Please e-mail faculty members with specific questions.

(1) Questions about liquid-based Pap tests or HPV testing: Dr. Clark

(2) Questions about abnormal Pap test results: Dr. Clark

(3) Frequently Asked Questions (FAQ's) about the Pap smear 

Johns Hopkins Cytopathology has taken the plunge.

Approximately two years ago, former Cytopathology Director, Dorothy L. Rosenthal, M.D., implemented liquid-based Pap tests at The Johns Hopkins Hospital and satellite clinics. The major impetus came from clinicians, who are desirous of reflex testing for HPV and other sexually transmitted diseases, utilizing the residual liquid to test for the infectious agents.

In addition to the advertised benefits of liquid-based Paps, the Hopkins faculty has discovered that interobserver reproducibility is extremely good, with minimal variation from among 8 pathologists of various levels of expertise and experience.

Watch this column for updates, including cost benefit analysis and helpful hints for painless processing.
 

Approximately 2 million women in the U.S. receive an abnormal or equivocal Pap test diagnosis each year. In fact, if a woman has an annual Pap, it is hard to imagine how she can avoid being told that her test is not normal at least once in her lifetime. The majority of these "abnormalities" are classified as atypical squamous cells of undetermined significance (ASCUS), meaning that there are microscopic changes that cannot be classified as definitely normal or definitely abnormal. These reports create considerable anxiety for patients, clinicians and the pathology laboratories that are left with lingering uncertainty about whether something is being missed. Fortunately, most of these changes do not reflect conditions that pose an immediate threat to patients. However, fear of missing something that could develop into cancer if not eradicated, frequently prompts aggressive treatment.

We now know that nearly all cervical cancers and precursors are due to infections with certain types of human papillomavirus (HPV), referred to as "high-risk," "oncogenic" or "cancer-associated." These are bad terms, because these viruses rarely produce cancer even if the patient is not treated. Our expanded knowledge about the role of HPV in cervical neoplasia has increased our understanding about how cervical cancer develops and has opened the way for us to improve the management of women with equivocal Pap tests.

HPV seems to be an extremely common sexually transmitted disease with some studies showing that over 40% of college-aged women become infected over a three-year period (Ho et al N Engl J Med). However, most HPV infections resolve spontaneously within months and do not result in any serious consequences. In the vast majority of women, it takes many years (probably one to two decades) for a persistent HPV infection to progress to cancer. Therefore, there is a growing tendency in the U.S. for gynecologists to recommend conservative management of women with mild Pap test abnormalities, referred to as low-grade squamous intraepithelial lesion, mild dysplasia, koilocytotic or condylomaotus atypia or cervical intraepithelial neoplasia (CIN) 1. Only a minority of HPV infections are associated with abnormalities that require immediate intervention. These more serious abnormalities are referred to as high-grade squamous intraepithelial lesion, moderate or severe dysplasia, carcinoma in situ, CIN 2 or 3, and of course carcinoma. However, the problem of how to manage women with the equivocal ASCUS Pap test remains unresolved.

The major problem with ASCUS Pap tests is that these uncertain results reflect a range of possible abnormalities including changes that are entirely reactive and therefore, unrelated to HPV infection and cervical cancer, all the way to high-grade lesions and even, rarely cancer itself. Perhaps only 5% to 10% of women with ASCUS have a serious lesion requiring treatment, but the medical community is very concerned about these women for fear of causing patient harm and provoking litigation. Studies demonstrate that pathologists, including experts, cannot agree on the diagnosis of ASCUS. However, most experts tend to downgrade ASCUS diagnoses to normal or reactive. 

Recently, a test for identifying HPV DNA in cervical samples that may help us manage women with ASCUS has been FDA approved for clinical use. Because a significant percentage of women with equivocal ASCUS Pap test results are not infected with HPV, women who test negative for the virus can feel reassured that they are not immediately at risk for cancer. Routine follow-up rather than intensive investigation may be all that is needed for these women, provided that their cytology shows only minor changes on review. Although this test is sensitive, it is not infallible, just like the Pap test. Therefore, this test does not eliminate the need for careful microscopic review of cytology and any histopathologic biopsies that may have been taken. However, the combination of traditional pathology and HPV testing can help us evaluate the status of the cervix. Women who have definitely abnormal cytology or test positive for the virus and have ASCUS cytology generally require colposcopy, a procedure that allows the gynecologist to view a magnified image of the cervix and perform a biopsy (remove tissue) of potentially abnormal areas. In the majority of women, the biopsies show minor abnormalities or may even appear entirely abnormal under the microscope. A minority will require immediate definitive treatment for a high-grade lesion.

The Johns Hopkins Team for evaluating and treating cervical disease:

Dr. Robert J Kurman, M.D. Professor of Pathology and Gynecology and Obstetrics, Director Division of Gynecologic Pathology

Dr. Kurman is the author or editor of numerous authoritative texts on gynecologic pathology including Blaustein’s Pathology of the Female Genital Tract and the AFIP Fascicle on Tumors of the Cervix, Vagina and Vulva. He has participated on numerous studies of HPV infection and cervical neoplasia and is the author of the Bethesda System monograph for Reporting Cervical and Vaginal Diagnoses.

Dr. Cornelia Trimble

Dr. Brigitte Ronnett

Dr. Rosenthal



For more information from Digene on HPV testing, visit http://www.thehpvtest.com

Frequently asked questions

1. If HPV (human papillomavirus) causes cervical cancer, does that mean that I should have an HPV DNA test even if my Pap test is normal?

In some countries, HPV DNA testing may be used in the future in combination with cytology for routine screening in women over 35 years of age. However, HPV testing will probably not be performed routinely on younger women because a high percentage will be positive, but these positives will represent innocuous infections in the vast majority of cases. The best protection for women against cervical cancer is having a routine Pap test that is carefully obtained and then screened and interpreted by a competent laboratory. It is also critical to follow your gynecologist’s recommendations regarding follow-up. Cervical cancer develops very slowly and is quite rare in young women under the age of 40.

2. Is there any way to protect myself against acquiring an HPV infection?

There is no effective way to avoid HPV infection short of abstinence. HPV DNA is almost never detected in virgins and the risk of acquiring HPV infection is related to the number of sexual partners that a women has had in her lifetime. Condoms may reduce the risk of infection, but these are not entirely protective because the virus usually is present in the cervix, vagina and external genitalia if a woman is infected. 

3. If I have been treated for a cervical abnormality can I develop another lesion?

Unfortunately, a woman who has been treated for cervical disease can develop new lesions either because of incomplete treatment of the lesion or development of a new infection. Furthermore, gynecologists can treat cervical lesions, but there is no effective treatment for the virus. Removal of the cervical lesion and immune responses may result in clearance of HPV infection, but the virus may remain in the lower genital tract and cause a new lesion.

4. If HPV is sexually transmitted, does that mean that men should be treated if their partners are infected or have an abnormal Pap smear?

Currently, men in the U.S. are not routinely treated. First, penile cancer is extremely uncommon in the U.S., so there would be no direct benefit to men from treatment. Second, it is very difficult to identify penile lesions in men using techniques similar to those employed for examining the cervix (e.g. colposcopy). Finally, there are no known methods for eliminating HPV from the male reservoir.

5. Is it possible to acquire HPV infection or have a bone fide Pap test abnormality if I am monogamous?

Women who are monogamous may develop cervical disease. This could reflect detection of a previously unrecognized infection acquired through a prior contact. Alternatively, if your male partner is infected, he may transmit the virus to you.

6. What are genital warts? Are warts related to HPV?

Genital warts or condylomata are related to types of HPV that almost never develop into cancer. However, it is important to remember that infections with multiple different types of viruses are not uncommon, so women with warts require cervical screening.

7. If most HPV infections resolve by themselves, do we know why this happens and is there any known way of increasing the chances that this will occur?

We think that immune responses (the defense system of the body) are important in eliminating HPV. Patients who are immunosuppressed because they have diseases such as AIDS or are required to take medications that reduce immune responses seem to have more persistent infections. It also seems that women who have many children or smoke may be slightly more likely to develop an advanced precursor lesion requiring treatment compared to other HPV infected women. However, the effects of smoking, childbearing and other possible co-factors are relatively small. There is also some unconfirmed evidence that genetics and other conditions may play a role.

8. What types of research are being conducted on HPV currently?

HPV research is being conducted to address a wide range of issues. Scientists are trying to determine how the virus can cause normal cells to turn into cancer cells. The National Cancer Institute is conducting a large clinical trial to evaluate the cost-effectiveness of HPV testing in managing equivocal and mildly abnormal Pap smears. Other studies are examining the possible role of HPV testing for primary screening. In addition, there are ongoing efforts to develop a vaccine that could prevent HPV infection, which are complemented by more basic research on immune responses to HPV. If effective, vaccination would be especially helpful from a public health point of view because most cervical cancer occurs in poor nations that are unable to perform effective cytology screening. Vaccines seem to be protective in animal models, however vaccine trials in humans are just beginning.

Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence that human papillomavirus causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958-64.

Sherman ME, Schiffman MH, Lorincz AT, et al. Towards objective quality assurance in cervical cytopathology: Correlation of cytopathologic diagnoses with detection of high-risk human papillomavirus types. Am J Clin Pathol 1994;102:182-7.

Bosch FX, Manos MM, Munoz N, et al. International Biological Study in Cervical Cancer (IBSCC) Study Group. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87:796-802.

Sherman ME, Schiffman MH, Lorincz AT, et al. Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing. Cancer Cytopathol 1997;1:89-97.

Sherman ME, Schiffman MH, Strickler H. Prospects for a prophylactic HPV vaccine: rationale and future implications for cervical cancer screening. Diagn Cytopathol 1998;18:5-9.

Schiffman M, Solomon D, Sherman M. Clinical Commentary. Why, how and when the cytologic diagnosis of ASCUS should be eliminated. J Lower Genital Tract Dis 1998;2:165-9.

Sherman ME, Kurman RJ. "Intraepithelial carcinomas of the cervix": reflections on a half-century of progress. Cancer 1998;83:2243-6.

Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423-8.

Manos MM, Kinney WK, Hurley LB, et al. Human papillomavirus testing for the triage of ASCUS Pap diagnoses using routine liquid-based cytology specimens. JAMA 1999;281:1605-10.

Ronnett BM, Manos MM, Ransley J, et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results and HPV DNA detection. Hum Pathol 1999;30:816-25. 

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Division of Cytopathology
Webmaster: Douglas Clark, M.D. 
dclark@jhmi.edu
Johns Hopkins School of Medicine 
Last updated: January 16, 2002