The Pap smear is no panacea, Katie Couric

Regular readers keeping up on infectious disease issues might have seen Seth Mnookin’s post yesterday, warning of an upcoming episode of the Katie Couric show  focusing on the HPV vaccine. Even though Mnookin previously spoke with a producer at length regarding this topic, the promo for the show certainly did not look promising:

“The HPV vaccine is considered a life-saving cancer preventer … but is it a potentially deadly dose for girls? Meet a mom who claims her daughter died after getting the HPV vaccine, and hear all sides of the HPV vaccine controversy.”

And indeed, reviews thus far show that unfortunately, Couric pretty much  mangled the issue and allowed heart-wrenching anecdotes to trump science (reminiscent of Jenny McCarthy’s appearance on Oprah). I won’t cover it all (you can view it here), but basically Couric allows stories about illness and death in the weeks following administration of the vaccine to go unchallenged, and brings on Dr. Diane Harper as her HPV expert (featured prominently in the anti-vaccine documentary “The Greater Good“). Dr. Harper believes the HPV vaccine is over-hyped, and that Pap screening is “100% accurate” so no HPV vaccine is really needed. This, frankly, is hogwash. Even with emphasis on screening, here in the U.S. we have 12,000 cases and 4,000 deaths from cervical cancer alone each year. (And in Mnookin’s post and in Matthew Herper’s Forbes post, both note that head and neck cancers can also be caused by HPV as well–but have no good screening process).

Even when HPV cervical infections are caught via screening, the treatment ain’t pretty. I’ve written before mentioning one such remedy–the LEEP procedure.  I had this done several years ago, after a Pap smear came back with abnormal cells and positive for HPV DNA:

“Next, a woman with abnormal cells can expect to undergo a LEEP procedure, where portions of your cervix are removed with a burning electric wire under local anesthetic, and the foul smoking remains of your cells are sucked up into the smoke shark, “a sleek, powerful, smoke-eating machine.” [And one gets to look forward to “coffee ground-like discharge” for up to several days following the procedure, due to the materials they use to stem the bleeding cervix]. After LEEP, side effects may include infection, hemorrhage and possibly cervical incompetence.  These are rare, but if we’re talking vaccine side effects versus possible outcomes from HPV infection, these types of outcomes need to be considered as well–not just death from cervical cancer.”

Being currently pregnant following such a procedure, cervical incompetence was something I was carefully monitored for. Nevertheless, it’s still been a huge source of stress throughout this pregnancy, as this is a significant cause of second-trimester miscarriage and there aren’t great, foolproof ways to detect it, or remedy it if it does occur. Harper acts as if finding HPV via Pap smears is like rainbows and unicorns, but it too has a risk-benefit equation, and I’d so much rather have received a vaccination than to have gone through that. And, some women’s treatments for HPV infections and cervical abnormalities are even more extreme than mine was.

This is why I had my now-almost-14-year-old daughter vaccinated for HPV, and why my pre-teen son will soon be getting his as well. There are multiple ways to prevent HPV-induced cancers, but the vaccine (in combination with routine Pap smears) is by far the least invasive and safest route, as multiple studies have confirmed.

Finally, the show was doubly disappointing because Couric has been such an outspoken advocate of colon cancer prevention, which was the cause of her husband’s death in 1998. While realizing this is a fluff talk show and not the kind of harder journalism she’s apparently now abandoned, she still failed to ask even the most basic of questions to the supposed HPV vaccine “victims” she featured on her show, nor to note during their segments that other possibilities may exist for the girls’ illnesses and death besides the HPV vaccine. In the second segment, Rosemary Mathis even admits blatantly doctor-shopping until one would “listen to her” about her daughter–in other words, give her a new diagnosis (vaccine injury). Why isn’t this even questioned? What did her previous doctors tell her about her daughter’s condition? Couric allowed ratings and anecdotes to trump actual science, potentially causing real harm to the public health. How disappointing that this is now part of her legacy.

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Is the HPV vaccine “weak science?” (Hint: no)

Oh, Discover. You’re such a tease. You have Ed and Carl and Razib and Phil and Sean, an (all-male, ahem) cluster of science bloggy goodness. But then you also fawn over HIV deniers Lynn Margulis and Peter Duesberg. Why can’t you just stick with the science and keep the denial out?*

But no, now they’ve let it spill into their esteemed blogs. I was interested to see a new blog pop up there, The Crux, a group blog “on big ideas in science and how these ideas are playing out in the world. The blog is written by an outstanding group of writer/bloggers and scientist/writers who will bring you the most compelling thoughts throughout the world of science, the stuff most worth knowing.” Sounds ok, let’s see what stories are up…oh, one on HPV! Right up my alley. And hey, a woman! Bonus.

*Reads story*

Ohhhhh, it’s actually one on HPV vaccine misinformation, written by the author of the fawning Duesberg article referenced above. Faaantastic.
Continue reading “Is the HPV vaccine “weak science?” (Hint: no)”

Does bestiality increase your risk of penile cancer?

Aah, the things one learns when awake at 3AM on a Saturday night. Via a few different Tweeps, I ran across this article from Men’s Health magazine, titled “Urgent Warning: Sex with Animals Causes Cancer.”

I probably should have just stopped there.

But no, I read the magazine article, which states:

Brazilian researchers polled nearly 500 men from a dozen cities, and found that–we’re not joking around here–roughly 35 percent of the men had “made it” with an animal. That’s a problem, because screwing a horse, donkey, pig, or any other animal was found to up your likelihood of developing cancers of the penis by 42 percent.

Of course, this meant that now, I had to go dig up the actual journal manuscript. Though nothing is cited by Men’s Health, a quick PubMed search using the terms “sex with animals” and “Brazil” turned up Sex with Animals (SWA): Behavioral Characteristics and Possible Association with Penile Cancer. A Multicenter Study, published last month in The Journal of Sexual Medicine.

Though the MH write-up makes the research sound ridiculous, it’s not a bad paper overall. Starting out with the observation that penile cancer is common in impoverished regions in the world but relatively rare in developed areas, the authors wanted to examine one possible difference in this urban/rural divide: bestiality. So they enrolled 492 individuals who had spent their childhood in rural areas: 118 cases who had penile cancers and 374 controls who were seen at the same clinics for other issues, including check-ups and “cancer prevention” (though it’s not really defined what’s included in that catch-all). All participants were asked a variety of questions about their sexual history, including sex with animals and humans (frequency, number of partners, the usual drill), circumcision status, as well as other factors that might influence cancer outcomes, such as smoking status and history of sexually transmitted diseases and other health conditions.

The authors did find in the univariate analysis (basically, looking at one factor at a time) that there were several statistically significant differences between the cancer group and the control group. These included smoking, a history of sex with prostitutes, the presence of penile premalignant lesions (not surprising) and phimosis (NSFW), a condition where “the foreskin cannot be fully retracted over the glans penis.” As the title suggests, they also found that having sex with animals was significantly higher in the case than the control group (44.0 vs 31.6 percent, p<.008). When they combined risk factors into their multivariate analysis, a few factors still remained in the model. Phimosis was the big one, with an odds ratio of 10.41; SWA was down the list at 2.07 (95% CI: 1.21-3.52, p=0.007). Penile premalignant lesions and smoking also remained, with odds ratios in the middle of the other two. Finally, just because I know many of you out there are curious, they also break down those who have SWA by types of animals they, um, frequent:

The animal types most often cited were mares (N = 80), followed by donkeys (N = 73), mules (N = 57), goats (N = 54), chickens (N = 27), calves (N = 18), cows (N = 13), dogs (N = 10), sheep (N = 10), pigs (N = 6), and other species (N = 3).

Yes, chickens for 27 of them. I don’t even want to know, but I’m sure if I did, I could find out somewhere on the Internets. Please, don’t educate me on that one. They also note that almost a third of the men reported “SWA with a group of men.” I’m leaving that one alone as well (especially as that one wasn’t any different between cases and controls, so it didn’t seem to be an important variable for penile cancer development).

So how do they explain these findings? Their discussion is a bit odd, in my opinion, and narrows in on the SWA finding to the exclusion of their other significant risk factors. Of course, coming from my background, my first thought regarding SWA and cancer jumps to infectious agents. They acknowledge in the introduction that the human papillomavirus (HPV) is associated with about half of penile cancers. Other species of animals can also be infected with papillomaviruses, such as the rabbit of jackalope mythology. A previous study identified five potentially novel papillomaviruses in Australia, just by doing skin swabbing. As such, it’s certainly safe to say that we know very little about the diversity of these viruses that exist in other animal species, much less their cancer-causing potential. It would be fascinating to look at tumor samples from the men in this group who were known to have sex with animals, and see if any novel viruses (papillomas or otherwise) could be identified.

However, they don’t limit their suggestion to only zoonotic infections. That’s when it gets a bit weird to me, as they say things like:

Speculation exists regarding cancer status as an infectious disease in humans [24,25], as studies have suggested that tumor cells can be transmitted from one mammal host to another within the same species [26,27]. PC is frequent in equines [28], but transmission of malignancies between animals and humans has not been reported.Virology does not consider possible viral movement from animals to humans except in cases of zoonosis, such as rabies or pandemic forms of bird or swine flu. However, the hypothesis that the HIV epidemic resulted from simian-human virus transmission has not been fully explored.

Um, huh? First, the citation they use for the HIV claim is from 1999–indeed, at that point there was still a lot that was unknown about cross-species HIV transmission, but that was 12 years ago! The field has moved on since then. I’m baffled as to what they mean by their first sentence–as far as I know, “Virology” doesn’t consider anything–“Virologists” do, and why would this not be a zoonosis? Though I think direct transmission of cancer cells (like in the case of the Tasmanian devil transmissible cancer) would be unlikely, transmission of microbes which could lead to cancer development is certainly plausible and well within the realm of virology/bacteriology/etc. In my opinion, it’s infinitely more likely than the idea they also suggest of more directly carcinogenic animal secretions.

There were also a number of limitations in the paper. Though they grouped frequency of sex with prostitutes into a “more/less than ten times” dichotomous variable, I don’t see any similar “dose” analysis for the frequency of SWA in their models, even though they did ask the men about this. They make one statement that “long-term SWA (>3 years) was reported by 64% of the PC patients and 46.6% of the controls (P = 0.044).” This difference was statistically significant at the usual cutoff (p< .05), but it doesn't appear that they studied this further--why not? If you have a typical dose-response relationship (the more times the men had sex with animals, the more likely they were to develop cancer in the future), that would strengthen their case for a connection between the two. They also didn't ask about sexual orientation or the nature of the self-reported past STDs. Are any of these participants HIV positive, for example? Anyway, with these limitations in mind, it does appear that Men's Health got it mostly right: don't have sex with animals if you value your penis. But it's unfortunate that they just go for the sensationalism and ignore the more important variables from a public health standpoint, like "don't smoke" and "if you have abnormal penile conditions, you may want to get those checked out, k?" References

Zequi SD, Guimarães GC, da Fonseca FP, Ferreira U, de Matheus WE, Reis LO, Aita GA, Glina S, Fanni VS, Perez MD, Guidoni LR, Ortiz V, Nogueira L, de Almeida Rocha LC, Cuck G, da Costa WH, Moniz RR, Dantas Jr JH, Soares FA, & Lopes A (2011). Sex with Animals (SWA): Behavioral Characteristics and Possible Association with Penile Cancer. A Multicenter Study. The journal of sexual medicine PMID: 22023719

Antonsson and McMillan, 2006. Papillomavirus in healthy skin of Australian animals.

The role of beta-HPVs in skin cancer development

Student guest post by Desiré Christensen

Human papillomaviruses (HPVs) are small DNA viruses that infect epithelial cells. There are well over 100 subtypes of HPV. The subtypes that infect cutaneous epithelia are termed beta-HPVs and those that infect the mucosal epithelia are termed alpha-HPVs. Some alpha-HPVs have received attention as strong risk factors for the development of cervical cancer. Less public awareness has been generated over the role of HPVs in the development of other cancers such as vulvar, vaginal, anal, head and neck, and penile cancers. Only recent research has focused on an association between HPV infection and skin cancer development.

Infection with beta-HPVs and development of skin cancer was first identified in patients with a rare inherited disorder called epidermodysplasia verruciformis (EV)(1). Roughly 50 percent of EV patients develop premalignant skin lesions and squamous cell carcinomas (SCCs) by the time they are 40 (2). Lesions and carcinomas mainly develop in sun-exposed regions, but HPV DNA has also been detected.3 Based on these findings, an interactive carcinogenesis between HPV and UV radiation has been suggested.

Immunocompromised patients are at increased risk of developing SCCs and other skin lesions, supporting the hypothesis that an infectious agent may play a role in skin cancer development. Organ-transplant recipients are at increased risk of developing warts and other skin lesions often followed by the development of SCC. The prevalence of beta-HPV DNA nears 100 percent in premalignant lesions and SCC in these immunocompromised individuals (4,5). In comparison, beta-HPVs have been detected in 30 to 60 percent of SCCs from immunocompetent patients (6).

A study by Karagas et al (7) aimed to describe the association between beta-HPVs and squamous cell carcinomas by testing for anti-HPV antibodies. Anti-HPV antibodies were found 60 percent more often in cases of squamous cell carcinomas compared to controls. A significant association between basal cell carcinoma and beta-HPVs was not observed. Beta-HPVs were associated with squamous cell carcinomas even after adjusting for smoking, drinking, medical and family history, and sun exposure (7).
Mechanisms for the role of HPVs in skin cancer are currently under investigation.

Recent research supports the biologic plausibility of a causal pathway from HPV infection to the development of skin cancer. The E6 and E7 proteins in high-risk types of HPV are known to modify and interact with cellular proteins leading to uncontrolled cell growth. In response to UV damage, the E6 protein from several beta-HPVs effectively inhibits cell apoptosis (8). The promoter of beta-HPV types 5 and 8 is also stimulated by UV exposure (9). Disruption of UV-induced thymine dimer repair has been demonstrated in cells expressing beta-HPV type 5 E6 protein, but has not been shown in cells expressing the E6 protein from other beta-HPVs (10).

The interaction between E6 and Bak, a proapoptotic effector, has been studied as a possible oncogenic pathway. Bak is degraded by the beta-HPV E6 protein resulting in protection from apoptosis in UV damaged cells. The degradation of Bak by beta-HPVs can occur without affecting regulators of Bak. The ability of the E6 protein to degrade Bak was not different between beta-HPV subtypes, suggesting other mechanisms should be studied to explain differential carcinogenesis (11).

More mechanistic studies are needed to determine the carcinogenic properties of beta-HPVs and their potential role in skin cancer development. More epidemiologic studies are needed to determine causality. Most studies have demonstrated an association between beta-HPVs and skin cancer through detection of HPV antibodies or DNA in cancer tissue and the sample sizes used have been small. The presence of HPVs in cancer tissue encourages further investigation but does not prove causation.
UV exposure is known to be a strong risk factor for the development of skin cancer, but recent research has indicated a potential role of HPV infection in skin cancer. It is possible that HPV interacts with UV exposure in oncogenic pathways. There is increasing evidence supporting the biologic plausibility of an interactive effect. Beta-HPVs are ubiquitous in the population and present in both normal and cancer tissues, making it difficult to conduct a prospective study. HPV detection methods have improved over time and should be combined with a strong epidemiologic study design to demonstrate causation (6).

References

1. Lutzner, M. A., C. Blanchet-Bardon, and G. Orth. (1984) Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dermatol 83:18-25

2. Orth, G., S. Jablonska, M. Jarzabek-Chorzelska, S. Obalek, G. Rzesa, M. Favre, and O. Croissant. (1979) Characteristics of the lesions and risk of malignant conversion associated with the type of human papillomavirus involved in epidermodysplasia verruciformis. Cancer Res 39: 1074-82

3. Pfister, H. (1992) Human papillomaviruses and skin cancer. Semin Cancer Biol 3:263-71

4. Bouwes Bavinck JN, Plasmeijer EI, Feltkamp MC. (2008) Beta-papilloma- virus infection and skin cancer. J Invest Dermatol 128:1355-8

5. Pfister H. (2003) Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31:52-6.

6. Asgari MM, Kiviat NB, Critchlow CW, Stern JE, Argenyi ZB, Raugi GJ et al. (2008) Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. J Invest Dermatol 128:1409-1417

7. Karagas MR, Nelson HH, Sehr P, Waterboer T, Stukel TA, Andrew A et al. (2006) Human Papillomavirus Infection and Incidence of Squamous Cell and Basal Cell Carcinomas of the Skin Journal of the National Cancer Institute 98:389-395

8. Jackson, S., and A. Storey. (2000) E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage. Oncogene 19:592-8

9. Akgul, B., W. Lemme, R. Garcia-Escudero, A. Storey, and H. J. Pfister. (2005) UV-B irradiation stimulates the promoter activity of the high- risk, cutaneous human papillomavirus 5 and 8 in primary keratinocytes. Arch Virol 150:145-51

10. Giampieri, S., and A. Storey. 2004. Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer 90:2203-9

11. Underbrink MP, Howie HL, Bedard KM, Koop JI, and Galloway DA. (2008) The E6 proteins from multiple beta HPV types degrade Bak and protect keratinocytes from apoptosis after UVB irratiation. J Virol 82:10408-17