Webcasts

Update on HPV: Beyond cervical cancer

Hope K. Haefner, MD
University of Michigan
Ann Arbor, Michigan

So now we get to talk about vulva and vagina. 

My disclosures, I’m a speaker for Merck and a consultant for Datamonitor.

So what are the learning objectives for you for this portion of the lecture? I’m a very visual person so you’re going be seeing a lot of gross (in more ways than one) slides looking at condyloma, VIN, VAIN and vulvar and vaginal cancer. So I want you to be able to look and get a differential diagnosis just from visualizing the vulva and vagina. And then understand the prevention of these diseases with the HPV vaccine.

Tom has already talked to you about the low-risk and high-risk types. The low-risk on the vulva, the 6 and 11, are important for the vulvar condyloma. Sixteen and 18- very important for vaginal and vulvar intraepithelial neoplasia, cancers.

As you’ve seen already, the 6 and 11, they’re very similar to one another. On the vulva it tends to be condylomas—HPV 6. Whereas when we’re talking about laryngea papillomatosis it’s often more 11.

When we’re talking about vulvar intraepithelial neoplasia, it’s almost more often than not 16 rather than 18.

So what about HPV vaccination incidence of VIN, VAIN and vulvar vaginal carcinomas? I’m going to be going through some of the data on each of these. But just to show you for the high-grade VIN, 76% incidence of HPV 16 or 18. VAIN’s high-grade, 64% and vulvar cancer lower at 42%.

So how do you evaluate the vulva and the vagina? You see on your left a picture of a colposcope and when we first started our center for vulvar disease that’s what we had. I used colposcopes all the time on the vulva but I would find I was constantly going back and forth trying to get closer and hitting the patient with the colposcope. And then I’d have to wipe it off and I’m a little germaphobic and it would bother me tremendously. So I was talking to Ray Kaufman one day and he said, “Well Hope I just use a magnifying lens” and you see on the main portion of that magnifying lens it’s a two time magnification and then you’ll see small circle, there by my thumb, and that’s a four time magnification. It works very very well and it’s very inexpensive. It’s a little hard to get that four time (magnification) working at first. And then after doing a sabbatical with my husband at his hospital where I learned to do grafts and flaps, he’s a hand surgeon, I bought some loops and let me tell you I love those loops for doing vulvoscopes. But for you, I really think on the vulva, this (magnifying lens) is just as adequate as looking through a colposcope. Not so with the vagina though, or the cervix.

Biopsy instruments for the vulva: I love using a Keyes punch biopsy. I tend to almost always do four millimeter Punch biopsies. Occasionally I’ll use one of these biopsies whether you use a Kevorkian or a Tischler, your choice. But more often than not on the vulva I’m using the Punch biopsy. On the vagina the other forms of biopsies, the Tischler, the Kevorkian.

So let’s first talk about external genital warts. They’re a very costly virus. About 167 million dollars per year are spent on external genital warts.

Here’s a picture of a patient with rather extensive condyloma acuminata. And one tip I can give you- when you see this much condyloma and you’re going to take care of it, obviously in the OR. Get one of those fine tip Bovie’s and use that to de-bulk off the majority of the disease process and then just take the laser and laser the base and all the edges, otherwise you’re going to be inhaling a heck of a lot of fumes.

Here’s a young three-year-old with condyloma on the vulva and diffusely on the anus.

So let me ask you as an audience, if the entire population at risk were to be vaccinated with a meningococcal vaccine we’d prevent 125 cases of meningitis from that organism annually.

But how about if we were to give the vaccine to all adolescent girls, 11 to 12 years of age, how many would it likely prevent in annual infectious cases? Would it be 100,000 cases of genital warts annually caused by 6, 11? 500,000? 900,000? Or it will not affect the number of patients with genital warts? Someone want to yell out which one you think it is?

It’s close to 900,000. Very, very impressive number. But that’s only if all were vaccinated.

Now vulvar intraepithelial neoplasia is fairly common, I see it frequently on a weekly basis. It can have all sorts of appearances.

You can see some gray here, you can see some white here, it can be diffuse, it can be localized. This patient has some darkened brown to black along with some white.

And then there’s the red form. Very erythematous, the entire vulva. When I first looked at this patient I would have thought she had Paget’s Disease rather than vulvar intraepithelial neoplasia, VIN 3. But on biopsy it was VIN 3. And I’m going to be talking to you in a few minutes about new terminology but until then I’ll call it VIN 3.

Here’s a young patient that had these brown areas that I thought were freckles but I happened to do a biopsy of one of them because if it changed and when something changes you biopsy …and it was VIN 3 and all of these were VIN 3.

And then don’t forget to look at the anus. You’ll have a talk by Dr. Palefsky in just a few minutes on the anus, but this patient has VIN here and AIN diffusely here.

I often put the patients in the knee chest position to get a good view of the anus. Here’s a patient that I thought might have a Bartholin cyst. This comes right down ---the labium minus comes right down the middle of it. She has VIN all over the place. But actually when we went to take the Bartholin cyst out and laser her VIN and excise the VIN, this was an epithelial inclusion cyst.

So here’s a case, you have a 29-year-old who presents with vulvar itching and burning.

Take a close view. You see some areas here. You see an area here. She’d had a biopsy done there.

A far away view-- you see some other areas here. See a little redness here.

So I’m going to circle these areas. And all of these areas are potential areas of concern that I’ve outlined.

And now I want you to tell me which of these areas are you going to biopsy? It’s a hard decision. When I first started out I think I biopsied a lot more than I would now but I've been fooled. So sometimes even when I get fooled, I start doing even more than I used to the month before. So you have to kind of take it with a grain of salt.

But especially if you’re first starting out on VIN you’re going to want to biopsy all four areas and know exactly where you’re going to need to treat. Now, if you’re in the OR unexpectedly and you haven’t biopsied an area and you’re not sure if you can treat, you can excise it. You can laser it, but you need to make sure you’ve at least ruled out a disease in that area.

All four biopsies in that patient revealed VIN usual or VIN 3.

So what about the clinical impact of VIN? Well over the last 20 years we’ve seen a significant increase in this disease. We’ve had three times increase in women less than 35 years of age. The incidence of increase, 2.1 cases per 100,000 women and the median age is about 40 years. The youngest patient I’ve seen was 17.

So if you look at VIN 2 to 3, I’ve already mentioned the instance of HPV 16 and 18 and it’s quite high. Even in some studies you’ll see above 80%.

So what I want to tell you now is there’s new terminology out there for vulvar intraepithelial neoplasia. This occurred over several years. The International Society for the Study of Vulvovaginal Disease… We got together and we felt that VIN 1, 2 and 3 and VAIN 1, 2, 3 didn’t quite act the same. We felt a lot of the VIN 1’s were being over-treated aggressively. So what we did is we made new terminology. We got rid of VIN 1. We call it now just condyloma and anything that needs treatment is called VIN. Within VIN there are two categories. VIN usual, which is HPV related and VIN differentiated.

Let me give you some data on why we made these decisions. VIN 1 of low grade is a challenging diagnosis. This is Leonardo Micheletti'’s paper from the mid-90’s.

He had several pathologists get together and while they all agreed pretty much on what looked histologically to be VIN 3, when they got to the condyloma or VIN 1, they were not at all consistent, even sometimes amongst themselves. One time one pathologist would call it VIN, another time condyloma or even maybe normal. So what they decided was lower grades of VIN were controversial. Criteria for diagnosis was subjective, poorly reproducible and there was some overlap with flat condylomas. And so the VIN 1 category was thrown out.

In fact, when they looked together with these pathologists, out of 21 cases that they called mild vulvar atypia or VIN 1, only four were confirmed to be VIN 1 when reviewed by a surgical pathologist and a dermatopathologist. It’s not reproducible.

This summarizes the old terminology 1, 2 and 3 and differentiated VIN to the new terminology. We just have condyloma and then VIN usual, VIN differentiated. VIN usual has three sub-categories. It can be warty, it can be basaloid or it can be mixed, both warty and basaloid. One of the things they wanted to do was to call it VIN undifferentiated and VIN differentiated. My concern with that was, if you looked at those two groups, which would you think was the most worrisome? The VIN undifferentiated, right? But actually if you have to choose, a VIN undifferentiated is less likely to go onto a squamous cell carcinoma whereas at the VIN differentiated tends to be with lichen sclerosus and often associated with a squamous cell carcinoma of the vulva.

Old terminology, high grade VIN, you see mitotic figures.

New terminology, VIN usual, warty type VIN. You see some koilocytes.

Histology of the basaloid type VIN. It’s got a bluer appearance, more dense, small nuclei from the basement membrane up to the surface of the epithelium. This is the basaloid type.

And then finally the worrisome type associated with lichen sclerosus. This is the differentiated type and you see here a keratin pearl.

If you look at the incidence of these types being associated with cancer, the warty and basaloid- about 5 to 20% of the time are associated with an underlying cancer. The differentiated VIN, between 48% to one study (that)had over 95%. I think that’s quite high of an estimate.

So more women are being diagnosed with VIN at a younger age. The incidence is increasing, as I told you, between 1973 and 2000 it increased 411% in the United States. More women between 35 and 54 years of age are being diagnosed with VIN usual. The mean age for VIN 2, 3 diagnosis is decreasing.

What’s the risk to progressing onto disease (cancer)? Well untreated VIN 2, 3 has a high association with a potential for invasion. There was a study done out of New Zealand where someone watched, over 20 years, VIN 3 and 7 out of 8 of the patients went on and developed invasive squamous cell carcinoma of the vulva. The annual progression of untreated VIN 3 to invasive cancer is at least 10% annually while it’s about 2% for CIN.

I’d like to show you now a patient that came in with chronic immunosuppression. She has a history of autoimmune hepatitis and she’d had vulvar changes since about 2005 and she complained of vulvar pain and some vulvar bleeding.

And when you look at her vulva you see some gray, you see some white, you see some (disease) extending into the hair bearing areas.

Higher power view of how diffuse this is. And, again, you see it going in the hair bearing areas.

So what treatment are you going to give this patient? She has VIN warty on histopathology. Should you laser? Should you do a wide local excision? Should you do a combination of laser and wide local excision? Or just observe her?

Well there’s not one correct answer. A lot of people, particularly GYN oncologists, think most of the VIN should be cut.

I personally feel in the non-hair bearing areas, you should laser the VIN. Because people tend to get re-occurrences whether you cut or laser, and if you’re going to be cutting, you’re constantly cutting the vulva off at the recurrences. You’re sometimes going to miss a normal vulvar appearance afterwards, whereas lasered vulvas tend to heal quite well. The people that have disease in the hair bearing area, I like to do wide local excisions. So she is going to have a combination. And the reason I do wide local excisions on them is the hair papillae, go quite deep (down to three millimeters at times) If you’re going to be burning that area that deep, the patient’s going to be very uncomfortable throughout her recovery process. So laser the non-hair bearing areas that you’re not suspicious for cancer and are the VIN usual, and excise the hair bearing areas. In the VIN differentiated,,with the high association with underlying cancer, I tend to excise those.

Next I’m going to move onto the vagina, VAIN 2 to 3, which has a 64% incidence of HPV 16 and 18.

On cytology you see koilocytes. The nucleai are a little bit enlarged but not as bad as high-grade, of course.

And on colposcopy with the colposcope, you put acidic acid you see some whitening in this area here and when you add the Lugol solution (if they’re not allergic to iodine), you see Lugol staining on the normal tissue and non-staining on the glycogen depleted tissue, the abnormal tissue.

And here’s what you see on histology. Again, you’re going to see some koilocytes, see a mitotic figure. And this is VAIN 1, many features of looking at flat condyloma.

In contrast, high-grade VAIN looks completely different. You see you have a high nuclear to cytoplasmic ratio.

When you look in the vagina, to me it doesn’t look that different from what I just showed you. Yes, it’s a little bit more thicker and maybe some mosaicism but in my experience, if I see something abnormal either with acetic acid or with Lugol’s I’m going to go ahead and biopsy and not say oh that’s just low-grade or I know that’s not high-grade, etc.

And this is what you see with Lugol’s, the non-staining area is where I would biopsy.

And on biopsy you have from the basement membrane on up to the surface, abnormal nuclei, high nuclear-cytoplasmic ratios.

How are you going to evaluate these patients. Well you need to look at the entire vagina. Sometimes I’ll use a clear speculum, but more often than not I’ll just take a metal speculum and rotate it around. It’s more common for the disease to be in the upper third of the vagina and at the cuff if someone’s had a hysterectomy. You have to make sure though that you look at the whole vagina.

If you’re having difficulty seeing certain areas, get a hook for exposure and don’t forget about your bimanual. You can palpate disease sometimes even when you can’t see it. I always change my gloves between the vaginal and rectal examination. And there’s a few patients that you need to do an examination under anesthesia if you can’t find what you feel is a disease process.

So HPV vulvar and vaginal lesions are going to be affected by the vaccine. Those that are affected by 6, 11, 16 and 18, the L1 virus-like-particle that Tom’s already talked to you about.

This was a study by Elmar Joura that looked at the vaccine from three studies. And in women who were HPV negative, the vaccine was 100% effective in preventing VIN and VAIN 2 and 3. Of the 15 women in this group that developed VIN 2, 3 or VAIN 2, 3 associated with HPV 16 and HPV 18, all had been given placebo. And finally in Elmer’s study he found in women previously exposed to HPV, vaccination reduced the incidence of VIN 2, 3 and VAIN 2, 3 by 71%.

Another study by Dr. Barr looked at genital warts and VIN 2, 3 and VAIN 2, 3 and similarly a high vaccine efficacy, anywhere from 98.8% up to 100% is seen.

Finally we’ll go to vulvar cancer. The incidence of HPV in vulvar cancer is 42%. I often wonder if when we start identifying other HPV viruses, with time it might get to be a higher number. Or as our population that was in the 1960’s gets to the age that they’re developing cancer, if maybe they won’t have more viruses in them.

When you look at the SEER incidence rates you see someone here in their twenties with cancer but the majority are up here in their sixties, seventies and eighties with cancer.

This is a patient that had an erythematous area that was bothering her -slightly eroded and then this whitening on her vagina. I biopsied this, invasive squamous cell carcinoma of the vulva—this is VAIN 2.

Another patient who is HEP C positive, an IV drug abuser, came in with a tender vulva and she had an area of suspicion throughout the vulva and down to the anus and this was invasive squamous cell carcinoma.

Vaginal cancers, if you look at the SEER incidence rates, it’s a little bit older of what I just showed you for the vulva, but in their thirties some people had vaginal cancer and then as you get up onto their sixties, seventies and eighties it rises.

Here’s a picture of a patient with invasive squamosus cell carcinoma. You see an area right here and an area right here and more obviously these areas all of invasive squamous cell carcinoma with bizarre atypical vessels. And you can palpate that it’s nodular. It can be whitened and you can see some branching vessels too. If you see this patient, do not rely on the Pap smear, sure go ahead and take it (Pap smear), but take a biopsy then and followup on it.

So I hope in these short moments I’ve been able to convince you that we can prevent many of these diseases with the HPV vaccine. Thank you very much.