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April 30, 2007
Pap and HPV
Basically, HPV is a family of over 118 viruses. Some of the types are responsible for various genital diseases and cancers. Two particular types cause most genital warts and fifteen other types cause cervical (and other anogenital) cancers, with two (16/18) causing over 70%. A virus gets into the basal layer cells of certain types of skin and takes over, using the host cells’ replicating processes to replicate itself.
For about 20 years, we have known that HPV is a causative agent. For over ten years, research has conclusively demonstrated that infection with carcinogenic types of HPV represents a nearly universal event in cervical cancer development. (That means you have to have these particular infections to develop cervical cancer.) From the other direction, though, most HPV infections do not cause cancer.
It is estimated that over a quarter of all American women have had HPV infection. (There is a new study in JAMA quantifying women with high-risk HPV infection but I can’t put my hands on it at the moment. It doesn’t change the argument.) In many, the infection clears on its own. (In 90%, the infection is cleared within two years.)
Only 1% will get significant histological changes (cell tissue changes seen under a microscope -- on Pap smear). [A Pap smear, named after Papanicolou, the pathologist who developed this technique, involves looking at cells wiped and scraped from the cervix, stained and examined under a microscope. Over the years, grading systems for changes from normal have developed. They used to be read as normal, “benign reactive atypia,” “severe reactive atypia,” “dysplasia,” “carcinoma in situ,” and”carcinoma.” The 2001 Bethesda criteria now reads them as: “negative,” “ASCUS (Atypical squamous cells of uncertain significance),” “LSIL(low-grade squamous intraepithelial lesions),” “HSIL (high-grade),” etc. ] Of the 1% who have significant changes, 70% will regress to normal within 6 years. (In other words they don’t get cancer.) Another 6% will progress to CIN3 (cervical intraepithelial neoplasia- cancer precursor) and only 10-20 % of those will progress to invasive cancer, or 1/10,000. So it is projected that about 11,000 US women will be diagnosed with invasive cervical cancer this year. (There are about 150 Million females in the US, but 40000 of them are under 13. So 1/10,000 is 11,000/110 Million.) This may sound like a high risk, but the risk of dying from suicide is higher, at 1/8000.
So to find the 1/10,000, it is urged that every woman receive an annual Pap smear. This obviously ignores that only women with high-risk HPV types are even at risk. It also ignores that it takes ten to twenty years for the cancer to develop. Even worse, it ignores the number of false positives that are found and must have follow-up testing, at a huge psychological cost (of thinking she is dying of cancer for the weeks or months the follow-up takes) and financial and physical and social costs.
Most low grade lesions regress on their own. What is the cost (psychological, monetary, social) of treating these?
The accuracy of the Pap is not great. Even at best it has a sensitivity of 70-80% and specificity of 95%. (68 and 75 more realistically). With a prevalence of CIN3 about 6/10000, the PPV (positive predictive value) of the pap is 1% and the NPV (negative predictive value) is 99%. (So the Pap would be useful for telling a woman she does not have cervical cancer (or its immediate precursors) if she is positive for high-risk HPV.
“Annually in the US, 50 million women undergo screening; about 3.5 million (7%) will be referred for further evaluation. Of these, more than 2 million will be referred for further evaluation of ASCUS.” 2 million unnecessary colposcopies? Or cryotherapy, which is associated with PID & cervical stenosis, and which makes subsequent colposcopy inadequate. Complication rate of 5-20% means 25-100,000 unnecessary complications to prevent a handful of deaths. Or even up to 11,000. Remember, again, that the women who are have cryotherapy or LEEP now on the basis of a questionable Pap have a very small risk of developing cancer, and that not for a decade.
So, to prevent a small risk, with better means of prevention (recall that HPV is a sexually transmitted infection), we cause more problems than we prevent. This is the nemesis.
| By Robert Maddox | 02:06 PM