(Published January 2009)

Screening for HPV-Related Diseases

The goal of cervical cancer screening is to identify and treat high-grade precursors to cervical cancer, thus reducing a woman’s risk of developing invasive cervical cancer:

Cytology showing low-grade squamous intraepithelial lesion (LSIL) identifies many women who have very little risk for cervical cancer.
In contrast, cytology showing high-grade squamous intraepithelial lesion (HSIL) may reflect the presence of a high-grade cancer precursor and will identify women who need additional testing or treatment.
Positive HPV test results allow for risk stratification and identification of women in need of additional follow-up.

Cervical Cancer Screening: Pap Test

Both conventional Papanicolaou tests and liquid-based cytology are acceptable screening methods.
Recent well-controlled clinical trials have found little difference in performance of the two methods for identifying high- grade disease.^{^1-3}
One benefit of liquid-based cytology is that its use facilitates “reflex” HPV DNA testing in which the original sample is used to determine HPV status, thus avoiding a second visit.

Age to Start Cervical Cancer Screening: Considerations

HPV infections are very common in young women and frequently result in abnormal Pap test results.
The prevalence of HPV infection drops considerably with increasing age.
Concurrently, the incidence of CIN-3 and cancer increases with age.
The positive predictive value of HPV testing increases as women age.
The evaluation of minor cytological abnormalities in young women is expensive, causes considerable anxiety, and can result in unnecessary exams and tests for follow-up.

Recommendations on Age to Start Screening

Based on the considerations listed above, women should begin combined HPV testing and cytology at age30.⁴
ACS, ACOG, and USPSTF all recommend that cervical cancer screening should start three years after sexual intercourse starts or no later than 21 years old.^5-7

Recommendations on Age to Stop Cervical Cancer Screening^5-7

ACS
- Can stop cervical cancer screening if woman is age 70 or older and has three documented, consecutive normal Pap tests results within preceding 10 years
- Does not apply to women with a history of exposure to diethylstilbestrol (DES), cervical cancer, or immunosuppression
- If HPV positive, continue screening
ACOG
- No age to stop screening specified
USPSTF
- No age to stop screening specified but recommends against routine screening in women >65 years old, if there has been adequate recent screening and the woman is not otherwise at high risk

Squamous cell abnormalities

Atypical squamous cells of undetermined significance (ASC-US)
Atypical squamous cells cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (LSIL)
High-grade intraepithelial lesion (HSIL)
Squamous cell carcinoma (SCC)

Glandular cell abnormalities

Atypical glandular cells (AGC)
- endocervical-endometrial
- not otherwise specified
Atypical glandular cells, favor neoplastic
- endometrial
- not otherwise specified
Adenocarcinoma in situ (AIS)
Adenocarcinoma

Recommendations for Screening Frequency^5-7

ACS
- Annual screening with conventional Pap test
- Every two years for screening with liquid-based test
- At age 30 if a woman has had three normal consecutive Pap tests results, can change to every two to three years (but not if she has history of DES exposure or immunosuppression)
ACOG
- Annually if <30 years old
- At age 30 if a woman has had three normal consecutive Pap test results, can change to every two to three years (but not if she has history of DES exposure or immunosuppression)
- For women age 30 or older, either Pap or Pap plus HPV can be used for screening
- At age 30 if HPV and Pap are both negative, change to no more frequently than every three years
USPSTF
- At least every three years

Screening Post-Hysterectomy

ACS, ACOG, and USPSTF all recommend against routine screening of women who have had a hysterectomy for benign disease.

Table 2: Clinical Significance of Cervical Cytological Abnormalities ^8-10
Abnormality	Epidemiology and Impact	Clinical Significance
ASC-US	The most common cytological abnormality in the United States (mean rate 4.7% in 2003). The prevalence of CIN 2/3 among women with ASC-US is 7%–12% in the United States. Almost half of all cases of CIN -2/ 3 are diagnosed in women with ASC-US.	Women with a cytological result of ASC-US require additional follow-up.* Most high-grade disease is found in women who have minor cytologic abnormalities.
ASC-H	It’s an uncommon finding (mean rate of 0.43% in 2003 in the United States). The risk of CIN-2/3 is higher for ASC-H than ASC-US (40% vs 15%). The prevalence of CIN-2/3 among women with ASC-H ranges from 26% to 68%.	ASC-H is a designation given to specimens that show atypical squamous cells for which HSIL cannot be excluded; clinicians should consider specimens given this designation to represent equivocal HSIL. All women with this Pap result will require colposcopy and management according to published guidelines.*
LSIL	Prevalence is moderate (mean rate of 2.6% in 2003 in the United States). A pooled estimate showed that 77% of women with LSIL are positive for high-risk HPV. Prevalence of CIN-2/3 among women with LSIL ranges from 12% to 16%.	LSIL is a common cytology abnormality that usually represents self-limited HPV infection. Except in special populations, colposcopy is recommended.*
HSIL	Is relatively uncommon (mean rate of 0.7% in 2003 in the United States). Prevalence varies with age: 0.6% in women 20–29 years old 0.2% in women 40–49 years old Prevalence of CIN 2/3 in women evaluated using a loop excision 84% to 97%. Approximately 2% of women with HISL have invasive cancer.	More often associated with persistent infection and progression than LSIL. Detecting CIN-2/3 has emerged as the central purpose of screening. Either colposcopy with endocervical assessment or loop electrosurgical excision is recommended, except in special populations.*
AGC-NOS	AGC is relatively uncommon (mean rate of 0.7% in 2003 in the United States). AGC is more common in women >40 years old. Recent series have reported that 3%–17% of women with AGC have invasive cancer.	AGC represents a possible abnormality of glandular epithelium. These lesions are difficult to assess by Pap testing because they develop higher in the cervical canal than other lesions. For the same reasons, glandular lesions are more difficult to identify at colposcopy than other lesions. All categories of AGC require endometrial sampling in women who are >35 years old or at risk for endometrial neoplasia.*
AGC-Favor Neoplasia	See AGC-NOS.	Represents a high degree of suspicion for significant disease or adenocarcinoma in situ. Requires a diagnostic excisional procedure.*
*See ASCCP guidelines for complete information on management, available at www.asccp.org/consensus.shtml.

Cervical Cancer Screening: HPV DNA Testing

Hybrid Capture 2 is an assay that uses a pooled mixture of probes to detect 13 of the high-risk HPV types (16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), but is not HPV-type specific.¹¹
Some laboratories routinely test for both high- and low-risk types; health care providers should request that the test for low-risk types not be performed.¹¹

Clinical Uses of HPV DNA Testing

In the clinical setting, HPV testing is performed to identify high-risk types only.
There are no clinical applications for low-risk HPV testing.
Well-established clinical uses of HPV DNA testing include:¹¹
- As an adjunct to cytology (either liquid-based or conventional) for screening women age 30 and older
- Management of women with ASC-US cervical cytology results starting at age 21
- Post-colposcopy follow-up of women with abnormal cytology results
- Post-treatment follow-up of women who have been treated for CIN-2/3 [Note: This applies to follow-up after any treatment and should not be conducted until six months after the treatment.]
- To triage menopausal women with LSIL
Use of HPV testing allows for less frequent screening because a normal Pap result and a negative HPV test result give a high assurance that cervical cancer is not present and will not likely occur in the next few years.¹²
The addition of the HPV test increases the accuracy of screening.
The risk of unidentified CIN-2 and CIN-3 or cervical cancer is approximately 1 in 1,000 in women with concurrent negative HPV and cervical cytology (ACOG Level A recommendation).¹³
HPV DNA testing also identifies women who need increased surveillance because a positive HPV test result and a normal Pap result reflect increased risk for either missed disease or for the subsequent development of CIN-2/3 and cancer.¹²

Situations in Which HPV DNA Testing Is NOT Appropriate

HPV DNA testing should NOT be used:¹⁴
- To triage women with Pap results other than ASC-US (with the exception of post-menopausal women with LSIL)
- As an adjunct to Pap testing in primary screening of women <30 years old (Concurrent Pap and HPV DNA testing in women <30 years old is not recommended because HPV is highly prevalent and the prevalence of cervical cancer is low.)
- As an adjunct to Pap testing in primary screening of women after a total hysterectomy for benign disease
- To triage women <21 with ASC-US

Recommendations on Use of HPV DNA Testing for Screening of Women Age 30 and Older

ASCCP has published guidelines for the use of HPV DNA testing as an adjunct to cytology for primary screening of women age 30 and older.
A clinical scenario that has received a great deal of attention is the HPV DNA positive/cytology negative result.
ASCCP recommends that women who are HPV DNA positive but have a negative cytology result should have repeat Pap and HPV testing in 12 months^10,15 Recommendations for subsequent follow-up based on testing at 12 months are shown in Table 4.

Table 3: Screening Frequency for Combined Pap and HPV Testing: Primary Screening^10,15
HPV Result	Cytology	Recommended Management
Negative	Negative	No screening for three years
Negative	ASC-US	Repeat Pap test in 12 months
Positive	ASC-US	Colposcopy
Any	LSIL or greater	Colposcopy
Positive	Negative	Repeat HPV and Pap tests in 12 months

Table 4: Management of Repeat Testing After HPV Positive/Cytology Negative Result^10,15
HPV Result	Cytology	Recommended Management
Negative	Negative	Routine screening at three years
Negative	ASC-US	Repeat Pap test 12 months
Positive	Negative	Colposcopy
Any	LSIL or greater	Colposcopy

Screening for HPV-Associated Anal Lesions

HPV-associated anal lesions include high-grade precursor lesions (anal intraepithelial neoplasia [AIN]) and anal cancer.
These lesions are associated with infection with high-risk HPV types. As with cervical cancer, HPV type 16 is most common, followed by type 18.¹⁶

Risk factors include 15 or more lifetime sexual partners, receptive anal intercourse, current smoking, HIV infection, and in women, a history of CIN.^{17, 18}
In one study, 95% of 357 gay males had anal HPV and 50% had high-grade AIN.¹⁹
The role of routine screening for AIN and anal cancer in high-risk individuals is controversial:
- Advocates believe that cytology is as effective for detecting anal disease as for cervical disease and note that cost-effective studies suggest that anal screening is an attractive option.
- Opponents point out that at present there are no data confirming that treatment of AIN prevents cancer.
Currently the Centers for Disease Control and Prevention (CDC), USPSTF, ACS, and the Infectious Diseases Society of America do not recommend routine anal cytology screening.
New York State Department of Health recommends anal cytology for individuals who are infected with HIV and meet at least one of the following criteria:²⁰
- Men who have sex with men
- History of genital warts
- History of CIN

Counseling Points

When counseling a patient about screening for cervical cancer, make sure she understands these points before she leaves your office or clinic:

HPV infections are very common in young women and frequently result in abnormal Pap test results. At the same time, cervical cancer is relatively rare in this age group compared with older women.
For these reasons, experts recommend that women begin cervical cancer screening three years after initiation of sexual intercourse or no later than 21 years old.
HPV DNA testing detects whether or not a woman has a current infection with one of the high-risk types of HPV. It does not detect all high-risk types, nor does it detect the types that cause genital warts.
In women age 30 or older, HPV DNA testing can be used in combination with Pap testing to improve the effectiveness of screening for cervical cancer or precancer. If both are negative, screening needs to be done only every 2-3 years.
If HPV testing and Pap testing were used together to screen women younger than 30, the tests would be positive in many women who actually have HPV infections that will go away on their own. It would also be expensive, cause considerable anxiety, and result in unnecessary exams and tests for follow-up.
Studies on the effectiveness of male testing have not yet been completed.

References

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Davey E, Barratt A, Irwig L, Chan SF, Macaskill P, Mannes P, et al. Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review. Lancet. 2006;367:122-32.
Ronco G, Cuzick J, Perotti P, Naldoni C, Ghiringhello B, Giorgi-Rossi P, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening randomised controlled trial. BMJ, doi:10.1136/bmj.39196.740995.BE (published 21 May 2007)
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Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting cervical cytology. JAMA. 2002; 287:2114-19.
Davey DD, Neal MH, Wilbur DC, Colgan TJ, Styer PE, Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004;128(11):1224-9.
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Wright T, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;2:304-9.
ACOG Committee on Practice Bulletins. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus. Obstet Gynecol. 2005;105:905-18.
Centers for Disease Control and Prevention. Human Papillomavirus: HPV Information for Clinicians. November 2006.
American Society for Colposcopy and Cervical Pathology. Adapted with permission from ASCCP’s Online CME Program: Primary Cervical Screening with HPV Testing and Cytology Combined
Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine. 2006;24(Suppl 3):1-10.
Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101(2):270-80.
Frisch M, Smith E, Grulich A, Johansen C. Cancer in a population-based cohort of men and women in registered homosexual partnerships. Am J Epidemiol. 2003;157(11):966-72.
Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19(13):1407-14.
New York State Department of Health AIDS Institute. Neoplastic complications of HIV disease. Available at: www.hivguidelines.org. Accessed September 24, 2007.