Definition

Cervical carcinoma originates from the endocervicalsquamocolumnar epithelial junction. Squamous cell carcinoma represents 90% of cervical carcinomas and develops from precancerous lesions and cervical dysplasia.1
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Prevalence
Cervical cancer is the second leading cause of death from cancer in women worldwide. It is the third most common gynecologic malignancy in the United States and ranks 13th in cancer deaths for American women.2 In the United States, an estimated 13,000 new cases of invasive cervical cancer were diagnosed each year, with 4100 deaths.3,4 Cervical cancer mortality in the United States has decreased over the last five decades by 70%, largely as a result of the introduction of the Papanicolaou (Pap) test.
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Pathophysiology
Invasive cervical cancer develops from a preinvasive state termed cervical intraepithelial neoplasia (CIN). CIN 1 represents mild dysplasia and is now classified as low-grade squamous intraepithelial lesions (LSILs), CINs 2 and 3 encompass moderate-to-severe dysplasia and are classified as high-grade squamous intraepithelial lesions (HSILs) based on the Bethesda cervical cytology reporting system.5 Most LSILs spontaneously resolve, whereas high-grade squamous intraepithelial lesions (HSILs) are more likely to progress to invasive cervical cancer. HSILs are typically detected at an average of 10 to 15 years younger than for invasive cervical cancer. For example, the typical age range for diagnosis of carcinoma in situ is 25 to 35 years, whereas that for invasive cancer is older than 40 years.6 Infection of the cervical epithelium with oncogenic types of human papillomavirus (HPV) is essential to the development of cervical cancer and its precursor lesions (Fig. 1).7,8 Early epidemiologic studies found that at least 76% of cases of CIN could be attributed to HPV infection.9 Women with CIN lesions in the study exhibited the typical epidemiologic profile of sexually transmitted infection: more sexual partners, earlier age at first sexual intercourse, and lower socioeconomic status.

Figure 1: Click to Enlarge Evidence supporting the association between infection by carcinogenic HPVs and the subsequent development of virtually all cervical cancer is conclusive. Cervical squamous intraepithelial lesions demonstrate the classic morphologic changes of HPV infection, such as epithelial hyperplasia (acanthosis) and degenerative cytoplasmic vacuolization (koilocytosis) in terminally differentiated keratinocytes with atypical nuclei.10 HPV has been observed in these lesions using electron microscopy.11 In addition, HPV structural proteins have been detected in surgical specimens using immunohistochemical staining with antibodies that specifically detect HPV viral antigens.12 Large serial studies from 22 countries have shown that more than 90% of cervical squamous cell carcinomas contain DNA from high-risk HPV types, presumably transmitted during sexual activity.7 A more recent study13 indicated the worldwide HPV prevalence in cervical cancer is as high as 99.7%. Furthermore, HPV DNA has been extracted from metastatic cervical cancer tissues and cervical cancer tumor cell lines in culture.14,15 Eighty types of HPV have been sequenced, and approximately 30 of these infect the female and male genital tracts.16Eighteen genital HPV subtypes (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) are classified as high risk because of their close causative association with cervical cancer.17 Research in the last decade has provided a better understanding of the molecular carcinogenesis of HPV. In vitro infection of human epithelial cells by carcinogenic HPV subtypes induces indefinite cell growth, or cell immortalization.18,19 Two HPV viral proteins, E6 and E7 proteins, are required for cell immortalization.20-22 Further studies23-25 revealed that E6 proteins from high-risk HPV interact with the cellular tumor suppressor protein p53. The p53 suppresses cell proliferation by arresting growth in the G1 phase of the cell cycle. E6 proteins from high-risk HPV complexes with p53 and results in the rapid proteolytic degradation of p53 proteins.23,24 The decreased level of p53 protein abolishes the cell's ability to suppress uncontrolled cell proliferation.25 On the other hand, E7 proteins from high-risk HPV bind to another cellular tumor suppressor, the retinoblastoma protein (pRB), and disrupt the complex between the cellular transcription factors E2F-1 and pRB. The free E2F-1 stimulates cellular DNA synthesis and uncontrolled cell proliferation.26 E6 and E7 proteins from HPV-16 can also cooperate to induce centrosome-related mitotic defects and genomic instability.27 It is clear that persistent infection by oncogenic HPVs is a prerequisite for the development of cervical cancer and its precursor lesions, although only a few women infected with HPV eventually develop cervical cancer.
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Screening

The conventional Pap test has been the mainstay of cervical cancer screening since its inception in the 1950s. Screening protocols remained unchanged for the first four of the last five decades. Standardization of cervical cytology and reporting terminology was accomplished in 1988 with the implementation of the Bethesda system. Remarkable new advances in the last decade have transformed our screening protocol. Cervical cytology specimen adequacy and more accurate interpretations of cervical cancer precursors have been achieved by using new liquidbased cervical cytologic smear technology (ThinPrep).28-30 Using the revised Bethesda cytology reporting system (2001), clinicians can better triage patients with abnormal cervical cytology based on less ambiguous terminology.31,32 Data from the National Cancer Institute-sponsored multicenter randomized clinical trial (ALTS trial, 2001) have demonstrated the clinical value of HPV testing in triaging women with atypical squamous cells of undetermined significance (ASC-US).31-33After a diagnosis of ASC-US, clinicians can determine on the basis of HPV testing results whether a woman requires colposcopic examination or needs only to repeat Pap tests 1 year later. More recently, multiple large-scale, cross-sectional studies from several countries have compelled the U.S. Food and Drug Administration (FDA) to approve the hybrid capture 2 test for HPV as an adjunct to the Pap test in primary screening (March, 2003).34-38 It is now evident that virtually all squamous-cell cervical cancers are caused by one of the 18 types of oncogenic HPV.39 As a result, many groups, including the American Cancer Society, the American College of Obstetricians and Gynecologists, the American Society for Colposcopy and Cervical Pathology, and the U.S. Preventive Services Task Force have issued new screening guidelines since 2002.40-42 The following discussions will highlight the consensus recommendations from these organizations and provide clinicians with updates in screening protocols.
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Current practice guidelines

Initiation of Screening
Because of the uncommon occurrence of cervical cancer in women younger than 21 years the high regression rate of LSIL, and the transient nature of HPV infection in sexually active young women, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the U.S. Preventive Services Task Force unanimously recommend that screening begins approximately 3 years after a woman begins having vaginal intercourse, but no later than age 21. The basis of the above recommendation is that cervical cancer and its precursor lesions are almost always related to acquisition of oncogenic HPV infection through vaginal intercourse. It usually takes 3 to 5 years to develop these lesions after the first exposure to HPV infection, and cervical cancer in patients younger than 19 years is rare.43-46 The incidence of invasive cervical cancer was 0/100,000/year for ages 10 to 19 years and 1.7/100,000/year for ages 20 to 24 years, according to the data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program.47 In addition, studies on the natural history of LSILs and HPV infection in young women

aged 13 to 22 years have shown that most HPV infections are transient, with a 70% regression rate within 3 years. Ninety percent of LSILs in this age group spontaneously regress.48-50 Furthermore, the average time of progression for HSILs to a carcinoma in situ or cancer for women younger than 25 years was approximately 5 years.51

Adding HPV DNA Testing to Screening

HPV DNA testing is now included in screening as an adjunct to the Pap test for women 30 years and older. This new screening protocol takes advantage of the high sensitivity and high negative predictive value of HPV DNA testing and the high specificity of cervical cytology. Multiple large-scale studies from several countries, evaluating the role of HPV testing in primary screening, have shown that the combination of a negative Pap test and a negative HPV DNA test indicates the absence of CIN 3 or cancer with almost 100% certainty.34-38 These studies demonstrate that 80% to 100% of cases of histologically confirmed CIN 2 or cancer were found to be positive for high-risk HPV. The sensitivity of HPV DNA testing to detect CIN 2 or a higher-grade lesion is higher than that of a single Pap test. The sensitivity is even higher than that of HPV DNA testing alone, when HPV DNA testing is combined with Pap testing. The rationale for recommending HPV testing in women 30 years and older is based on the finding that the prevalence of high-risk HPV infection declines with age. Among women older than 29 years who have ASC-US, only 31.2% have a high risk for HPV positivity, whereas in women age 28 or younger, high-risk HPV positivity rises to 65%.52 Although HPV infections are extremely common in sexually active younger women, most of these infections will resolve spontaneously or cause only transient, minor lesions. It is very likely that HPV DNA positivity with increased age may reflect the persistence of HPV. This group of older women is at increased risk for development of cervical cancer. Therefore, the specificity and the positive predictive value of an HPV DNA test increases with the age of the woman. The American Cancer Society and American College of Obstetricians and Gynecologists endorse combined Pap and HPV DNA testing in primary screening. Traditional annual screening with a Pap test is still an acceptable option. However, the U.S. Preventive Services Task Force found insufficient evidence to recommend for or against the routine use of HPV DNA testing in a primary screening protocol.

Screening Interval
Women Younger Than 30 Years
The American Cancer Society recommends that cervical screening be performed annually with conventional Pap tests or every 2 years using liquid-based cytology after initiation of screening.40 The American College of Obstetricians and Gynecologists recommends that women in this age group should undergo annual screening.41 The recent guideline of the U.S. Preventive Services Task Force calls for screening every 3 years.42 The rationale for this screening interval was based on relative-risk data on invasive cervical cancer after a negative Pap test result. The difference in risk for progression to invasive cancer in the intervals between screenings is very small when 1-, 2-, and 3-year screening intervals are compared by using conventional Pap tests. Most studies suggest that the relative risk with a 2-year screening interval is 1 to 2 above annual screening, and the relative risk with a 3-year screening interval is in the range of 2 to 3 above annual screening. Longer screening intervals of 4 to 10 years correlate with

increased risk of invasive cervical cancer during the interval.53-59 A large, prospective cohort study of more than 120,000 women in the United States found no significant statistical difference in the age-adjusted incidence rate of HSILs, carcinoma in situ, or invasive carcinoma among women screened at 1, 2, or 3 years after a normal Pap test.60 In addition, the absolute risks of cervical cancer after one, two, and three or more consecutive negative Pap tests was estimated as 3.09, 2.56, and 1.43 per 100,000 women, respectively, based on long-term follow-up data from 2.4 million women belonging to a prepaid health plan.61 It is the consensus recommendation from the American Cancer Society and the American College of Obstetricians and Gynecologists that younger women (younger than age 30) be screened at a shorter interval: 1 year rather than 2 to 3 years, because the sensitivity of the Pap test alone is less than ideal.

Women Older than 30 Years

If the Pap test and the HPV DNA test are both negative in a woman at or after age 30, screening should be performed every 3 years, according to the latest guideline from the American Cancer Society and the American College of Obstetricians and Gynecologists. This recommendation is based primarily on the following key evidence: high-risk HPV infection is required for the development of virtually all cervical cancer,39 and the time from initial HPV infection to development of cervical cancer usually exceeds 10 years.62 A similarly effective screening model exists in colon cancer screening. In a person age 50 years or older who has average risk and a negative colonoscopy, the next colonoscopy should be performed in 10 years. In contrast, because of the lack of definitive prospective data, the U.S. Preventive Services Task Force does not recommend for or against the routine use of HPV testing as a primary screening test.

Discontinuing Screening
Current American Cancer Society guidelines recommend that women older than 70 years who have had three or more normal Pap tests and no abnormal Pap tests in the last 10 years may choose to stop Pap test screening. The guidelines of the U.S. Preventive Services Task Force call for discontinuing screening at age 65. The guidelines issued by the American College of Obstetricians and Gynecologists suggest that physicians should determine on an individual basis when to discontinue screening. There is very low risk of developing cervical cancer for women older than 50 years in the screened population.63-68 In women older than 65 years with at least one negative Pap test within the last 3 years, there is a low rate of LSIL and HSIL. In addition, it is also difficult to obtain satisfactory samples for interpretation from older women because of cervical atrophy and stenosis. However, it is probably reasonable to screen women age 70 and older who have not been screened previously and have new sexual partners.

Screening After Hysterectomy

According to the guidelines issued by the American Cancer Society, the American College of Obstetricians and Gynecologists, and the U.S. Preventive Services Task Force, screening after total hysterectomy for benign

gynecologic disease is not indicated when there is no history of prior CIN, the cervix has been completely removed, and there is no histologic evidence for CIN in the hysterectomy specimen. The incidence of vaginal carcinoma is 1 to 2/100,000/year, far lower than that for cervical carcinoma.69 Thus, the diagnostic yield of vaginal cytology to screen for this cancer after a hysterectomy that includes cervix removal is quite low. Two hundred and twenty women randomly selected from 2066 women who had had a hysterectomy for benign conditions and were followed for an average of more than 7 years in a retrospective study identified only seven patients who had intraepithelial cytologic abnormalities but no vaginal cancer.70 In addition, a cross-sectional study of more than 5000 screening cytology tests in women who had had hysterectomy for benign reasons found only one case of dysplasia and no cancer.71 However, a recent study indicated that almost 10 million women who had had a hysterectomy are being screened even though they are not at risk of developing cervical cancer.72 Education for clinicians and patients is critical in following cervical cancer screening guidelines (Box 1).

Box 1: Current Practice Guidelines for Screening Recommendations for Cervical Cancer Screening 43-45

HPV DNA testing for primary screening ACS: Yes, in combination with the Papanicolaou (Pap) test in women 30 years and older ACOG: Same as ACS recommendation USPSTF: Insufficient evidence to recommend for or against routine use

When to Start Screening

ACS: Approximately 3 years after the onset of vaginal intercourse; no later than age 21 ACOG: Same as ACS USPSTF: Same as ACS

Screening Interval

ACS: Annual with conventional Pap test or every 2 years using liquid-based ThinPrep until age 30. At or after age 30, Pap combined with HPV testing; if both negative, every 3 years ACOG: Annually in women <30 years; in women >30 years, same as ACS USPSTF: Every 3 years

When to Stop Screening

ACS: Age 70 and older who have had three or more consecutive normal Pap tests ACOG: Individual basis USPSTF: Age 65 if patient had adequate recent screening with normal Pap smears

Screening after Hysterectomy

ACS: If hysterectomy for a benign condition: no more screening; if hysterectomy was for precancer: continue screening for 10 years to achieve three consecutive negative Pap tests; if hysterectomy was for cancer, continue screening as long as the patient is in reasonably good health

ACOG: If hysterectomy was for grade 2 or 3 cervical intraepithelial neoplasia, continue annual screening until three consecutive Pap smears are negative

USPSTF: Same as ACS

ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; USPSTF, United States Preventive Services Task Force. The Cleveland Clinic Foundation. All rights reserved.

Management of Women with Abnormal Cervical Cytology

Figure 2: Click to Enlarge

Figure 3: Click to Enlarge Every year approximately 3.5 million women receive a diagnosis of abnormal cervical cytology requiring further evaluation or follow-up. Ignoring this low-grade abnormal cervical cytology is clearly dangerous, yet performing immediate colposcopy for 3.5 million women is definitely not cost-effective and is unnecessary. To help physicians make appropriate evidence-based clinical decisions, the American Society for Colposcopy and Cervical Pathology issued a consensus guideline for the management of women who had an abnormal Pap test in 2002.73 The recommendations are outlined in Figure 2.

Guidelines for Women with Specific Combinations of Combined HPV and Pap Test Results
Following the recent approval by the FDA of HPV testing as an adjunct in primary cervical screening, many more women will undergo combined HPV and Pap tests each year. Clinicians will need to effectively manage women with different combinations of test results. Therefore, the National Cancer Institute, the American Cancer Society, and the

American Society of Colposcopy and Cervical Pathology cosponsored a workshop in 2003 and issued an interim guideline to assist clinicians in using HPV testing in primary screening.74 This interim guidance is summarized in Figure 3.
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Prevention
One of the most exciting advances in cervical cancer prevention is the successful development of the HPV-16 vaccine and its efficacy in preventing HPV-16/18-associated preinvasive cervical lesions and persistent HPV-16/18 infection.75-77 The FDA approved Merck's Gardasil, a quadrivalent HPV 6.11.16, 18 recombinant vaccine, in June of 2006. This vaccine consists of recombinant L1 capsid proteins of specific HPV types that form viral-like particles (VLP). It induces type-specific neutralizing antibody and is given as intramuscular injections at 0, 2, and 6 months. Data from a large clinical trial have demonstrated that HPV vaccine is highly efficacious. No one in the vaccine group and 21 women from the placebo group have developed HPV-16/18-associated CIN 2/3 or adenocarcinoma in situ or cervical cancer in more than 10,000 women enrolled in the study. The Advisory Committee on Immunization Practices (ACIP) of the Center for Disease Control and Prevention (CDC) has recommended immunization for cervical cancer prevention in females 9 to 26 years of age. This elegant study demonstrated for the first time that cervical cancer could be prevented by an HPV vaccine. Future successful development of an HPV vaccine against all oncogenic HPV strains could make the dream of cervical cancer eradication a reality.
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Conclusion
Screening for cervical cancer reduces invasive cervical cancer incidence and mortality. New knowledge of the development of cervical cancer, new technologies such as the liquid-based cervical cytologicsmear, and HPV DNA testing have transformed cervical cancer screening. Clinicians should be aware of the current concepts and practice guidelines and make decisions based on the most current evidence.
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Summary

Cervical cancer is one of the few highly preventable cancers. The early detection and removal of precancerous cervical lesions effectively abolish the development of invasive cervical cancer. The Pap test has been the standard screening test in the Western world for the last five decades. Cervical cancer incidence and mortality have been reduced dramatically as a result of successful screening in many countries.

Tremendous advances in newer cytologic techniques and in our in-depth understanding of cervical cancer pathogenesis have led to many updates of our screening strategy since the turn of this century.

The Female Reproductive System

Female Reproductive Organs

2008 Nucleus Medical Art, Inc. The female reproductive system includes the: Vagina a muscular passage that connects the cervix with the external genitals Cervix the lower part of the uterus that connects to the vagina Uterus a hollow, muscular structure in which the fertilized egg implants and fetus grows during pregnancy Ovaries two glands that produce eggs, as well as the female hormones estrogen and progesterone Fallopian Tubes two tubes that connect the ovaries with the uterus During a womans menstrual cycle, which usually lasts about 28 days, her body prepares for the possibility of a pregnancy.

In the first half of the menstrual cycle, estrogen levels rise to thicken the lining of the uterus. At the same time, an egg begins to mature in one of the ovaries. Around the midpoint of the menstrual cycle (for example, day 14 of a 28-day cycle), a surge of luteinizing hormone (LH), which is produced by the pituitary gland in the brain, causes the mature egg to leave the ovary, a process called ovulation . In the second half of the menstrual cycle, fingerlike projections located at the opening of the fallopian tubes sweep the released egg into the tube toward the uterus. At the same time, rising levels of progesterone help prepare the lining of the uterus for pregnancy. If sperm cells are present at this time, the egg may become fertilized. If no sperm cells are present, the egg either dissolves or is absorbed into the body, no pregnancy occurs, hormone levels drop, and the thickened lining of the uterus is shed during the menstrual period. If fertilization does occur, the fertilized egg grows and divides until it becomes a blastocyst , which is a hollow ball of cells. The blastocyst moves to the uterus, where it attaches itself to the lining, in a process called implantation . The blastocyst is nourished, and continues to grow and divide until it becomes an embryo , which eventually becomes a fetus. Pregnancy lasts for an average of 280 days, or about nine months, until the baby is ready for birth and moves from the uterus through the cervix and out of the vagina.