1. HPV-related anogenital cancers
Good morning everyone, and thanks for being here.
Sarah Bradley, MD
University of Wisconsin
School of Medicine and Public Health
Wisconsin HPV Vaccine Summit
May 12, 2016

2. Disclosures
None

3. Outline HPV-related anogenital cancers
Cervical cancer
Precancerous cervical dysplasia
Vulvar and vaginal cancer
Penile cancer
Anal cancer
HPV transmission and auto-inoculation
For the talk today, I’m hoping to give you a broad overview of all of the genital cancers in both men and women that are caused by HPV, including cancers of the cervix, vulva, and vagina in women, cancer of the penis in men, and anal cancer in both men and women. For each type of cancer we’ll cover common symptoms, typical treatment, and prognosis, as well as the prevalence nationally and here in Wisconsin. Then I’ll end by sharing some information about the transmission of HPV particularly as it relates to these types of these cancers.

4. Cervical cancer Nearly 100% caused by HPV
I’m going to start by talking about cervical cancer. This is a picture of Harald zur Hausen. He’s the German virologist who discovered that HPV causes almost all cervical cancers. This is him in 2008 accepting the Nobel Prize in Medicine for his work . Cervical cancer was the first cancer that we recognized is caused by HPV infection, and we know more about the natural history of cervical HPV infection leading to cancer than we do any other cancer type.
Harald zur Hausen, Stockholm, 2008

5. Pathophysiology of HPV
This slide shows the pathophysiology of HPV infection and how it can lead to cervical cancer. This first picture shows HPV infecting the cervical cells. The virus targets proliferating basal cells in epithelium of the cervix, and then within weeks it will replicate within those host cells and shed viral particles off that can infect others. The average infection is cleared by the body’s immune system within about 8 months; and 85-90% of people will clear the virus within two years. If your body is unable to clear the infection, then the HPV DNA will actually incorporate into your own cells and into your DNA as shown on the right here. At that point, the HPV genes, specifically E6 and E7 genes, shut off tumor suppressor genes that prevent cancer formation. Ultimately, over the next few decades it’s the loss of function of tumor suppressor genes that causes cancer.

6. Persistent HPV infection  Cancer
HPV infection is necessary but not sufficient
Persistent infection occurs in 10-15%
Average time from infection  cancer is years
Risk factors for persistent HPV
Oncogenic, high risk subtypes
16 and 18 cause 70-75% of all cervical cancer
Smoking
Compromised immunity
From the last slide, we know that it’s not just infection with HPV alone that causes cancer, because most people get infected and then clear the virus. It’s the 10-15% of women with persistent cervical HPV infection that lasts over several decades who develop cancer. The average time from infection to developing cervical cancer is years. One of the biggest risk factors that an HPV virus will persist is whether or not it is a high risk subtype. The most common high risk subtypes are 16 and 18, which cause over 2/3 of all cervical cancer. Other risk factors include smoking and compromised immunity, for example with HIV infection.

7. Cervical Cancer Diagnosis
Mean age at diagnosis 48
Symptoms
Irregular or heavy vaginal bleeding
Post-coital bleeding
Vaginal discharge
Abnormal pap smear
In Wisconsin in 2012
191 new cases
54 deaths
Most women diagnosed with cervical cancer are in their 40s-60s, and the average age at diagnosis is 48. Of women diagnosed with cervical cancer, many of them have not had a pap smear in several years, or they’ve never had a pap in their entire life. Cancer makes the cervical tissue very fragile, so that it bleeds very easily. So the most common symptom of cervical cancer is abnormal bleeding. This may include bleeding that is irregular or heavy, or post-coital bleeding which is bleeding after intercourse. Some women may have vaginal discharge that is abnormal. And although the goal of pap smear screening is really to identify pre-cancerous changes before they become cancer, some women are initially diagnosed because of an abnormal pap smear.

8. Treatment and survival
Early stage cancer
Stages IA1 to IB1
Surgery
Radical hysterectomy
Fertility sparing in some
5 year survival 93%
Locally advanced cancer
Stages IB2 to IVA
Chemoradiation
5 year survival 15-80%
Like any cancer, the type of treatment and survival rates are a function of the stage at which the cancer is diagnosed. For women with early stage cervical cancer which is shown here on the left, this would include either cancer that is microscopic or very small visible lesions. Women in these early stages can usually be treated with surgery. This usually consists of a radical hysterectomy but in some patients who are early stage and desire future fertility, they may be able to have treatment with removal of part or all of their cervix only, in order to be able to have children in the future. Overall survival for these early stage patients is quite good, with up to 93% survival at 5 years. If cervical cancer is not caught early, it spreads by direct extension to the surrounding tissues. So for example, it might spread to the uterus, upper vagina, pelvic sidewalls, and in very late stages, to the bladder or bowel. These later stage cancers are treated more commonly with chemoradiation, and depending again on stage, 5 year survival might be anywhere from 15-80%.

9. This next slide shows rates of cervical cancer here in WI from 1995 through We’ve gone from about 8 cases per 100,000 women in WI to just under 6 cases per 100,000 women in Nationally we had a really significant decrease in cervical cancer after we developed pap smear screening, and I think this trend has continued because we’ve had funding for women without health insurance to get paps. In terms of actual #s, in 2010 we had 160 new cases of cervical cancer in WI and about 50 deaths from cervical cancer.

10. Progression of Pre-cancerous Cervical Dysplasia
CIN 1
Represents acute HPV infection
Most will regress
CIN 3
30% will progress to cancer if untreated
I next want to back up a little bit and talk about pre-cancerous changes of the cervix, which are referred to as cervical dysplasia, or CIN, which stands for cervical intraepithelial neoplasia. All of those terms are used interchangeably. This cartoon is another way to look at progression of HPV infection in cervical cells. So starting over here on the left, this is a normal basal cell of the cervix, and after being infected with HPV there is a progression to first CIN 1 or mild dysplasia. And at any point on this path, the cell can develop progressively worsening dysplasia, or it can go back the other way and regress to normal. We know now that CIN 1 or mild dysplasia represents acute HPV infection, and for most women this will regress without any intervention. Once you develop CIN 3 or severe dysplasia, this is a clear precursor to cancer, and about 30% of these women will develop cervical cancer over the next 5-7 years if left untreated.

11. Secondary Prevention of Cervical Cancer
Pap smear screening
3 million abnormal paps/year in the US
Evaluation with follow up pap or colposcopy
So this is where I intervene as a general ob/gyn physician. Pap smear screening is essentially secondary prevention of cervical cancer. Every year in the US, there are about 3 million abnormal pap smears, and these pap all have to be followed up and triaged to determine if there is any dysplasia present, and if so what is the severity the dysplasia and what do we need to do about it. Depending on the pap result, most of these women end up having a colposcopy exam, which is shown here. This is a procedure where I apply a vinegar solution to the cervix, evaluate the cervix with a microscope, and then biopsy any abnormal appearing areas. The results of this evaluation will determine the severity of any dysplasia present.

12. Secondary Prevention of Cervical Cancer
Management of cervical dysplasia
Low grade dysplasia  observe
High grade dysplasia  treat
Cryotherapy/LEEP/cold knife cone
Adverse effects
Anxiety
Preterm labor risk
So in terms of management, we know that CIN 1 or low grade changes usually represents acute HPV infection, so these women can be observed and have a repeat pap in a year, because we know it’s most likely to clear up on its own. But those women who have high grade changes need some type of treatment to prevent further progression to cervical cancer. This may include a cryotherapy, which is a freezing treatment of the cervix, or a LEEP procedure which is shown here. This is an office procedure that removes a chunk of the cervix to get rid of all the abnormal cells. A cold knife cone is another version of this which is done in the OR with a scalpel instead of a loop electrode. And while it’s great that we can do these things to prevent someone from developing cancer, I can tell you that having to go through these procedures and the recovery is not a walk in the park. Aside from the discomfort of the actual procedures, there’s a lot of anxiety involved in waiting for 6 months or 12 months for follow up to see if the cervical dysplasia has resolved. For women who have to have part of their cervix removed, they have a risk of preterm labor in future pregnancies and may have an increased chance of miscarriage. So the HPV vaccine is great thing because it’s really primary prevention of cervical cancer, and can potentially decrease the number of women who need treatment for cervical pre-cancer.

13. Other Genital Cancers in the US
I’m going to move now from cervical cancer to other genital cancers caused by HPV. This graph shows cancers in men and women in the US, with the purple representing the proportion for each cancer that can be attributed to HPV infection. Here in women, we just talked about cervical cancer which is the big player, but HPV also causes about 80% of vaginal cancer and 50-60% of vulvar cancer. In both men and women, about 85-90% of anal cancer is caused by HPV. And in men, about 50% of cancer of the penis is HPV related.

14. Other HPV-related genital cancers in women: vulvar and vaginal cancer
So in women, we’ll next talk about vulvar cancer.

15. Vulvar cancer In Wisconsin (2012): Symptoms 90 cases 30 deaths Itching
Visible lesion
We have about 5000 new cases of vulvar cancer/year in the US, and about 95 cases in WI. Vulvar cancer is most frequently seen in postmenopausal women; the average age at diagnosis is The most common symptoms include vulvar itching and the presence of visible lesion on the vulva. This is an example of what vulvar cancer might look like. You can see here there are patchy white and pink areas that are asymmetric, and in this other case it appears more as an ulcerated area. The diagnosis is made by biopsying these areas.

16. Vaginal cancer In Wisconsin (2012) Symptoms 23 cases 17 deaths
Vaginal bleeding
Vaginal discharge
Vaginal cancer is the most rare gynecologic cancer. There are only 3000 cases nationally every year and only about 15 in WI. Women can develop either localized or multifocal disease with multiple sites throughout the vagina. These women usually present with abnormal bleeding or abnormal vaginal discharge.

17. Vulvar and Vaginal Cancer Treatment
Surgical excision
+/- Chemoradiation
Depending on the stage at diagnosis, vulvar and vaginal cancer can be treated either by surgery in early stages or a combination of chemotherapy and radiation. Surgery may include either a partial or radical vulvectomy, and also usually involves a lymph node dissection in the groin area. The prognosis varies depending on stage at diagnosis, with patients at earlier stages having much better survival rates. This is a picture of what a vulvectomy looks like – over here on the left is a partial vulvectomy, and then a radical vulvectomy includes removing this entire area. I wanted to include this picture as a reminder to mention that aside from just all of the physical issues of treatment and whether or not you’re going to live, people with these kinds of cancers who survive also end up having huge quality of life issues. This is true not just of vulvar cancer but all of the cancers I’m talking about today. This includes issues related to loss of normal function, sexuality, relationships, and even your identity as a man or a women.

18. Incidence of vulvar and vaginal cancer in WI
Per 100,000 women, age adjusted
This slide shows rates of vulvar and vaginal cancer in WI. The blue line is vulvar cancer cases per year per 100,000 women. The red line is vaginal cancer. Both of these cancers are rare so I can’t really make any generalizations about trends, but I can tell you that nationally we’ve seen an increase in vulvar dysplasia.
Wisconsin Cancer Reporting System, 2014

19. HPV-related cancer in men: Penile carcinoma
So now we’ll move onto the only HPV related genital cancer that is specific to men – and that is cancer of the penis.
HPV-related cancer in men: Penile carcinoma

20. Penile cancer Usually presents in older men (> age 50) Symptoms
Painless
Lump, rash, or ulcer
Lymphadenopathy
30-35 cases/year in WI
Penile carcinoma usually presents in older men, mostly commonly in their 50s and 60s. The most common type of symptom is a painless lump, rash, or ulcer. This picture is actually showing penile carcinoma in situ, which is essentially the highest grade precursor to cancer before it actually becomes cancer. If there are swollen lymph nodes in the groin region, this is a sign that it has spread to the lymph nodes.

21. Penile cancer 50% attributed to HPV
Higher rates globally where there are high rates of cervical cancer
There are several different types of penile carcinoma, and it seems that around 50% are related to HPV. Though it is rare in developed countries, there are high rates in the developing world, for example, in parts of Africa and South American, where there are also high rates of cervical cancer. This makes sense if you think about it, because in those countries women with precancerous cervical dysplasia aren’t being treated with LEEP and other cervical procedures to prevent cancer like they are here, so there are many more women around with persistent cervical infection who then end up being a reservoir for men to acquire new infections. Systematic review of HPV prevalence in invasive penile cancer.
Giuliano gyn onc article

22. Anal cancer in men and women
Anal cancer is an HPV –related cancer that affects both men and women.
Anal cancer in men and women

23. Anal cancer diagnosis Symptoms Rectal bleeding (45%)
Anal pain or sensation of mass (30%)
The most common symptom of anal cancer is rectal bleeding, that happens in almost half of patients. Other symptoms can include pain or the sensation of a mass. About 20% of patients are asymptomatic and are diagnosed on routine colonoscopy.

24. Anal cancer treatment and survival
Most diagnosed early
Surgery +/- chemoradiation
70% 5-year survival
Advanced Stage
Chemoradiation
19-59% 5-year survival
Most anal cancers are diagnosed early, in stage I. At that point 5 year survival is about 70%, and it can be treated with surgical excision if it is a small tumor, with chemoradiation added if it is a larger but still localized tumor. In advanced stages, anal cancer is usually treated with chemoradiation, and the prognosis of course is worse. Farrah Fawcett was initially diagnosed in 2006 and had surgery and chemoradiation, and ultimately developed metastatic liver cancer and died 3 years later at the age of 62.

25. Progression of pre-cancerous anal dysplasia
HPV infection 
 anal intraepithelial neoplasia (AIN 1  2 3) 
 anal cancer
AIN 3
8.5% risk of progression to cancer next 5 years
Similar to cervical cancer, we know that there is a progression from HPV infection of the anal canal to pre-cancerous anal intraepithelial neoplasia or AIN, and then ultimately to anal cancer. It seems that AIN 1 or mild anal dysplasia is likely to clear without intervention whereas AIN 3 is a true cancer precursor, and there is at least an 8.5% chance of it becoming cancer in the next 5 years if not treated. AIN – corresponds to CIN in cervical cancer. HPV infection, anal IN, and anal cancer. Stanley.
Moscicki et al. Updating the Natural History of Human Papillomavirus and Anogenital Cancers. Vaccine

26. Rates of anal cancer 85-93% attributed to HPV
Incidence increasing nationally and worldwide
Last 30 years in the US
3-fold increase in men
1.7 fold increase in women
In Wisconsin (2012)
107 cases
17 deaths
Over 85% of all anal cancer is caused by HPV. In the last 30 years in the US, the incidence of anal cancer in men has tripled, and in women has almost doubled. Globally rates of anal cancer are increasing as well.
Giuliano, gyn onc article. Need something about auto-inoculation. Also Abbas, management of anal cancer in Highest incidence in MSM and HIV infected males
Giuliano et al. Epidemiology and pathology of HPV disease in males. Gynecologic Oncology

27. Anal cancer incidence in WI
Around 100 cases/year in WI and about 10 deaths from the last year.
Wisconsin Cancer Reporting System, 2014

28. Transmission and auto-inoculation of HPV
In preparing for this talk I ran across some data about HPV transmission and auto-inoculation that I thought was really interesting and important to present.

29. Transmission of HPV Easily transmitted by contact alone Skin to skin
Genital to genital
Condoms only 60% protection
Oral to genital
? Oral to oral
The most important thing to recognize about HPV transmission is that it is very easily transmitted by contact alone. We know that cutaneous HPV and warts are transmitted from skin to skin contact or touching. HPV viral particles can be found all over the genital surfaces of both men and women. So whether you’re taking swabs of the cervix, the vagina, the vulva, any part of the penis, or the scrotum, you can find HPV viral particles in all of those areas. And condoms don’t protecting all of those areas, for example, they don’t prevent the labia and scrotum from direct contact, so they only provide about 60% protection against HPV transmission. We also know that HPV can be transmitted from oral to genital contact areas and vice versa. Michael Douglas was in the media last year for saying that he got throat cancer from oral sex, and this was probably an acurate statement though I don’t know that it was fair to blame his current wife as it could have been HPV from a previous partner. And finally, there are at least two studies out there that suggest that HPV lives in your mouth and can be transmitted from open mouth kissing.

30. Genital HPV transmission in couples
Concordance of sexual partners 40-60%
New couples
HPV rapidly transmitted to the other partner
Usually both partners clear infections within 1-2 years
In my clinic, I frequently get questions about transmission of HPV in couples, for example, women want to know if they clear their cervical dysplasia and their pap becomes normal, can they just get reinfected from their partner again. We don’t have all the answers, but we do know that there is fairly high concordance of HPV type within partners. In cross-sectional studies, in about half of all couples they will both be positive for the same HPV type. In new couples who were followed over a few years, when initially only one partner was positive for HPV, the other partner seemed to rapidly acquire the infection, and usually tested positive for that HPV type within a few months after they initiated sexual activity. Usually both partners cleared the virus within 1-2 years. But we really don’t know if you then seem to clear the virus and your HPV test is negative, is it really gone for good or is it just latent hiding out somewhere and can be reactivated later?
Human papillomavirus: What every provider should know. Moreira. Incidence, clearance, and disease progression. Still elucidating natural history, factors that affect time to transmission (condom use, is there an HPV reservoir?, etc)
Moscicki et al. Updating the natural history of human papilloma virus and anogenital cancers. Vaccine 2012.
Hernandez et al. Transmission of human papillomavirus in heterosexual couples. Emerging Infectious Diseases

31. Oral autoinoculation NHANES 2010 42.7% of women had cervical HPV
3.8% of women had oral HPV
Of those with cervical HPV, 5X > risk to have oral HPV also
? autoinoculation of remote sites
? oral to genital transmission
The last topic I wanted to cover is the concept of auto-inoculation. This is the idea that if you get an HPV infection in one location, it can then spread on its own to other parts of the body. There’s some evidence from this when we look at the NHANES data. In the 2010, around 43% of women had cervical HPV, and a much smaller number, only 4%, had oral HPV. But, of those women who did have cervical HPV, they were 5X more likely to have oral HPV also. So we don’t know for sure how this is happening, but one possibility is that you’re touching your own genital areas, getting HPV virus on your fingers, touching your mouth, and transmitting it yourself. Or, it could be related to oral to genital transmission; so for example, if you have a cervical HPV infection, and then you get a new boyfriend, maybe you transmit it to him through intercourse and then if you perform oral sex on him you get it transmitted back to you. Prevalence of cervical and oral HPV among US women. STeinau
Steinau et al. Prevalence of cervical and oral human papillomavirus infections among US women. Journal of Infectious Disease, 2014.

32. Autoinoculation of the anal canal
Anal HPV prevalence in men
Up to 50% in MSM
Up to 17% in heterosexual males
Anal HPV prevalence in women
Autoinoculation occurs after cervical infection
50% have new anal HPV within 1 year of cervical infection
I think stronger evidence for this idea of auto-inoculation comes from data related to the prevalence of HPV in the anal canal. In men, we know that about 50% of men who have sex with men will have HPV present in the anal canal, but you can also find HPV present in the anal canal of up to 17% of heterosexual males, so presumably the virus is shedding directly from the penis and scrotum onto the perineum and the peri-anal skin. In women, we know that of those who develop a new cervical infection, 50% will develop a new anal infection with the same type of HPV within the next year, and it seems to be the same type of phenonemon occuring with direct shedding of the HPV virus from the cervix into the vagina, and out onto the vulva and perineum and then to the peri-anal skin.
HPV infection, anal IN, and anal cancer: current issues. Stanley
Stanley et al. HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues. BMC Cancer

33. HPV Rates in the US 14 million new infections/year
79 million with current infection
At any given time in the US population
% of the population has genital HPV
About 7 % has oral HPV
Lifetime risk > 80 %
Dunne et al. MMWR. 2014;63(4):
Dunne et al. JAMA. 2007; 297(8):
Hariri et al. J Infect Dis 2011;204(4):
Sanders et al Oral Dis; 18(5),

34. Questions?