Monday, December 26, 2005

Cervical Cancer Screening and HPV Typing

While we're on the subject of cervical cancer, I thought you might find this article--on the human papillomaviruses (HPV) screening standard of care--useful. It's a bit heavy on medspeak, but here are the main points:

  • [I]n the U.S., in 2005, there will be an estimated 10,370 cases of cervical cancer and about 3710 related deaths.

  • On a worldwide basis, HPV has been demonstrated to be present in more than 95% of all cervical cancers of all histologic types.

  • HPV16 accounts for approximately 50% of all invasive cervical cancers and more than 25% of cancer precursors. [For more on HPV go here.]

  • The conventional Papanicolaou (Pap) smear is the world's most successful cancer screening test.

  • [M]ore than 50% of the patients in whom cervical cancer develops have never been screened, and another 10% to 20% of those patients have not been screened in at least 5 years.

  • [A]t least 30% of the patients in whom cervical cancer develops have had a "false negative" Pap smear and approximately half of those false-negative results are due to sampling error while the remaining 50% actually are screening or interpretive errors.

  • Any single cervical cancer screening event may only be 50% sensitive for prevalent disease. Thus, it is only through the repetitive application of independent screening events, at relatively short intervals, that the Pap smear "system" is really efficacious.

  • [An aside. There are two types of Pap smear techniques: 1) the older one, or conventional dry-slide Pap (small wooden collection device, and sample is smeared on glass slide), and 2) the newer one, liquid-based Pap, or ThinPrep (small, brush-like collection device, and sample is rinsed in liquid).]

  • 60% of colposcopically derived biopsies read as high-grade cervical intraepithelial neoplasia (CIN) come from patients who have Pap smears read as either ASCUS [Atypical Squamous Cells of Undetermined Significance] or LSIL [Low-Grade Squamous Intraepithelial Lesion].

  • [I]n patients with cytologically diagnosed LSIL, high-risk HPV testing has little utility. This is because at least 84% of patients with LSIL on cytology are already high-risk HPV positive. Hence, HPV testing will not effectively triage these patients in whom it was established that there is a 25% to 30% likelihood of detecting a high-grade cancer precursor over 2 years.

  • In contrast, for the ASCUS group,

  • [The ALTS study] firmly established adjunctive testing for high-risk HPV as the standard of care for the triage of patients with mildly abnormal cervical cytology... [T]he essential finding of the ALTS trial was that HPV triage was 92% sensitive for prevalent CIN3 in the ASC-US group while referring only 53% of patients for colposcopy.

  • So, if you already have an abnormal Pap test, you should have high-risk HPV testing. But what about doing HPV typing at the same time as the initial Pap test? Would HPV testing at this stage be useful? After all:

    Several epidemiologic studies looking at the prevalence of HPV detection vs age demonstrated that there is a significant reduction in HPV prevalence throughout the third decade, such that women in their 30s routinely show prevalence of detectable HPV of 10% or less.

    The short answer to our question is that performing both a Pap test and HPV typing for primary screening might be useful (depending on particular patient circumstances), so it is an option that you should be aware of:

    The primary data supporting the utility of HPV testing in conjunction with cytology for screening consist of several studies that evaluated more than 40,000 women in a variety of clinical settings. All studies demonstrated that HPV testing was more sensitive than cervical cytology regardless of the clinical setting. The combination of HPV plus cytology achieved sensitivities of over 95% in 6 of 8 studies. At such high levels of sensitivity, many have been concerned that too many patients would be referred to colposcopy, and those referred would fail to have identifiable lesions. The inherent advantage of cytology is that cytologic abnormality tends to have very high specificity, particularly when interpretations are adjudicated. Surprisingly, HPV testing achieved specificities that were comparable to or only slightly less than those with cytology alone. This undoubtedly reflects the problem of interpretive variability inherent in morphologic assessment. The combined test had a specificity of more than 90% in 6 of the 8 studies presented to the US Food and Drug Administration (FDA).These data led to widespread discussion and eventual publication by both The American Cancer Society and The American College of Obstetrics and Gynecology of revised practice guidelines that included the option of HPV testing in conjunction with cytology for the primary screening of patients.

    One advantage of primary screening with Pap + HPV typing is that patients who have both a normal Pap smear as well as a negative high-risk HPV test do not need a repeat screening examination for at least 3 years (provided baseline stays constant--e.g., same partner, still in a monogamous relationship, etc).

    Last, but not least, here are the guidance recommendations on how to incorporate HPV testing as an adjunct to Pap smear screening:

    -- patients with SIL cytology or ASCUS and a positive HPV test result are referred routinely for colposcopy

    -- patients who are double negative [normal Pap, no HPV] are recommended to have repeat testing every 3 years

    -- patients who have equivocal cytologic abnormalities [ASCUS] but who are HPV negative are recommended to have a repeat examination in 1 year*

    -- patients who are high-risk HPV-positive but cytologically normal [~ 3% to 5% of pts; HPV testing detects one of the high-risk HPV types, like HPV16, but the Pap test is normal] should undergo a repeat examination in 6-12 months with both HPV testing as well as cervical cytology*

    The rationale for repeat testing, rather than colposcopy referral:

    Because it is well established that HPV persistence is the major risk factor for developing cervical neoplasia, several recent studies have shown that patients who are high-risk HPV positive and cytology negative have a risk of developing CIN2+ of approximately 4% to 8% at 12 months. This scheme of repeat testing is nearly 100% effective at identifying all patients who have high-grade disease. Conversely, approximately 40% to 60% of patients initially identified as being HPV positive and cytology negative will clear their HPV infection over this short follow-up.

    [*I would strongly urge you to discuss this recommendation with your Ob/Gyn in detail. While for some selected patients this guideline might be applicable, for others, waiting for up to one year to follow-up is simply too long.]