoplakia and abnormal vessels. Acetic acid 3% to 5% is applied with a cotton ball held in a ring forceps or with a rectal swab. Scan the cervix with low power (typically 5×) and determine if the entire TZ, including the entire squamocolumnar junction (SCJ) can be seen. The borders of all lesions must be entirely visible (not disappearing into the canal) for the examination to be adequate.
• Most of the normal cervical findings are derived from the physiologic transformation of the exposed columnar epithelium to squamous epithelium (Figures 88-1 and 88-3). Noncancerous findings may include epithelial thinning and whitening as a result of lack of estrogen, and polyp formations. The damage to the cervical epithelium from various infections often produces inflammation, friability, discharge, and bleeding.

Clinical Features

• Normal colposcopic findings include:5
  • Original squamous epithelium, which is a featureless, smooth, pink epithelium without gland openings or nabothian cysts (Figure 88-4).
  • Columnar epithelium is a single-cell layer, mucous-producing epithelium that extends between the endometrium and the squamous epithelium. Columnar epithelium appears red and irregular with stromal papillae and clefts (Figure 88-4). With acetic acid application and magnification, columnar epithelium has a grape-like or “sea-anemone” appearance.
  • SCJ is a clinically visible line seen on the ectocervix or within the distal canal, which demarcates endocervical tissue from squamous (or squamous metaplastic) tissue (Figure 88-4).
  • Squamous metaplasia is the physiologic, normal process whereby columnar epithelium transforms into squamous epithelium. At the SCJ, it appears as a “ghostly white” or white-blue film with the application of acetic acid. It is usually sharply demarcated toward the cervical os and has very diffuse borders peripherally (Figure 88-4).
  • TZ is the geographic area between the original squamous epithelium (before puberty) and the current SCJ. It may contain gland openings, nabothian cysts, and islands of columnar epithelium surrounded by metaplastic squamous epithelium (Figures 88-3 and 88-4).
  • In some women, the juvenile type TZ persists into adulthood or is present after trauma or childbirth and is termed an ectropion (Figure 88-8). It has a reddish appearance similar to granulation tissue. Ectropion is common in adolescents, pregnant women, and those taking estrogen-containing contraceptives. Although usually asymptomatic, vaginal discharge and postcoital bleeding may occur.6
• Other nondysplastic colposcopic findings:
  • Nabothian cysts are normal areas of mucus-producing epithelium that are “roofed over” with squamous epithelium (Figure 88-4). They may appear translucent or opaque, whitish to yellow, and can range from a few millimeters to several centimeters in size. They always occur in the cervical TZ. They are usually asymptomatic and do not require any treatment.2
  • Cervicitis from an infection may make colposcopic assessment for dysplasia and cervical cancer difficult. Cervicitis appears as friable, inflamed epithelium, often in the presence of a vaginal discharge. Trichomonas may cause an inflamed cervix that has a strawberry appearance (Figure 88-5 and Chapter 84, Trichomonas Vaginitis).
  • Atrophic vaginal or cervical epithelium is frequently white and easily traumatized (Figure 88-6 and Chapter 81, Atrophic ­Vaginitis).
  • Cervical polyps are focal benign hyperplastic protrusions of the endocervical folds. They usually appear as polypoid growths protruding for the cervical os.3

Biopsy

• The colposcope is used to examine the cervix for signs of dysplasia or cancer before performing cervical biopsies (see Chapters 89, Colposcopy of Low-Grade Lesions, 90, Colposcopy of High-Grade Lesions, and 91, Colposcopy of Cervical Cancer for details of suspicious colposcopic findings).

• Friability from infections must be differentiated from dysplastic changes by a history of possible exposure to STDs, presence of discharge, wet prep, and STD testing.

Nonpharmacologic

• Nabothian cysts do not require any treatment. If you tell patients that they have a nabothian cyst, please tell them that this is a normal finding.

Medications

• Atrophic vaginal or cervical epithelium can be treated with intravaginal estrogen for 2 to 4 weeks before colposcopy in order to “normalize” the epithelium. SOR C This is generally safe, even if dysplasia or cancer is present, because the duration of therapy is short, and these lesions do not express any more estrogen receptors than a normal cervix.7
• Vaginocervicitis is treated with antiinfectives once the source is diagnosed.
• Treatment for cervical polyps is removal by twisting the polyp with ringed forceps. Smaller polyps may be removed with colposcopy biopsy forceps. Polyps with a thick stalk may require surgical or electrosurgical removal. If polyps are removed after a recently abnormal Pap test, the polyp should be sent for analysis as dysplasia may be found on the polyp.8
• Cervical dysplastic changes should be handled according to national evidence-based guidelines (see Chapters 89, Colposcopy of Low-Grade Lesions and 90, Colposcopy of High-Grade Lesions).9
• An ectropion may be treated with ablation (such as cervical cryotherapy) if significant discharge or postcoital bleeding is present after dysplasia and cancer have been ruled out.2

• If an infection coexists with an abnormal Pap smear or grossly abnormal appearing cervix, the infection should be treated and the colposcopic assessment should be performed 1 month later.

• Patients should be discouraged from douching as it irritates the mucous membranes, disrupts normal flora, and makes acquisition of an STD more likely if exposed. Safer-sex education should be given to all patients at risk of acquiring an STD.

Patient Resources

• National Cancer Institute. Cervical Cancer Screening—http://www.cancer.gov/cancertopics/screening/cervical.
• WebMD. Colposcopy and Cervical Biopsy—http://www.webmd.com/cancer/cervical-cancer/colposcopy-and-cervical-biopsy.
• MedlinePlus. Nabothian Cyst—http://www.nlm.nih.gov/medlineplus/ency/article/001514.htm.

Provider Resources

• American Society for Colposcopy and Cervical Pathology (includes colposcopy and treatment algorithms)—http://www.asccp.org.
• Medscape. Colposcopy—http://emedicine.medscape.com/article/265097.

A 23-year-old woman has a low-grade squamous intraepithelial lesion on her Papanicolaou (Pap) test. One colposcopic view of her cervix shows acetowhite changes consistent with a cervical intraepithelial neoplasia grade 1 lesion (CIN 1) (Figure 89-1). She has no other suspicious findings and biopsy of the acetowhite area confirms CIN 1. The endocervical curettage is negative for disease. During the follow-up visit, the doctor and patient together decide to proceed with watchful waiting and repeat Pap tests at 6 and 12 months.

Our knowledge of the genesis and development of cervical cancer has grown greatly over the last 20 years. It was once believed that human papillomavirus (HPV) infection and CIN 1 disease were the first steps in cancer formation. We now know that HPV infection and CIN 1 are essentially the same thing and will resolve without treatment in most immunocompetent women.

• In low-grade squamous intraepithelial lesion (LGSIL) tests, the abnormalities are typically associated with HPV infection or CIN grade 1 lesions.1 Overall rates of Pap test abnormalities are often estimated from regional studies. For example, in an observational cohort study of routine cervical tests in the Northwest United States, in women of all ages (n = 150,052), atypical squamous cells was diagnosed at a rate of 9.8 per 1000, LGSIL was diagnosed at a rate of 3.5 per 1000, and negative routine tests occurred at a rate of 278.5 per 1000.2

• Essentially all CIN is caused by HPV. Ten percent to 15% of CIN 1 lesions progress to CIN 2-3I, and 0.3% progress to cervical cancer.3
• There is no way to determine which CIN 1 lesions (Figures 89-1, 89-2, and 89-3) or simple HPV lesions (Figures 89-4 and 89-5) will regress or progress.
• Colposcopy is the standard of care for assessing abnormal Pap tests and cervical dysplasia. It entails the use of a field microscope to examine the cervix after acetic acid (Figures 89-1, 89-2, 89-3, and 89-4) and Lugol iodine (Figure 89-5.) Ten percent to 15% of CIN 1 lesions progress to CIN 2 or 3, and 0.3% progress to cervical cancer.3
• An atypical transformation zone is defined as a transformation zone with findings suggesting cervical dysplasia or neoplasia. Differences in thickness, density of the cells, degree of differentiation, and keratin production determine the color and opacity of the epithelium, and may produce the abnormal findings of leukoplakia and acetowhite epithelium.

• Sexual intercourse.
• Other types of sexual activity including digital/anal, oral/anal, and digital/vaginal contact.
• Immunosuppression.

Clinical Features

• The diagnosis of low-grade cervical abnormalities is made on colposcopic examination. Findings consistent with this diagnosis include:1
  • Acetowhite changes (Figures 89-1, 89-2, 89-3, and 89-4). A transient, white-appearing epithelium following the application of acetic acid may be abnormal and correlates with higher nuclear density. The more sharp and angular the margin is, the likelier it is to be dysplastic. The margins of low-grade disease are usually feathery or geographic borders. Most low-grade lesions are snowy white with a shiny surface. A uniformly papillary surface is often indicative of HPV disease.
  • Punctation is a stippled appearance of small looped capillaries seen end-on, often found within acetowhite area, appearing as fine-to-coarse red dots. Fine punctuation has fine-caliber vessels that are regularly spaced, and is usually associated with benign conditions or low-grade disease (Figures 89-3 and 89-4).
  • Lack of iodine staining (Schiller test) may be used when further clarification of potential biopsy sites is necessary (Figure 89-5). It need not be used in all cases. The sharp outlining afforded by Lugol solution can be dramatic and very helpful.

Laboratory Testing4

• High-risk HPV testing can be used to further define a patient's risk for dysplasia and cancer after an atypical squamous cell (ASC) Pap result. Patients with ASC and a positive high-risk HPV test should be triaged to immediate colposcopy and patients with a negative HPV test may be triaged to re-Pap in 1 year.
• High-risk HPV testing may also be used in conjunction with cytology testing to screen low-risk women at 3-year intervals.

Biopsy

• Biopsy is usually indicated to establish the histologic grade of the abnormalities present.

• CIN 1 and HPV lesions must be differentiated from nonmalignant inflammatory lesions such as yeast vaginitis and sexually transmitted diseases, which usually present with vaginal itching, odor, and/or discharge (see Chapter 83, Candida Vulvovaginitis).
• High-grade dysplasia (CIN 2 and CIN 3) and cancer must also be ruled out, usually by colposcopic examination and biopsy (see Chapter 90, Colposcopy of High-Grade Lesions).

Nonpharmacologic

• According to the 2006 consensus guideline, the preferred treatment for women with CIN 1 and satisfactory colposcopy is repeat cytology at 6 and 12 months or DNA testing for HPV types at 12 months.3,5 SOR B Most cases of CIN 1 spontaneously regress.
• Observation without treatment is acceptable in pregnant women with CIN 1 and in women with unsatisfactory colposcopy.3,5 SOR B
• Pap test screening is not recommended for females younger than the age of 21 years, but if they are inappropriately screened, observation without treatment is recommended for CIN 1 disease.

Complementary and Alternative Therapy

• In one study, oral supplements of indole-3-carbinol were shown to promote regression in high-grade cervical dysplasias when administered orally for 12 weeks.6 SOR B Indole-3-carbinol occurs naturally in cruciferous vegetables, such as broccoli, cabbage, cauliflower, Brussels sprouts, collard greens, and kale, or can be purchased as a supplement.

Surgical

• Treatment options for CIN can be grouped into chemically destructive, surgical ablative, and surgical excisional methods. Cryotherapy, laser, and loop electrosurgical methods are commonly employed when treatment is selected.
• Candidates for outpatient cervical cryotherapy are patients with smaller lesions that do not enter the cervical os. Endocervical sampling is recommended before applying any ablative treatment.3,5 SOR B
• Large lesions (more than 1 inch in diameter, more than a 0.5 inch from the os, or involving more than 2 cervical quadrants) may be more appropriate for loop or laser therapy.3,5 SOR B

• The patient should also be counseled that an HPV vaccine may still be of benefit, if indicated. The U.S. Advisory Committee on Immunization Practices (ACIP) recommends giving the vaccine to girls and women in the indicated age group (11 to 26 years of age) even if they have had an abnormal Pap test; although it will not change the course of the current infection, it will protect from any HPV types to which the patient has not yet been exposed.7
• According to the National Cancer Institute, scientific evidence supports the following for prevention of HPV infection.8
  • Abstinence from sexual activity.
  • Barrier protection and/or spermicidal gel during sexual intercourse.
  • Vaccination against HPV-16/HPV-18.

• Follow-up is in 4- to 6-month intervals until the patient has two serial normal examinations, with colposcopy or colposcopy interspersed with Pap tests. Recurrence is most common in the first 2 years after therapy. Recurrences are most common in the os and on the outside margins.
• After two consecutive negative Pap tests or one negative high-risk HPV DNA test, patients should continue to be routinely screened.

• Smoking cessation counseling is an important part of therapy for women who continue to smoke (see Chapter 236, Tobacco Addiction).

Patient Resources

• American Social Health Association. HPV—http://www.ashastd.org/std-sti/hpv.html.
• Centers for Disease Control and Prevention. HPV VaccineInformation For Young Women—Fact Sheet—http://www.cdc.gov/std/hpv/stdfact-hpv-vaccine-young-women.htm.
• Oncolink. Cervical, Vaginal, Vulvar Cancers—http://oncolink.upenn.edu/types/types.cfm?c=6.

Provider Resources

• Treatment algorithms based on the American Society for Colposcopy and Cervical Pathology 2006 Consensus guidelines for the management of women with abnormal Cervical Cancer Screening Tests—http://www.asccp.org/consensus/cytological.shtml.
• National Cancer Institute. Cervical Cancer Prevention (PDQ®)—http://www.cancer.gov/cancertopics/pdq/prevention/cervical/HealthProfessional.
• Medscape. Colposcopy—http://emedicine.medscape.com/article/265097.

A 36-year-old woman presented for follow-up of a persistently abnormal Papanicolaou (Pap) test. She is a smoker and has had multiple new sexual partners in the last few years. Although she has had several “abnormal Pap tests” in the past, she states she has never needed treatment. She was found to have a dense acetowhite (AW) lesion on colposcopy that was biopsied (Figure 90-1). The pathology returned cervical intraepithelial neoplasia grade 3 (CIN 3) and the patient was treated with loop electrosurgery. She had negative margins on the loop electrosurgical excision procedure specimen and remained recurrence-free at 3 years.

High-grade squamous intraepithelial lesions in adult women are considered true cancer precursors because if left untreated, they have a significant chance of developing into invasive cancer.

Cervical intraepithelial neoplasia (CIN 3 and CIN 2) are high-grade lesions.

• Overall rates of Pap test abnormalities are usually estimated from local or regional studies. For example, in an observational cohort study of routine cervical tests in the Northwest United States, in women of all ages (n = 150,052), high-grade squamous intraepithelial lesion was diagnosed at a rate of 0.8 per 1000 compared to negative routine tests that were diagnosed at a rate of 278.5 per 1000.1

• In high-grade squamous intraepithelial lesions, the abnormalities are immature parabasilar cell types. They have an increased nuclear-to-cytoplasmic ratio, enlarged hyperchromatic nucleoli, few nucleoli, and a reticular or granular appearance.
• On histology, abnormal maturation and nuclear atypia defines CIN. Koilocytosis (perinuclear cytoplasmic vacuolization) is indicative of human papillomavirus (HPV) infection and may be found with high-grade CIN. High-grade CIN is diagnosed when immature basaloid cells with nuclear atypia occupy greater than the lower one third of the epithelium. With increasing lesion severity, there is also increased nuclear crowding, pleomorphism, normal and abnormal mitosis, and loss of polarity.2
• Traditionally, high-grade CIN is thought to arise as a small focus within a larger area of low-grade CIN that expands and eventually replaces much of the low-grade lesion.
• This “monoclonal” theory is supported by the fact that there is a 5-year difference between the peak prevalence of CIN 1 and CIN 2 or 3, and detection of a low-grade squamous intraepithelial lesion. Pap greatly increases the risk that a high-grade CIN will be found on subsequent tests.
• It has been difficult to document the rate of progression because most studies use cervical biopsy to establish an accurate diagnosis, which influences the rate of disease progression.
• With the discovery that most CIN 1 lesions regress or persist, the question has been raised as to whether high-grade CIN might be a process that develops concurrently and somewhat independently from low-grade CIN.
• This theory is supported by the fact that CIN 3 can develop without a detectable preceding low-grade CIN lesion, and high-grade CIN is almost always found closer to the squamocolumnar junction than concomitant low-grade lesions. It has also been found that women who turned HPV-16/-18-positive had a 39% rate of high-grade CIN at 2 years compared to HPV-negative women.
• Schiffman et al. reported that both CIN 1 and CIN 2 or 3 lesions developed within the same time frame in a large group of women who turned HPV-positive and were followed for 4 years.3
• Which theory is most correct is a matter of debate. Many practitioners still treat CIN 1 level lesions on the basis of the monoclonal theory or on the theory that if both lesions arise concomitantly, then treating CIN 1 lesions may be the best way of eliminating high-grade CIN. Others promote the idea of observing CIN 1 lesions and treating only high-grade CIN lesions.

• HPV infection.4
• Nonuse of barrier protection and/or spermicidal gel during sexual intercourse.
• No Pap testing within the last 3 years in low-risk women with a cervix or within 1 year for high-risk women.
• Nonvaccination status for HPV-16 and HPV-18.
• Tobacco smoking.

Clinical Features

• Leukoplakia, as shown in Figure 90-2, is typically an elevated, white plaque seen prior to the application of acetic acid. It is caused by a thick keratin layer that obscures the underlying epithelium and may signal severe dysplasia or cancer. Although it may be associated with benign findings, it always warrants a biopsy.
• AW epithelium following the application of acetic acid is typical for CIN 2 and 3 lesions (Figure 90-1). The AW effect tends to develop more slowly than in lower-grade lesions and to persist longer. The margins of high-grade CIN are straighter and sharper compared to the vague, feathery, geographic borders of CIN 1 or HPV disease.
• With increasing levels of CIN, desmosomes (intracellular bridges) that attach the epithelium to the basement membrane are often lost, producing an edge that easily peels. This loss of tissue integrity should raise the suspicion of high-grade dysplasia. The extreme expression of this effect is the ulceration that sometimes forms with invasive disease.
• High-grade CIN lesions are usually proximal to or touch the squamocolumnar junction, even when contained in larger lesions (Figures 90-1, 90-2, 90-3, 90-4 and 90-5).
• Nodular elevations on the surface of lesions and ulceration are suspicious for high-grade or invasive cancer.
• Increases in local factors such as tumor angiogenesis factor or vascular endothelial growth factor, which are much more commonly produced by CIN 3 lesions, cause growth of abnormal surface vasculature, producing punctuation (Figures 90-3 and 90-4), mosaicism (Figures 90-5 and 90-6), and frankly abnormal vessels. However, most high-grade lesions do not develop any abnormal vessels.
• Punctation is a stippled appearance of small looped capillaries seen end-on, often found within AW area, appearing as fine-to-coarse red dots (Figures 90-3 and 90-4). Course punctation represents increased caliber vessels that are spaced at irregular intervals, and is more highly associated with increasing levels of dysplasia.
• Mosaicism is an abnormal pattern of small blood vessels suggesting a confluence of “tiles” or a “chicken-wire pattern” with reddish borders. Mosaicism represents capillaries that grow on or near the surface of the lesion that forms partitions between blocks of proliferating epithelium (Figures 90-5 and 90-6). It develops in a manner very similar to punctation and is often found in the same lesions. Course mosaic forms a consistently irregular cobblestone effect with dilated coarse vessels which is highly associated with CIN 2 and 3.

Typical Distribution

• CIN 2 or 3 disease usually touches the active squamocolumnar junction (SCJ).
• When CIN 2 or 3 coexists in the same lesion with a lower-grade lesion, the higher-grade lesion often presents with a sharply defined internal border (also known as a border-within-a-border). The higher-grade disease is usually proximal to the os.

Laboratory Testing

• High-risk HPV testing is not useful for the diagnosis of CIN 2 or 3. It can be useful for posttreatment follow-up.5

Biopsy

• Biopsy is usually indicated to establish the histologic grade of the abnormalities present. Biopsies are performed under colposcopic direction.

• CIN 2 and 3 lesions must be differentiated from nonmalignant inflammatory lesions, especially trichomoniasis and Chlamydia infections, which usually present with vaginal itching, odor, and/or discharge (see Chapter 84, Trichomonas Vaginitis, and Chapter 85, Chlamydia Cervicitis).
• Flat HPV lesions may mimic the dense AW lesions of CIN 2 and 3.
• CIN 2 and 3 lesions must be differentiated from both CIN 1 and cancer (see Chapter 89, Colposcopy of Low-Grade Lesions, and Chapter 91, Colposcopy of Cervical Cancer).

• Except in special circumstances, women with biopsy-confirmed CIN 2 or 3 should be treated. CIN 2 may be followed with colposcopy and Pap tests in patients who have not attained their 21st birthday.5,6
• Effective treatment of CIN 2 and 3 requires the removal of the entire transformation zone rather than just the removal of the lesion. When colposcopy is satisfactory, any ablative or excisional modality will treat CIN effectively.5 SOR A However, because excisional modalities allow for the pathologic identification of unanticipated microinvasive or occult invasive cancer, some physicians prefer these methods to treat biopsy-confirmed CIN 2 and 3.2 SOR C
• Both excision and ablation are acceptable treatment choices for nonpregnant adult women with a histologic diagnosis of CIN 2 and 3 and satisfactory colposcopy. For adolescents and young women with a histologic diagnosis of CIN 2, observation with colposcopy and cytology at 6-month intervals is preferred, but treatment is acceptable.
• Observation is unacceptable in women with CIN 2 except during pregnancy and in very compliant adolescents with satisfactory colposcopy and negative results on endocervical curettage.6 SOR C
• A randomized clinical trial demonstrated that condom use promotes regression of CIN and clearance of HPV.7 SOR B
• Because a small number of women with biopsy-confirmed CIN 2 or 3 and unsatisfactory colposcopy have occult invasive cancer, excisional procedures should be performed. Cold knife and loop electrosurgical excision procedure conizations effectively diagnose and treat these women.6 SOR B

Complementary and Alternative Therapy

• In one study, oral supplements of indole-3-carbinol have been shown to promote regression in high-grade cervical dysplasias when administered orally for 12 weeks.8 SOR B Indole-3-carbinol occurs naturally in cruciferous vegetables, such as broccoli, cabbage, cauliflower, Brussels sprouts, collard greens, and kale, or can be purchased as a supplement.

• The patient should also be counseled that an HPV vaccine may still be of benefit if indicated. The U.S. Advisory Committee on Immunization Practices (ACIP) recommends giving the vaccine to women in the indicated age group (11 to 26 years of age) even if they have had an abnormal Pap test. Although it will not change the course of the current infection, it will protect her from other HPV types to which she has not yet been exposed.6
• According to the National Cancer Institute (NCI), scientific evidence supports the following for prevention of cervical cancer:9
  • Prevention of HPV infection through abstinence from sexual activity and barrier protection and/or spermicidal gel during sexual intercourse.
  • Vaccination against HPV-16/HPV-18.
  • Screening via gynecologic examinations and cytologic screening.
• Avoidance of all tobacco smoke.

• For untreated CIN 2, approximately 43% will spontaneously regress, 35% will persist, and 22% will progress to carcinoma in situ or invasive cancer.2 The regression rate of CIN 2 is higher in adolescents.
• For untreated CIN 3, approximately 32% will regress, 56% will persist, and 14% of CIN 3 will progress to carcinoma in situ or invasive cancer.2

• After treatment for CIN 2 or 3, acceptable management methods include cytology with or without colposcopy at 4- to 6-month intervals until three negative evaluations have been obtained, or HPV DNA testing no sooner than 6 months after treatment.5,6 SOR C
• The preferred management for CIN identified at the margin of a diagnostic excisional procedure or in postprocedure endocervical sampling is colposcopy and endocervical sampling at the 4- to 6-month follow-up evaluation.5,6 SOR C

• Tobacco smoking has been linked to the development and recurrence of CIN. Part of any treatment program should include smoking cessation.

Patient Resources

• National Cancer Institute. What You Need to Know About Cancerof the Cervix—http://www.cancer.gov/cancertopics/wyntk/cervix.
• Oncolink. Cervical, Vaginal, Vulvar Cancers— http://oncolink.upenn.edu/types/types.cfm?c=6.

Provider Resources

• National Cancer Institute. Cervical Cancer Prevention (PDQ®)—http://www.cancer.gov/cancertopics/pdq/prevention/cervical/HealthProfessional.
• Treatment algorithms based on the American Society for Colposcopy and Cervical Pathology 2006 Consensus guidelines for the management of women with CIN—http://www.asccp.org/ConsensusGuidelines/tabid/7436/Default.aspx.

A 51-year-old woman presents with postcoital bleeding. She has not had a period in 3 years, but has started spotting after intercourse. Her last Papanicolaou (Pap) smear was after the birth of her last child 25 years ago and was normal. Other than an occasional mild hot flash, she has no other complaints. On colposcopy she was found to have a densely acetowhite lesion with abnormal vessel near the cervical os (Figure 91-1). Biopsy demonstrated invasive squamous cell carcinoma. The patient then had a radical hysterectomy with pelvic/paraaortic lymphadenectomy. Fortunately her lymph nodes were all negative.

Colposcopy is an important visualization technique used to investigate abnormal Pap smears and to direct biopsies for histologic diagnosis of cervical cancer. Because human papillomavirus (HPV) is present in 95% to 100% of all squamous cell cancers (SCCs), the International Agency for Research on Cancer proclaimed cervical cancer to be the first human cancer known to have a single necessary cause.1,2

• Carcinoma of the cervix is the second most common cancer in women worldwide with an estimated 400,000 to 500,000 cases of cervical cancer diagnosed each year.3,4
• In the United States, an estimated 12,170 new cases and approximately 4220 deaths occur annually, even though more than 50 million Pap smears are performed each year.5
• Half of the cases occur in women never screened and an additional 10% in women not screened within the past 5 years.6
• Ninety-three percent of invasive cervical cancers are SCCs (Figures 91-1, 91-2, 91-3, and 91-4). They almost all contain HPV DNA, and 90% are subtypes 16 or 18, which are most virulent.7
• Approximately 7% of cases are adenocarcinomas but these are on the rise7 (Figure 91-5).
• It is rare to find invasive cancer of the uterine cervix in pregnancy. The incidence varies from 1 to 15 cases per 10,000 pregnancies, and the prognosis is similar to that of nonpregnant patients.8
• The peak prevalence of invasive cervical cancer is 40 to 50 years of age.9

• Oncogenic HPV serve as initiators, and other factors relating to immune status, such as cigarette smoking, nutrition, or other genital infections, may be promoters.10
• Cervical cancer is unique in that no other human cancer has been shown to have such a clearly identified cause, which are oncogenic strains of HPV.1

• HPV infection.11
• Nonuse of barrier protection and/or spermicidal gel during sexual intercourse.
• No Pap testing within the last 3 years in low-risk women with a cervix or within 1 year for high-risk women.
• Nonvaccination status for HPV-16 and HPV-18.
• Tobacco smoking.

Clinical Features

• Leukoplakia is typically an elevated, white plaque seen prior to the application of acetic acid. It is caused by a thick keratin layer that obscures the underlying epithelium (Figure 91-1). It always ­warrants a biopsy.
• Early invasion often is associated with a decline in the acetowhite reaction. Yellow hued color change is also a marker for early or frank invasive lesions (Figure 91-4).
• With increasing levels of cervical intraepithelial neoplasia (CIN), desmosomes (intracellular bridges) that attach the epithelium to the basement membrane are often lost, producing an edge that easily peels. This loss of tissue integrity should raise the suspicion of high-grade dysplasia. The extreme expression of this effect is the ulceration that sometimes forms with invasive disease. The ulcer can have a rolled edge around the ulcer without vessels visible in the ulcer cavity.
• Nodular elevations and ulceration are suspicious for high-grade or invasive cancer.
• Course punctation and course mosaic patterns may be associated with high-grade dysplasia or cancer (see Chapter 90, Colposcopy of High-Grade Lesions).
• Abnormal blood vessels are atypical irregular surface vessels that have lost their normal arborization or branching pattern (Figures 91-1 and 91-2). This represents an exaggeration of the abnormalities of punctation and mosaicism, and it usually represents increasing severity of the lesion. They can be indicative of invasive cancer, but can occasionally be seen with high-grade CIN. These vessels are often best seen before application of acetic acid. They are usually nonbranching, appear with abrupt courses and patterns, and often appear as commas, corkscrews, hairpins, or spaghetti. They may also appear as coarse parallel vessels. There is no definite repetitive pattern as with punctation or mosaic.
• A thin watery vaginal discharge is the most common early complaint of a woman with cervical cancer. As the lesions progress or enlarge, complaints occur of postcoital bleeding or painless intermenstrual bleeding.
• More advanced lesions present with heavier and frequent bleeding until it may become continuous. Pain, hematuria, obstipation, and rectal bleeding are symptoms of late disease because of local direct invasion of surrounding paracervical structures. Lower-extremity edema may occur with pelvic sidewall involvement of tumor. Hemorrhage and uremia are preterminal events.
• Findings on speculum examination include an exophytic mass (Figures 91-3 and 91-5), cervical ulcer, or barrel-shaped cervix.

Laboratory Testing

• Although HPV testing is used for screening for cervical cancer, it is not useful in the diagnosis of the disease.

Imaging

• The staging of biopsy proven cervical cancer remains clinical. Physical examination with cystoscopy and proctoscopy usually starts the process. Routine x-ray studies are also used, including chest x-ray, intravenous pyelogram, and barium enema.

Biopsy

• Colposcopy and biopsy are needed to make the diagnosis. A histologic biopsy that is suspicious, but not confirmatory, of invasion requires cervical conization for definitive diagnosis. A biopsy of microinvasive carcinoma requires conization for definitive diagnosis and to rule out a more invasive lesion. A biopsy with definitive invasion greater than 5 mm does not require conization to plan therapy. Any frank lesion of the cervix requires biopsy for diagnosis.

• Because some cancers of the cervix ulcerate, cervical cancer must be differentiated from nonmalignant ulcerative diseases such as herpes virus infections (see Chapter 129, Herpes Simplex).
• Cervical cancer must be differentiated from CIN II and CIN III lesions (see Chapter 90, Colposcopy of High-Grade Lesions).
• Flat HPV lesions may mimic dense acetowhite lesions or leukoplakia (see Chapter 133, Genital Warts). A colposcopically directed biopsy can distinguish between these conditions.

• Table 91-1 shows the staging and treatment methods for cervical cancer.

• Most cases are detected in the precancerous stages or as early disease in industrialized countries through the use of the Pap test and HPV testing.12 The current death rate, however, is far higher than it should be because the Pap test and HPV testing are not performed on approximately 33% of eligible women.

• The prognosis for patients with cervical cancer is mostly defined by the extent of disease at the time of diagnosis (see Table 91-1).13 Clinical stage, volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion also affect prognosis. The factors that best predict decreased disease-free survival are depth of stromal invasion, capillary-lymphatic space involvement by tumor, and increased tumor size.

• Early stage (International Federation of Gynecology and Obstetrics stages IA to IIA) SCC is treated with radical hysterectomy and pelvic/paraaortic lymphadenectomy or radiation therapy. In patients with positive resection margins or positive lymph nodes, post­operative chemotherapy and/or radiotherapy is often used.
• Stages IB2 and IIA disease is treated with either chemoradiotherapy alone, surgery followed by chemoradiotherapy, or chemotherapy and radiotherapy followed by hysterectomy.
• For patients with stages IIB, III, and IVA cervical SCC, chemotherapy plus radiotherapy is usually recommended over radiation therapy alone.

• Fertility-sparing surgery is available for very early stage cervical cancer. Menopausal symptoms are a common side-effect of chemotherapy.

Patient Resources

• Oncolink. Cervical, Vaginal, Vulvar Cancers—http://oncolink.org/types/article.cfm?c=6&s=17&ss=129&id=8226.
• National Cancer Institute. General Information About Cervical Cancer—http://www.cancer.gov/cancertopics/pdq/treatment/cervical/Patient.
• National Cancer Institute. What You Need To Know About Cancer of the Cervix—http://www.cancer.gov/cancertopics/wyntk/cervix.

Provider Resources

• American Society for Colposcopy and Cervical Pathology- sponsored Consensus Conference. 2006 Consensus Guidelines for the Management of Women with Cervical Intraepithelial Neoplasia or Adenocarcinoma in Situ—http://www.asccp.org/consensus/histological.shtml.
• National Cancer Institute. General Information About CervicalCancer—http://www.cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional.