It was once a pervasive theory that warts come from playing with toads and frogs, but it is now nothing more than an old wives’ tale. Today, for most people, it is an absurd concept. But it is derived from an old medical axiom, which is really medical folklore, about “like producing like.” Simply put, because toads and frogs have wart-like bumps, playing with them transfers those wart-like bumps to humans. Forget about the fact that frogs are smooth, or the fact that neither actually have warts. It was a simple and easy way to understand and explain an unknown phenomenon. In fact, it would not be surprising if this folklore were still passed down from parent to child in some remote corner of this country.
The good news is that we know most warts are caused by viruses. We also know there are over 70 strains or subtypes that are responsible for viral warts. The collective name of these viruses is papillomavirus. If the name seems familiar, it may be because papillomaviruses have been in the news quite often in recent years. There are at least 118 human papillomaviruses (HPVs) that can cause various ailments, such as warts or even cancer. However, the vast majority of HPVs are relatively benign. In fact, it has been proposed that HPVs are so common that specific strains of HPVs are ubiquitous and commensal in human skin.
There are 5 groups, or 5 HPV genera: alpha, beta, gamma, mu, and nu. The recent and controversial vaccine Gardasil protects against a few strains in the alpha genus; of particular importance are HPV-16 and -18. HPV-16 and -18 are highly associated with cervical cancer (roughly 70% of cases). However, alpha strains are not the only strains associated with cancer. With the exception of the occasional wart, most people need only to worry about the alpha strains HPV-6, -11, -16, and -18, but in some individuals, beta strains are extremely problematic.
Beta-HPVs infect roughly 80% of the general population but most people remain asymptomatic. However, individuals with a novel mutation in the chromosomal region of 17q25 have a form of genodermatosis known as epidermodysplasia verruciformis (EV). A mutation in either of the adjacent genes, EVER1 or EVER2, is linked to EV. EVER is a member of the transmembrane channel-like (TMC) gene family. TMCs encode transmembrane proteins, although the exact mechanism that produces EV is still undetermined. It may be that those genes are necessary to mobilize an immune response to specific HPV capsids. EV is quite rare, with only about 200 cases worldwide. It is inherited in a recessive fashion, although there are reports of X-linked and dominant inheritance patterns. EV is characterized by recalcitrant skin lesions that resemble flat warts and/or present as macules or elevated brownish plaques. Roughly 70% of the time, lesions begin to develop in infancy or early childhood. There are approximately 30 strains of HPVs implicated in EV. About one-third of individuals will go on to develop malignancies.
There are 2 main phenotypes of lesions based on their potential to become malignant:
- Flat, wart-like lesions that are typically benign. They develop on the trunk, neck, and extremities. They appear as hyper-pigmented or hypo-pigmented papules and may grow into scaly patches or plaques with irregular borders
- Verrucous or seborrhoeic keratosis–like lesions that typically develop on sun-exposed areas and are potentially oncogenic
Individuals with EV are usually infected with more than one strain of HPV. However, there are about 15 strains that may produce a malignancy, and the HPV-5 strain is the most predominant culprit. These lesions never regress and may convert into nonmelanoma skin cancers such as squamous cell carcinomas, Bowen’s disease, and occasionally basal cell carcinomas.
Popular Culture and EV
Dede Koswara grew up in Indonesia and became a television and Internet sensation in 2007 when a photo of his extreme condition was posted online. Several shows, including Medical Mysteries on ABC, detailed Dede’s life and strange affliction. He was dubbed the “Tree Man” because of the strange bark-like growths that protruded from his extremities and face. Before his fame, Dede was married and worked in construction, but by 2007, he had lost his job and his wife. In order to earn a living, he was forced to join a traveling freak show and was known as the “Tree Man of Java.”
Oddly enough, according to one report, Dede had no lesions until he fell and scraped his knee in the jungle at the age of 10. Afterward, small warts developed around the wound, growing slowly over the years to encompass his entire body. At age 18, he married and had 2 children, but about a decade later, the growths became incapacitating, resulting in the loss of his livelihood. He has had several surgeries to remove the growths, including a well-publicized one in 2008 that removed 13 pounds of tissue. Each time, his growths returned. Dede’s case is quite sad and an extreme version of EV. His condition is complicated by a severely depressed immune system that is so extreme that his doctor originally thought he may have had AIDS.
HPV Lifecycle and EV
It is believed that cutaneous HPVs target basal stem cells and transit-amplifying cells. These are slow-cycling, self-renewing cells that essentially maintain epidermal homeostasis. These cells have limited proliferative potential, and are terminally differentiated. It’s a complex concept, but simply put: under normal conditions, they are not very active. They produce identical stem cells and/or give rise to amplifying cells that can rapidly divide, providing the skin with new epidermal basal cells, typically when there is some kind of injury and inflammation occurs. Once the new epidermal basal cells are produced, they detach from the basement membrane and differentiate into the different layers of the epidermis. The HPV needs to trick the basal stem cells and the amplifying cells to proliferate in order to hitch a ride on the new basal cells. HPV’s ability to replicate is dependent on non-dividing terminally differentiated cells. Specific proteins in the HPV activate DNA synthesis in the host cell and also prevent apoptosis (programed cellular death). This is one way in which the immune system fails to recognize the invading virus. Another way is by the type of cells they hijack to replicate within: keratinocytes. These cells are already programed for death and, again, no immune response occurs. Some high-risk HPVs are also thought to down-regulate interferon alpha-1 and beta-1 through a variety of mechanisms, such as gene expression, interfering with signal pathways, and /or completely abrogating those pathways. Essentially, HPV stealthily evades the innate immune response and slows the adaptive immune response.
One may ask, if HPVs are so good at hiding, why aren’t warts more common? The answer is because of a strong locally cell-mediated immune response (adaptive immune response). This cell-mediated immunity is associated with the generation of serum-neutralizing antibodies to HPV. In non-EV individuals, lesion/wart regression is linked to cell-mediated cytotoxicity. However, EV patients have a drastically impaired cell-mediated immunity to specific EV HPVs. In general, their humoral immunity seems intact and their antibodies appear to be within a normal range for various pathogens but they are unable to detect some HPVs and/or keratinocytes infected with those HPVs.
A simple analogy is that HPVs behave like thieves breaking into a home. At first they get in without tripping any alarms. Then they turn on the lights and move around but still no one is alerted. In fact, they even trick the home owner into opening up his or her safe without setting off any warning bells. It’s only when they have virtually gotten away that the 150-pound rottweiler sleeping in the bedroom notices something’s wrong and stops them. However, in cases of EV, the rottweiler could be standing next to the thief and never recognize them as a threat. In those instances, the thief gets away every time.
Acquired Epidermodysplasia Verruciformis
Acquired EVs have also been reported. They occur in cases of severe immunodeficiency, such as in individuals with HIV or lymphoma, similarly to Dede Koswara, except he also had a genetic predisposition for EV. A depressed immune system can increase the likelihood of EV symptoms. In one review, 25% of individuals who were symptomatic for EV did not have either EVER mutation. One may conclude additional mutations may be involved in EV. A potential second locus (2p21-24) may have been identified in one family with an X-linked inheritance pattern. Another aspect worth noting is that HPV-5 antibodies have been reported in non-EV individuals during the epidermal repair process. This phenomenon is seen in individuals with psoriasis, autoimmune bullous disease, and extensive burns.
Collectively, we have made some great strides in our understanding of HPVs. Vaccines for genital and mucosal HPVs are presently available and more are being researched. One day, there may be vaccines for individuals with EV.
- ABC News website. “Tree Man” medical mystery. August 15, 2008. http://abcnews.go.com/WNT/video?id=5566524.
- Darwich E, Darwich L, Cañadas MP, et al. New human papillomavirus (HPV) types involved in epidermodysplasia verruciformis (EV) in 3 HIV-infected patients: response to topical cidofovir. J Am Acad Dermatol. 2011;65:e43-e45.
- Dede Koswara: “The Tree Man Of Java.” The Noising Machine website. July 14, 2008. http://thenoisingmachine.wordpress.com/2008/07/14/dede-koswara-the-tree-man-of-java/.
- Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005:32S:S7-S15.
- Epidermodysplasia verruciformis. Dermnet NZ website. Modified December 29, 2013. http://dermnetnz.org/viral/epidermodysplasia-verruciformis.html.
- Epidermodysplasia verruciformis. Orphanet website. Updated February 2010. http://www.orpha.net/consor/cgi-bin//OC_Exp.php?lng=EN&Expert=302.
- Glionna JM. Indonesian ‘Tree Man’ trapped in his mutating body. Los Angeles Times website. July 16, 2010. http://articles.latimes.com/2010/jul/16/world/la-fg-indonesia-treeman-20100716.
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- ‘Tree man’ new pictures: Dede Koswara continues treatment in Indonesia. Telegraph website. http://www.telegraph.co.uk/news/picturegalleries/howaboutthat/6818324/Tree-man-new-pictures-Dede-Koswara-continues-treatment-in-Indonesia.html.