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Abnormal PAP Smear and Diethylstilbestrol

Atypical squamous cells of undetermined significance? For those of you who are in practice, what percentage of ASCUS smears do you get abnormal pap smear, diethylstilbestrol, diethylstilbesterol? Letís say out of 100 smears, how many get ASCUS for 15% of their smears, 20, 10% or less, 5% or less, 5% should be the absolute maximum that any body should see, and those of you who are getting 10 to15% are being bamboozled by your cytology lab. They are using that diagnosis much too often and they are putting unreasonable stress both on you and on your patientís. So, letís look a little bit at atypical squamous cells of undetermined significance. Itís been a wastebasket term that the cytologists are now trying to eliminate. Most of these lesions have nothing in them. Some of them occasionally can hide a high grade lesion. This is a study from nine years ago looking at a number of patientís with minimally abnormal smears. There was no ASCUS then, but this is essentially as ASCUS smear.

Interestingly, of the abnormal smears of these 136, 21 had CIN, so in other words, you have an AGUS smear, but a high percentage of them have squamous abnormalities. If you eliminate those, you have 77 left over, the found the pathology on them, there were numbers of adenocarcinoma in situís, invasive adenocarcinomas, still, squamous cell abnormalities, so they found that about one in six had a significant lesion, and thatís very worrisome, thatís a very high rate of abnormality. At our institution, a recent review of atypical glandular cells of undetermined significance, we had 89 patientís with followup.

Because of the confusion that the Bethesda system started, some guidelines for the management of abnormal cervical cytology came out in the Journal of the American Medical Association in 1994 and I was privileged to be able to serve on that panel, and a couple of important points here, particularly for those of you out in practice. Some women will develop invasive cervical cancer despite adherence to accepted screening.

Routine electroexcision of the transformation zone to evaluate a low grade lesion or ASCUS is not recommended. The one exception I would give you to that is the patient who comes back to you, letís say in her 40s or 50s, has been having dysplasia on and off for a number of years.

The plan of management to consider, the history of the womanís PAP results, reliability of followup. That is crucial. If you have an unreliable patient, you cannot practice these conservative guidelines mentioned above. Those patientís have to be sent for immediate triage, so if you have patientís who are in the sexually transmitted disease clinic who are not likely to come back, triage them right away. If you have a patient in whom you suspect or whom you know, things like immunosuppression, HIV infection. Triage them right away, but I am talking about the more general population. Now, letís switch for a minute to HPV. Generally speaking, there are over 100 types identified as shown on the slide right here.

This is a study that came out for Cox and his colleagues, will get HPV testing, simply called hybrid capture, which is an easily available technique where a bunch of different HPV types are put into a cocktail, these were 217 patientís in a student health service, they did colposcopy and biopsy to evaluate an ASCUS smear. Now, they also did repeat PAP and colposcopy and biopsy if indicated. The did low risk and high risk hybrid capture, they found out that among the patientís, everybody got HPV testing, that if there was a positive HPV type high or low risk, that individual was eight times more likely to have CIN. For any type of CIN, there was positivity in 43 out of 50, but if you get up to the high grade lesions, 93% was positive.

There is a clinical trial thatís going on as we speak that was started a number of years ago, at the NIH, looking to the following, to see in a randomized trial over a three year period, if HPV testing or more conservative PAP smear followup that I mentioned to you a few minutes ago, could be used in the management of ASCUS or low grade lesions.

There are three arms, one arm is the conventional immediate colposcopy and biopsy, immediate triage. The second arm, do a PAP smear in a six months and they do a cervicography which means just take a picture of the cervix, and thatís just to protect the patient, that is to say the patient supposedly has only ASCUS or low grade SIL and taking a picture of the cervix is essentially like doing a colposcopy and you can see obviously if there is a malignant lesion there, so thatís just for quality assurance. Then the third arm is doing this HPV private capture test and if the HPV is positive, then go on to colposcopy and biopsy, and if itís negative, then you continue the followup, and this was randomized and it was begun three years ago, so the trial is essentially over, but the results are now just coming out.

So here are the results that were just published this year in the Journal of the National Cancer Institute for the low grade lesions. The results: HPV DNA detected in cervical samples, from 82% of woman, this high frequency of HPV positivity was confirmed by PCR in a subset of woman because so many of the women were HPV positive who had LGSIL, there is only limited potential to make clinical decisions about the management of these patients. In other words, they close the trial off because so many of the patientís had HPV infection that it didnít differentiate one way or the other.

Of the 50,000,000 PAP smears, an estimated 2 Ĺ million have low grade lesions. So what do you do, you need to reach the unscreened people, we all know that. Now, going back this trial that I just mentioned to you, that included women 16 years and older who had either ASCUS or a low grade lesion. Patientís positive for high risk HPV types were referred, and the interim analysis suggests that while hybrid capture was biologically and technically feasible. It may not be clinically useful as a primary triage tool.

It was very common years ago, because we were all concerned about the malignant potential of HPV, the thought was, letís eradicate it, well this is a study that was done as you can see in 1989, but the lesson is still applicable today. In fact, you couldnít get this study as you will see in just a minute through your IRB today. Twenty five million women with subclinical HPV, you know if itís in the cervix itís also in the vagina and also on the vulva. They did biopsy, the found male partners, they evaluated them and treated them, and then they used our friendly laser to vaporize the entire lower genital tract, cervix, vagina and vulva. Now, you will not be surprised to learn that 100% of the patientís develop severe pain, 3/4 of them got meaningful fever, a number of them ended up in the hospital, and on followup exam at three months.

The normal PAP smear that we all take, has 300,000 to 500,000 cells. A number of these have fewer than 100 abnormals. A number of them had small cells which the called atypical immature mesoblastic cells, these are very small CIN III cells, and then there were various other problems on the smears. There are number of new technologies that have been introduced and these include liquid base preparations which are all over the United States, I think you are also going to see molecular techniques as a way to improve the PAP smear. I donít believe any of these today have been proven to be cost effective in spite of the barrage of advertising to which you are all subjected. In my own practice, I still use the regular PAP smear.

Now, what treatment? These are premalignant lesions, all you have to do is get rid of them, so either laser therapy, cryotherapy, electrocautery have been reported to have equivalent results, the idea is to eradicate the lesion. Cryotherapy got a somewhat bad rap a number of years ago because of the fact that high grade lesions are not only at greater risk for malignant progression.