Affecting an estimated 500,000 new patients each year, cervical cancer is the second most common malignancy in women worldwide and remains a leading cause of cancer-related death among women in developing countries.  In the United States, however, cervical cancer is fortunately less common, having declined over the past few decades as a result of improved screening practices, preventative immunizations, and timely treatment of invasive disease.¹ In an effort to further improve outcomes, screening guidelines are currently being revised to target women most likely to benefit from assessment, while concurrently reducing potential harms associated with over-screening and over-diagnosis.²  New scanning devices, designed to detect cervical disease through optical spectroscopy, are also under investigation and may prove to be valuable diagnostic tools.³ In implementing and complying with best practices, it is imperative that healthcare professionals be well-informed regarding current and emergent screening tools and recommendations.

Pathogenesis and Etiology of Cervical Cancer

In reviewing general pathophysiology of cervical cancer in broad strokes, potentially cancerous precursor lesions found on the uterine cervix are referred to as cervical intraepithelial neoplasia (CIN), or intraepithelial squamous abnormalities that exhibit nuclear atypia.⁴ These lesions may be further classified as mild, moderate, or severe, based on the extent of epithelial involvement. CIN I, or mild dysplasia, typically involves one-third of the cervical epithelium; CIN II, which denotes moderate to marked dysplasia, involves two-thirds of the epithelium, while CIN III, which indicates severe dysplasia or carcinoma in situ (CIS), involves the full thickness of the epithelium.⁵ CIN I generally corresponds to a low-grade squamous intraepithelial lesion (LSIL), while CIN II and III are considered high-grade squamous intraepithelial lesions (HSIL).⁵ Experts generally believe that CIN I and II lesions typically regress or persist unchanged, while CIN III is more likely to advance to cancer. Table 1 delineates specific disease outcomes based on degree of dysplasia. Importantly, progression to cervical cancer is known to be a slow process that typically occurs over many years.¹ Therefore, regular screening and management is vital in preventing progression, even among those with high-grade lesions.

As increasingly documented in published literature, strong evidence supports involvement of human papillomavirus (HPV) in the development of cervical cancer, with HPV viral DNA detected in more than 90% of premalignant and malignant cervical lesions.¹ Thus far, over 100 different genotypes of HPV have been identified, with an estimated 40 having the potential to infect anogenital tissues and approximately 15  considered oncogenic.⁵ HPV types 6 and 11 are known to be low-risk viruses that may be associated with LSILs, but not with invasive cervical cancer. Conversely, HPV types 16 and 18 are high-risk viruses that are found in 50% to 80% of low- and high-grade lesions, as well as in up to 90% of invasive cancers.¹

While other factors (e.g., age, host immunity, smoking, oral-contraceptive use, vitamin deficiencies) are certainly involved in the carcinogenesis process,¹ persistent HPV infection is considered the primary causative factor and is requisite to the development of cervical neoplasia.⁵ As such, HPV vaccination, which protects against commonly implicated HPV genotypes, has become a  critical public-health initiative in reducing the risk of cervical cancer development. In examining the currently available vaccinations, Gardasil® [Human Papillomavirus Quadrivalent (Types 6, 11, 16 & 18) Vaccine, Recombinant] (Merck), which covers HPV types 6, 11, 16, and 18, is indicated for use in males and females 9 to 26 years of age,⁶ while Cervarix® [Human Papillomavirus Quadrivalent (Types 16 & 18) Vaccine, Recombinant] (GlaxoSmithKline), which covers HPV types 16 and 18, is indicated for use in females between 9 and 25 years of age.⁷ According to the Centers for Disease Control and Prevention (CDC), immunization is recommended for preteens 11 or 12 years of age, as efficacy is greatest among those who are vaccinated prior to engaging in sexual activity.⁸

Table 1.  Disease Outcomes Based on Degree of Dysplasia⁵

Degree of Dysplasia	Regression (%)	Persistence (%)	Progression to CIN III (%)	Progression to Invasive Cancer (%)
CIN I	60	30	10	1
CIN II	40	40	15	5
CIN III	33	55	N/A	>12

CIN = cervical intraepithelial neoplasia
Adapted from Premalignant lesions of the cervix.  American Society for Colposcopy and Cervical Pathology (ASCCP).  Accessed January 4, 2012.  Available at:  http://www.asccp.org/practicemanagement/cervix/premalignantlesionsofthecervix/tabid/7504/default.aspx

Cervical Cancer Screening Tests

Currently employed screening tests for cervical cancer include the Papanicolaou (Pap) test and the HPV test. The Pap test, a microscopic examination of cells scraped from the cervix (endocervical canal and ectocervix), is the customary approach used to screen for cervical cancer. Although it has a false negative rate of 20% (primarily resulting from sampling error), data indicates that use of this test reduces the incidence of malignancy by 60% to 90%. Once a sample has been obtained, it should be placed on a slide (e.g., conventional Pap test) or in a preservative solution (e.g., Thin Prep Pap test) and sent for analysis. However, upon physical inspection, if suspicious or abnormal specimens are found. a biopsy should be done regardless of cytologic findings.⁹

Approved by the US Food and Drug Administration in 2003, the Hybrid Capture II assay for HPV is another method used to screen women for cervical cancer.  This test, which screens for the presence of high-risk HPV DNA, is indicated for women 30 years of age and older, and is to be used in combination with the Pap test. The HPV test may also be used to interpret ambiguous Pap test findings; additional workup is indicated for women with a Pap test result showing atypical squamous cells of undetermined significance (ASC-US), in conjunction with a positive HPV test.⁹

Current Screening Guidelines

The American Cancer Society (ACS) and US Preventive Services Task Force (USPSTF) currently recommend that all women commence screening either three years after beginning to engage in vaginal intercourse or at 21 years of age, whichever is earlier⁹; guidelines recommend yearly screening with conventional Pap tests or biannual screening with liquid-based Pap tests.¹⁰ In the absence of high-risk factors (e.g., diethylstilbestrol (DES) exposure, HIV infection, other immunodeficiencies), women 30 years of age and older who have had three consecutive normal Pap test results may extend this screening interval to every two to three years.

An alternate option for women 30 years of age and older is to undergo screening every three years with a Pap test and an HPV DNA test. In addition, according to ACS guidelines, women 70 years of age and older with three or more normal consecutive Pap test results and no abnormal results within the last 10 years may discontinue screening. The USPSTF recommends against routine screening for women older than 65 years of age, who have had recent normal Pap tests and are not otherwise at high risk for developing cancer.  Finally, those who have had a total hysterectomy may discontinue cervical cancer screening, unless they have a history of cervical carcinoma or pre-invasive changes.⁹

The American Society for Colposcopy and Cervical Pathology (ASCCP) has developed guidelines for the management of abnormal cervical cytology and histology, as detected by Pap and HPV screening tests. These recommendations are delineated in Table 2.^11,12

Table 2.  Recommendations for the Management of Cervical Abnormalities^11,12

Screening Results	Recommendation
ASC-US, high-risk HPV-positive	Colposcopy
ASC-US, high-risk HPV-negative	Repeat Pap test in 12 months
ASC-H	Colposcopy
LSIL	Colposcopy
HSIL	Loop electrosurgical excision or colposcopy with endosurgical assessment; follow-up with diagnostic excisional procedure or colposcopy and Pap testing at 6 month intervals for 1 year, if CIN II/III not identified
AGC	Colposcopy with endocervical assessment and possible endometrial evaluation; also perform HPV testing if not already done
Colposcopic Findings	Recommendation
CIN I (preceded by ASC-US, ASC-H, or LSIL)	Pap test every 6 to 12 months or high-risk HPV test every 12 months; colposcopy for any abnormality
CIN I (preceded by HSIL or AGC)	Diagnostic excisional procedure or colposcopy and Pap testing at 6-month intervals for 1 year
CIN II	Excision or ablation
CIN III	Excision or ablation
AIS	Hysterectomy preferred; excisional therapy followed by repeat Pap, HPV testing, and colposcopy with endocervical sampling in 6 months is acceptable

AGC = atypical glandular cells; AIS = adenocarcinoma in situ; ASC-H = atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesions; ASC-US = atypical squamous cells of undetermined significance; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial lesions; LSIL = low-grade squamous intraepithelial lesions; Pap = Papanicolaou

Proposed Changes to Cervical Cancer Screening Guidelines

The ACS, the ASCCP, the American Society for Clinical Pathology (ASCP), and the USPSTF have recently proposed new recommendations for prevention and detection of cervical cancer.  Importantly, the proposed revisions advise reductions in screening frequency, to maximize benefits while minimizing risks.¹⁰ These recommendations are based on evidence suggesting that annual screening does not detect cancer more effectively than screening every three years, but does place women at higher risk for vaginal bleeding, pain, infection, and missed disease.  Moreover, abnormal results may cause undue anxiety and lead to unnecessary therapy (e.g., treatment of lesions that would have otherwise regressed with time).²

Both the USPSTF and ACS-ASCCP-ASCP have drafted proposed guideline revisions, outlined in Table 3.^10,13  Public feedback will be considered when developing final guidelines, which are to be released in mid-2012.²

Table 3.  Proposed Changes to Cervical Cancer Screening Guidelines: Draft Recommendations^10,13

ACS-ASCCP-ASCP Recommendations All women should begin screening at 21 years of age , regardless of HPV-vaccination status Women 21–29 years of age, Pap testing should be conducted every 3 years Women 30 years of age and older, Pap testing should be conducted every 3 years Women 30 years of age and older, combined Pap and HPV testing should be conducted every 3–5 years Women aged 65 years of age and older, screening is not recommended, provided that they have had 3 or more consecutive normal Pap test results and no abnormal results in the last 10 years, or have had 2 or more negative HPV tests in the last 10 years Women with normal Pap test results and a positive HPV test should undergo testing for HPV genotypes 16 and 18, or repeat Pap and HPV testing in one year; immediate colposcopy should not be performed Women with mildly abnormal Pap results (ASC-US) and a negative HPV test result should undergo HPV and Pap testing or HPV testing alone at intervals of 3 or more years; immediate colposcopy should not be performed in women with discordant test results USPSTF Recommendations All women should begin screening at 21 years of age irrespective of sexual history Women 21–65 years of age, Pap testing should be conducted every 3 years in those who have had vaginal intercourse and have a cervix Women younger than 30 years of age, HPV testing, alone or in combination with cytology (Pap test), should not be performed Women aged 30 years of age and older, due to the high rate of spontaneous clearance, there is not enough evidence to evaluate the benefits vs. risks of HPV testing, alone or in combination with Pap testing

Emerging Screening Technology: Spectroscopy

In addition to conventional screening techniques, spectroscopy may be used to identify cervical abnormalities by reflecting light changes in cervical tissue. Compared to the Pap test, spectroscopic devices offer various advantages. Namely, data are collected and analyzed in an objective fashion, thereby eliminating the potential for human error. In addition, the availability of immediate findings may enable more timely detection and management and eliminate the need to await biopsy results. Instruments may be used as an adjunct to cervical cytology, for triage after indeterminate cytology results, for localization of biopsy sites during colposcopy, or as primary screening alternatives.³

LightTouch and LuViva, two devices currently under investigation, have been shown to detect cervical disease up to two years in advance of traditional screening methods (e.g., Pap testing, HPV testing, colposcopy, biopsy).^14,15 Findings revealed that LightTouch was able to detect over 86% of cervical abnormalities missed by conventional screening tests, and reduced the number of unnecessary biopsies by approximately 40%.¹⁵ Similarly, LuViva, which is under investigation for intermediary testing in women with abnormal Pap test results, was found to increase detection of CIN II/III by 20%.¹⁴ If approved for use, such devices may prove to be valuable tools for the detection and management of cervical cancer.

Conclusion

While early detection with Pap and HPV testing improves the chances of successfully treating cervical cancer, copious testing is of no additional value and may place women at higher risk for vaginal bleeding, pain, infection, and missed disease. Moreover, abnormal results may cause undue anxiety, and may even lead to unnecessary therapy.² As such, the ACS, ASCCP, ASCP, and USPSTF have proposed new screening guidelines advising reductions in screening frequency.^10,13 In addition, scanning devices designed to detect cervical disease through optical spectroscopy are currently under investigation, and may prove to be useful diagnostic tools.³ It is important that healthcare professionals be well-informed about current and emergent screening tools and recommendations.

References:

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8. HPV vaccines.  Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hpv/vaccine.html. Accessed January 4, 2012. 
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11. Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.  Am J Obstet & Gynecol. 2007;197(4):346-355.
12. Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ.  Am J Obstet & Gynecol. 2007;197(4):340-345.
13. Mitchell D.  USPSTF issues draft recommendation obesity, cervical cancer screening.  American Academy of Family Physicians (AAFP). http://www.aafp.org/online/en/home/publications/news/news-now/health-of-the-public/20111109uspstf-obesskincervca.html. Accessed January 5, 2012.
14. Goodman A.  New device is rapid, accurate in cervical cancer.  Medscape. http://www.medscape.com/viewarticle/743663_print. Accessed January 6, 2012. 
15. FDA accepts Guided Therapeutics’ non-invasive cervical cancer scanner PMA application for review.  Guided Therapeutics. http://www.guidedinc.com/News/PMA%20Accept%20Release%20December%202%202010.pdf. Accessed January 6, 2012.