By: Sin Hang Lee, MD
Pathologist, Milford Hospital and Director, Milford Medical Laboratory, Milford, CT
August 17, 2010
The American health care system is unfixable at the national level because there are too many competing interests. There is an emerging consensus in the health policy community that informed and engaged consumers have a vital role to play in improving the quality of care that the U.S. health system delivers to patients. The expectation is that when consumers are armed with the right information they will demand high-quality services from their providers, choose treatment options wisely, and become active participants and self-managers of their own health and health care. However, the frontier of medical research has expanded so much and so fast in the past few decades that the relevant correct information is not easy to find. It is also difficult for the consumers to distinguish genuine medical progress from promotional publications for commercial products without proven health benefits. This document presents some important information to the women consumers who wish to be informed and engaged on the issue of cervical cancer prevention, and may be used as materials for discussion in consultation with their health care providers.
Cervical cancer is a major lethal malignancy in underdeveloped countries, but not in the U.S. The Centers for Disease Control and Prevention (CDC) record showed that 3,976 women died from cervical cancer in the U.S. in 2006. For comparison, uterine endometrial cancer will kill about 7,950 American women in 2010, according to a National Cancer Institute (NCI) estimate. The Papanicolaou (Pap) smear program, started in the 1940’s in the U.S., has reduced the cervical cancer prevalence from 44 per 100,000 to less than 5 per 100,000 among the mainstream American women. However, there has been a business trend initiated by some advocates in the NCI and their closely-allied commercial interests, begun in the late 1980’s, to replace the traditional Pap smear technology with a human papillomavirus (HPV) test kit. A historical analysis of this business trend with its associated risks was summarized in an Editorial by Dr. R. M. Austin, entitled “Dismantling of the U.S. cytotechnology educational infrastructure is premature and carries significant risks,” which was published in the Archives of Pathology and Laboratory Medicine 2008 Feb;132(2):154-8. Unfortunately, the Editorial drew little attention from the medical establishment and the news media because it was not “trendy” in business.
Now, Drs. Schiffman and Wentzensen from the NCI have proposed in a recent article entitled “From Concept to Practice: from human papillomavirus to cervical cancer,” published in the official journal of the American College of Obstetricians and Gynecologists , to further reduce the role of Pap smears in future medical practice. They recommend using prophylactic vaccination of adolescents against carcinogenic HPV infections, HPV testing, and colposcopy to replace the traditional Pap smear screening for cervical cancer prevention. The consumers must be informed that while the concept of such a proposal may be debatable, the practice is highly risky for the following reasons:
1) The current type-specific HPV vaccines have been claimed to be almost 100% effective against infection by HPV-16 and HPV-18, and perhaps also against HPV-31 and HPV-45 infections. However, we do not know if these four HPV types are the most prevalent carcinogenic HPV genotypes in the U.S. According to two published reports [2, 3] – one by the CDC, HPV-52 not HPV-16 or HPV-18 was found to be the most prevalent “carcinogenic” genotype infecting young American women. In addition, the clinical trial studies of the HPV vaccines were largely conducted in foreign countries, such as Costa Rica, where the cervical cancer prevalence rates are much higher than in the U. S. The genetic make-up, dietary habits and the life-styles of the women in these foreign trial populations may be quite different from those of the mainstream American women. Extrapolation of the efficacy results of HPV vaccination obtained in such foreign populations to marketing a vaccine for the American women consumers as the major means to prevent cervical cancer is highly risky. In the clinical trial designs for follow-up, at least in one of the publications it stated “At the 6-month clinic visit, all sexually experienced womenwere instructed to self-collect a cervicovaginal specimen usinga Dacron swab. Exfoliated cells from this collection were storedin Preservcyt solution and used for HPV DNA testing .” It is hard to believe that the women in Costa Rica could self-collect the cells of the transformation zone, where squamous epithelium gradually undermines and replaces glandular epithelium-namely the site of cervical cancer development-for HPV study. Failure to collect the right samples for follow-up HPV testing during the post-vaccination period might generate false-negative results, and might have artificially augmented the efficacy of the vaccines. Furthermore, there is evidence to show that HPV vaccination does not accelerate clearance of an existent vaccine-relevant HPV infection, and instead it may cause harm in women who have had a vaccine-relevant HPV infection acquired before vaccination.
2) The accuracy of the currently marketed Food and Drug Administration (FDA)-approved HPV tests is open to question. One of the two FDA-approved HPV tests has been found to generate 2 to 4 times more positive results than the other FDA-approved HPV test . The latter test was developed using a 25-year old technology. In 2009, the FDA guidance recommended polymerase chain reaction (PCR)/DNA sequencing to be used as the standard for validating all new HPV genotyping tests .
3) By eliminating Pap smear cytology as a gatekeeper, referrals to colposcopic biopsies would be largely based on HPV testing. According to a report from the Harvard School of Public Health , about 95% of colposcopic biopsies based on the current FDA-approved HC2 HPV assay to determine the needs for cancer work-up in the U.S. have been found to be excessive and cause unnecessary harm to women at a great cost to society.
Based on the above three evidence-based arguments, American women consumers should take an active role in future cervical cancer prevention as follows:
1) Continue visiting your gynecologist for regular Pap smear screenings.
2) If the Pap smear is reported as “negative,” demand to see the cytology report and find out if the report states “endocervical cells present,” which is the traditional Pap smear technology requirement for specimen adequacy. If the report only states “specimen adequate for evaluation” without mentioning the presence of endocervical cells, the result may have a chance to be false-negative because the gynecologist did not collect the cells correctly from the transformation zone in the cervix, or the commercial laboratory did not prepare the slides properly.
3) Accept the recommendation for immediate colposcopic examination and biopsy to rule out precancer or cancer if the cytology diagnosis is “HSIL” (high-grade squamous intraepithelial lesion), cancer, or suggestive of cancer.
4) Ask why a colposcopic biopsy is needed if the Pap cytology result is less severe than “HSIL.” A caring gynecologist will give you a good reason why you should be subjected to a traumatic procedure. This is a judgment call, a decision usually based on persistent high-risk HPV infection and an ambiguous Pap smear cytology.
5) If a positive HPV is reported, ask for the exact genotyping and demand to see a DNA sequence for the HPV genotyping report. Without a DNA sequencing electropherogram (a color tracing with DNA bases) and a matched GenBank genotyping result, the HPV genotyping result can be erroneous and should not be used for making a decision for your further treatment.
6) If you decide to receive HPV vaccinations, it is prudent to let your gynecologist know that you want to be sure that you are not already infected by HPV-16, HPV-18, HPV-31 or HPV-45 – the four vaccine-relevant HPV genotypes – and you want to be tested by a PCR/DNA sequencing method as the 2009 FDA guidance recommended for evaluating HPV testing kits [see Ref. 6 below].
7) If you have had your HPV vaccinations and are now found to have an abnormal Pap cytology after vaccination, you should ask your gynecologist to order an HPV test by PCR/ DNA sequencing to make sure that the abnormal Pap result is not associated with a vaccine-relevant HPV-16, HPV-18, HPV-31 or HPV-45 infection because such association may carry a higher risk of developing precancer or cancer of the cervix, and may require a closer monitoring schedule.
1) Schiffman M, Wentzensen N. From human papillomavirus to cervical cancer. Obstet Gynecol 2010;116:177-85.
2) Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis 2005;191:182-92.
3) Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA 2007;297:813-9.
4) Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR; Costa Rican HPV Vaccine Trial Group. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;15;298:743-53.
5) Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPV DNA tests. Am J Clin Path 2010;134:193-9.
6) US Food and Drug Administration Document: Draft Guidance for Industry and FDA Staff -Establishing the Performance Characteristics of In Vitro Diagnostic Devices for the Detection or Detection and Differentiation of Human Papillomaviruses. September 9, 2009. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm181509.htm
7) Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med 2008;168:1881-9.