HPV testing in cervicovaginal cytology: Where are we today and where do we go from here?
Dina R. Mody, MD
ASC-US triage. High-risk HPV typing has more or less become
the standard for atypical squamous cells-undetermined significance, or ASC-US,
triage. Thanks to the ALTS trial and American Society for Colposcopy and Cervical
Pathology guidelines,1 most health care providers and insurance carriers
now offer this test and reimburse for it.
Primary screening. In March 2003, the Food and Drug Administration
approved high-risk HPV typing for women over 30 in conjunction with Pap tests
for primary screening. Although this has been available for more than a year,
many payers do not cover this test and many providers do not offer it. With
the publication of the interim guidance document2 and the HART study,3
some of the issues related to managing women with disparity between Pap and
high-risk HPV typing should be clarified. The interim guidance document offers
the following recommendations:
- Age to initiate: 30 years or more.
- Age to discontinue: 65 years as per U.S. Preventative Service recommendations
for cervicovaginal screening or age 70 as per American Cancer Society recommendations.
- Who should not receive HPV DNA testing in screening mode? Women under 30,
immunocompromised patients, and patients who have had a total hysterectomy
for benign gynecologic disease.
- A combination of negative high-risk HPV typing and a negative cytology should
result in longer screening intervals, that is, three years.
- For cytology-negative, HPV-positive patients, repeat both in six to 12 months.
If either abnormal at six to 12 months, then colposcopy. If negative colpo,
then repeat both at 12 months.
- If HPV-negative but abnormal cytology, follow up as per management for abnormal
Post-treatment followup. A third and less publicized potential
use is in the followup of patients with high-grade squamous intraepithelial
lesions after treatment with cone or LEEP. In recent years, many publications,4-10
especially in the European literature, have addressed this topic. No large U.S.
study is available. Table 1
is a compilation of the results from pertinent studies. Although the sensitivity
of high-risk HPV for recurrent/residual HSIL is high, it is the negative predictive
value of a negative HPV test in conjunction with a negative cytology that could
be used to triage these patients to routine screening quickly. The patients
with positive post-treatment HPV and/or cytology could be followed more closely
or colposcoped if they continue to be positive.
Atypical endocervical cells. The guidelines of the ASCCP do
not recommend high-risk HPV typing for atypical endocervical cells, citing limited
data. As per the current ASCCP guidelines, cases with a diagnosis of atypical
endocervical cells undergo colposcopy and biopsy. However, as more data emerge,
it appears that a compelling case could be made for testing in cases of atypical
endocervical cells. Based on limited studies,11-14 most if not all
endocervical adenocarcinoma in situs are high-risk HPV-positive. The usual mucin-producing
endocervical adenocarcinomas have a high rate of positivity in the 90+ percent
range. Followup studies on atypical endocervical cells show squamous dysplastic
lesions to be the most common histologic diagnosis. Table
2 is a compilation of the data from recent studies on high-risk
HPV typing in glandular lesions with histologic followup. Endometrial lesions
are not HPV-related and HPV testing has no role other than distinguishing between
an endocervical versus an endometrial primary. This is being used in surgical
Quality improvement. High-risk HPV testing could also be used
for quality improvement in the laboratory. Monitoring percentage positivity
in ASC-US cases (50 to 60 percent is the reported range) can help a laboratory
determine if it is in range. Percentage positivity rates can also be monitored
for individual pathologists. Other scenarios include testing of selected postmenopausal
women and followup of adolescent patients with LSIL. The 12-month HPV test has
been recommended in the ASCCP guidelines for followup of patients (ASC-US, ASC-H
confirmed on review of cytology, LSIL) with negative colposcopy. The era of
HPV testing is still in its adolescence. Stay tuned for more.
Dr. Mody, chair of the CAP Cytopathology Committee, is professor of pathology,
Baylor College of Medicine, Houston, and director of cytopathology at Baylor and
The Methodist Hospital, Houston.
- Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. Consensus guidelines
for the management of women with cervical cytological abnormalities. JAMA.
- Wright TC, Schiffman M, Solomon D, et al. Interim guidance for the use of
human papillomavirus DNA testing as an adjunct to cervical cytology for screening.
Obstet Gynecol. 2004; 103: 304–309.
- Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive
for high-risk types of human papillomavirus: the HART study. Lancet.
- Chua K-L, Hjerpe A. Human papillomavirus analysis as a prognostic marker
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testing after conization by loop electrosurgical excision for high-grade squamous
intraepithelial lesions. Gynecol Oncol. 2003; 90: 587–592.
- Jain S, Tseng C-J, Horng S-G, Soong Y-K, Pao CC. Negative predictive value
of human papillomavirus test following conization of the cervix uteri. Gynecol
- Zielinski GD, Rozendaal L, Voorhorst FJ, et al. HPV testing can reduce
the number of follow-up visits in women treated for cervical intraepithelial
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cervical intraepithelial neoplasia. Br J Cancer. 2001;84(6):796–801.
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- Pirog EC, Kleter B, Olgac S, Bobkiewicz P, et al. Prevalence of human papillomavirus
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- Plunkett M, Brestovac B, Thompson J, et al. The value of HPV DNA typing
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