Please confirm that you would like to log out of Medscape.
If you log out, you will be required to enter your username and password the next time you visit.
Log outCancel
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017
| Contributor Information
Swipe to advance
Adapted images of a Buschke-Lowenstein tumor before (left) and after resection (right) courtesy of Oussaid M, Hassani KI. Pan Afr Med J. 2014;18:38. [Open access.] PMID: 25368727, PMCID: PMC4215367. The arrow indicates the anal opening, with a Foley probe in place.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Human papillomavirus (HPV) comprises a large family of double-stranded DNA (dsDNA) viruses that affect keratinocytes in the epithelial layer of the skin, mucous membranes, and genitals, forming proliferations commonly known as warts.[1] More than 200 strains of HPV have been identified to date,[2,3] causing conditions that range from nongenital cutaneous disease, such as verruca planus (flat warts), to less common, more severe conditions, such as epidermodysplasia verruciformis.[4] In addition, some HPV strains are associated with a higher risk of certain cutaneous and genital neoplasms.[3-7]
Image of vulvar carcinoma in an elderly woman with HPV-66 courtesy of Kotsopoulos IC, Tampakoudis GP, Evaggelinos DG, et al. J Med Case Rep. 2011;5:232. [Open access.] PMID: 21702970, PMCID: PMC3150314.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
In the United States, HPV is not only the most common sexually transmitted infection (STI)[5] but also the most common viral infection of the reproductive tract.[7] It is spread by direct skin-to-skin contact and, potentially, from fomites and/or direct contact with an object (eg, toy) shared during sexual activity with an infected person.[5,6] Infection also has a tendency to occur at sites of superficial trauma, often in a linear fashion, which is referred to as the Koebner phenomenon.[6] There is no definitive cure for HPV, and recurrent breakouts are not unusual.
Images courtesy of DermNet New Zealand (top left and right; bottom left) and Wikimedia Commons/Marionette (bottom right).
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Types of HPV
HPV infection has a varied presentation; in general, the lesions are separated into four categories: verruca vulgaris (common warts) (top left and right, bottom left), verruca plana (flat warts), verruca plantaris (plantar warts) (bottom right), and condyloma acuminatum (anogenital warts).[6,9]
The appearance of cutaneous HPV can range from common, plantar, flat, and filiform warts, to periungual, mosaic, and Butcher warts, among others.[4] Mucosal infection variants include recurrent respiratory papillomatosis, oral focal epithelial hyperplasia, and papillomas of the conjunctiva, larynx, and sinuses.[4]
Anogenital HPV disease includes condyloma acuminatum and Buschke-Lowenstein tumors (giant condyloma), as well as anogenital carcinoma.[4] Anogenital infection with certain high-risk strains of HPV is a predisposing factor to the development of intraepithelial neoplasia and squamous cell carcinoma (SCC). Oral florid papillomatosis,[9] Buschke-Lowenstein tumors,[10] and epithelioma cuniculatum are forms of verrucous carcinoma, a low-grade, well-differentiated SCC variant that has been associated with HPV infection, but whose pathogenesis remains poorly understood.[8,10]
Images of common warts courtesy of DermNet New Zealand (left) and Bissek AC, Tabah EN, Kouotou E, et al. BMC Dermatol. 2012;12:7. [Open access.] PMID: 22720728, PMCID: PMC3445843 (right).
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Cutaneous Disease
Verruca vulgaris (common warts)
HPV 2 is the most frequent genotype involved in common warts, but HPV 1 and 4 as well as other strains (eg, HPV 27 and 57) have also been identified.[6,11] The warts may appear anywhere on the skin—but typically occur on the dorsal hands or periungual areas. Less frequently, they can be found on the oral mucosa—as firm, hyperkeratotic, flesh-colored papules with a clefted surface (left). The lesions may occur singly or in multiples (right). The warts may expand in a linear pattern if the involved area has been excoriated or traumatized, causing autoinoculation.[6,11]
Very low magnification micrograph of a verruca vulgaris courtesy of Wikipedia Commons/Nephron.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
On histopathologic examination, verruca vulgaris demonstrates a papillomatous epidermis with hypergranulomatosis and overlying parakeratosis.[12] Biopsy or special staining, however, is often not needed, as most cases can be diagnosed solely on the basis of clinical evaluation.[6,11,13]
About 50% of cutaneous warts spontaneously resolve within 1 year and 65% of common warts regress or spontaneously disappear within 2 years,[11] more often in children than adults.[13] There are many treatment options available, including the use of cantharidin, cryotherapy, electrosurgery/curettage, and surgical excision[13]; however, the process make take weeks or months. Therapeutic selection is typically made on an individual patient basis with consideration of the patient’s age, the location of the wart, and previously tried therapies.[4,11,13]
First-line treatment generally involves agents that directly ablate the lesions,[4,6,11] such as combination topical salicylic acid and cryotherapy, which is effective due to its exfoliative effect on the infected epidermis as well as its stimulation of local immunity.[14] Refractory warts may respond to topical contact allergens (eg, dinitrochlorobenzene)[14]; immunomodulators (eg, imiquimod, interferon alpha, cimetidine, diphencyprone); chemotherapeutic agents (eg, topical 5-fluorouracil [5-FU], podophyllin, podophyllotoxin, intralesional bleomycin); virucidal agents (eg, formaldehyde, glutaraldehyde, cidofovir); and laser therapy.[4,11,13]
Images courtesy of DermNet New Zealand (left) and Wikimedia Commons/James Heilman, MD (right).
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Verruca plantaris (plantar warts)
Plantar warts are typically caused by HPV 1, 2, and 4, and they occur on the soles of the feet, especially in weight-bearing areas of the heels, toes, and mid-metatarsals (left).[6,11,15] The lesions often present as circular plaques with a hyperkeratotic surface (right). HPV 1 is associated with deep, painful lesions known as myrmecia, and HPV 2 is associated with more superficial, painless, hyperkeratotic plaques that may coalesce and are known as mosaic warts (left).[11,13]
Predisposing factors for the transmission of plantar warts include excessive sweating, showering in public facilities, and repetitive microtrauma to the feet, which allows for viral entry past the epithelial barrier.[15]
Management for plantar warts is similar to that for common warts.[6,11,13,15] However, because weight-bearing areas of the soles of the feet are most vulnerable to inoculation, treatment can be challenging due to the fact that repetitive trauma and recurrence in these areas is common and often difficult to avoid.
Image courtesy of Bissek AC, Tabah EN, Kouotou E, et al. BMC Dermatol. 2012;12:7. [Open access.] PMID: 22720728, PMCID: PMC3445843.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Verruca plana (flat warts)
Flat warts are skin-colored or lightly pigmented, slightly raised, circumscribed papules that tend to present on the face and dorsal hands but may also occur on the neck, legs, and torso (shown).[11,13] They often appear in groups and clusters, particularly as linear arrangements in regions of scratching or shaving (eg, beards, lower legs) but can also occur as a single papule; the lesions may be inconspicuous but can also cause cosmetically undesirable pigmentary changes.[11,13,16] HPV 3 and 10 are the most common causative strains, but HPV 27, 28, and 49 have also been detected.[11]
Treatment of flat warts consists of similar modalities as those for plantar and common warts; however, cosmetic outcome must be considered, particularly when the face is involved.[16-18] Salicylic acid and cryotherapy are acceptable as general therapeutic options—but avoid salicylic acid for facial lesions due to the possibility of excessive skin irritation.[6,16,17] Some clinicians prefer to use tretinoin, topical 5-FU, or imiquimod specifically for the treatment of facial warts.[14,18] The potential for pigmentation changes following these treatment modalities must be discussed with patients prior to initiating therapy, as no management option is completely devoid of this risk.[14]
Image courtesy of Wikimedia Commons/Schweintechnik.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Filiform warts
Filiform warts appear as small, hyperkeratotic, fingerlike projections (shown) that most commonly arise on the face and neck as isolated or multiple lesions.[6,11] These warts are morphologic variants of common warts and are also associated with HPV 1, 2, and 4.
Usual treatment modalities for filiform warts include cryotherapy and surgical removal with snip excision, followed by electrodesiccation or topical aluminum chloride for hemostasis.[14] These treatments are particularly useful for filiform warts given their size and shape, which make for easy removal.[14]
Butcher warts
Butcher warts are large, cauliflowerlike lesions that appear on the hands of individuals who handle raw meat, poultry, and fish.[19,20] They are primarily associated with HPV 2 and 7[11]; it is thought that these strains can be transmitted from animal tissue to humans, which may explain the prevalence of this type of wart among such a specific population.[18]
Treatment options for these warts is similar to that for other cutaneous warts, including salicylic acid, imiquimod, 50% trichloroacetic acid, cantharidin, cryotherapy, electrodesiccation, and/or surgical excision.[20]
Image courtesy of Science Photo Library.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Periungual warts
Periungual warts are most often caused by HPV 1, 2, and 4.[21] The lesions are common among nail biters and cuticle pickers, as they inflict trauma to the periungual region and thus allow for inoculation with HPV strains.[21]
Periungual warts may be difficult to treat due to the associated discomfort, especially if the lesions have advanced under the nail plate; in addition, available treatments may damage the nail matrix and cause permanent nail dystrophy. Cryotherapy, bleomycin treatment, and electrodesiccation all pose a serious risk for scarring and damage of the nail matrix. Therefore, topical therapy with keratolytic agents, 5-FU, retinoic acid solutions, and immunotherapy should be considered first-line approaches.[21-23]
Endoscopic view of laryngeal papilloma in a child with RRP courtesy of Omland T, Lie KA, Akre H, et al. PLoS One. 2014;9(6):e99114. [Open access.] PMID: 24918765, PMCID: PMC4053369.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Nongenital Mucosal Disease
Recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis (RRP) is a disease characterized by quickly growing benign papillomas in the upper respiratory tract, although dysplastic and malignant transformation may occur[6,24]; it is the most common laryngeal neoplasm of children.[20] The majority of cases of pediatric RRP are caused by HPV 6 and 11 (which are also involved with genital tract disease), typically via maternofetal transmission.[6,20] The disease frequently presents as airway obstruction and hoarseness but may also include choking episodes, coughing, dyspnea, stridor, and/or wheezing.[6,24] Maternal history of condylomas during pregnancy as well as HPV type 11-associated disease appear to correlate with more severe disease.[6,25]
The onset of RRP has a bimodal distribution, typically occurring in those younger than 5 years as juvenile-onset recurrent respiratory disease (JORRP), as well as among adults in their 40s (AORRP).[6,24] Risk factors for developing JORRP include vaginal delivery, low socioeconomic status, maternal age younger than 20 years, and being firstborn.[24] Children born to mothers with condyloma during pregnancy have a more than 230-fold risk of developing JORRP.[26] In adults, the mode of transmission is not fully understood; however, evidence suggests that affected adults are more likely to have had more oral sex and sexual partners than disease-free controls.[24,27]
Image courtesy of Omland T, Lie KA, Akre H, et al. PLoS One. 2014;9(6):e99114. [Open access.] PMID: 24918765, PMCID: PMC4053369.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The histologic image reveals laryngeal papilloma without atypia in a patient with AORRP (hematoxylin and eosin stain, ×20 magnification).
Laryngoscopy or bronchoscopy and biopsy are used to confirm the diagnosis of RRP.[24] Adequate biopsy sampling and specimens are essential for viral typing and for histologic evaluation to rule out malignant transformation.[24]
The mainstay of therapy for RRP involves reducing airway obstruction with surgical debulking, microdebridement, cryotherapy, and angiolytic or carbon dioxide laser therapy.[6,24] The goal of debulking the papillomas is to secure an adequate airway and improve the quality of the voice, if applicable.[24,27] Tracheotomy is typically reserved for the most aggressive cases in which there is impending airway compromise and multiple debulking procedures have been unsuccessful; decannulation should follow as early as possible to prevent further spread of the infection as well as to improve the patient's quality of life.[26,27]
Adjuvant treatments are aimed at reducing the recurrence of papillomas; they include intralesional cidofovir, oral indole-3-carbinol, interferon, photodynamic therapy, and antiviral therapy.[6,24,27] Note that most of these treatment modalities have conflicting evidence regarding their efficacy or require further investigation. Cidofovir administration has shown the most evidence for partial to complete regression of the papillomas.[24,26]
Images courtesy of Prabhat MP, Raja Lakshmi C, Sai Madhavi N, Bhavana SM, Sarat G, Ramamohan K. Case Rep Dent. 2013;2013:871306. [Open access.] PMID: 24455323, PMCID: PMC3884697.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The images depict multiple coalescent papillary projections involving the oral mucosa in a patient with Heck disease. Note the lesions affecting the patient's gingiva (top left), palate (top right), dorsal tongue (with fissuring) (bottom left), and commissure (bottom right). This patient also had extraoral involvement of the face, scalp, and trunk (not shown).
Oral focal epithelial hyperplasia (Heck disease)
Oral focal epithelial hyperplasia, also known as Heck disease, affects the oral mucosa of the lips, cheeks, and tongue, typically in Native American and Eskimo children and young adults.[11,28] These benign lesions appear pale to pink and usually occur as multiple small individual papules or plaques,[6,11] creating a cobblestoned appearance.[28] They typically heal spontaneously over several months[6,11]; thus, treatment is generally not necessary unless for cosmetic reasons or there is a decline or disruption in normal functioning of the oral cavity.
Poor hygiene, poverty, and communal lifestyles are among the risk factors for Heck disease, which may explain in part the populations affected by this condition. HPV 13 and 32 are associated with this disorder.[11,28]
Image of penile condyloma acuminata courtesy of DermNet New Zealand.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Genital Tract HPV
Over 40 types of HPV can be easily spread with direct sexual contact and affect the male and female genital tract,[3,4] with nearly 85% of sexually active US women and 91% of sexually active US men likely to become infected with at least one type of HPV during their lifetime.[29] Of those who become infected, more than 50% will be affected with a high-risk strain of HPV, which predisposes them to a greater likelihood of developing anogenital cancer.[30] Risk factors for genital tract HPV include early age at first intercourse and having multiple sexual partners over the lifetime.[4]
Most cases of anogenital HPV infections are subclinical; however, about 1% of infected individuals develop clinical lesions that may progress to anogenital SCC,[14] often associated with cofactors such as tobacco use, ultraviolet radiation, immune suppression, high parity, poor hygiene, and chronic inflammation.[3,4]
Image of condyloma acuminata in a female courtesy of SOA-AIDS Amsterdam via Wikimedia Commons.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Anogenital HPV
Anogenital HPV strains are classified as low risk or high risk for malignancy. An estimated 90% of anogenital warts are caused by low-risk strains HPV 6 and 11.[4,31] The majority of HPV-related cancers are caused by HPV 16 and 18[3,4]; other high-risk types include HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.[11] The lesions may be flat, papular, or pedunculated.[31]
Although strains of HPV associated with anogenital warts are highly infectious, most individuals are asymptomatic and unaware of their infection until they develop lesions 2-3 months after inoculation.[4,32] The disease course is variable, with 20%-30% of cases resolving spontaneously, whereas other lesions may continue to grow and spread.[4,32] Even when lesions spontaneously resolve, subclinical infection may persist for life, and the patient may be able to inoculate other sexual partners with the infection.[5] The diagnosis is typically made on a clinical basis and confirmed by biopsy.[31] Note that HPV testing is not recommended for the diagnosis of anogenital warts as the findings are not confirmatory and do not guide management.[31]
Goals of treatment for anogenital warts include symptomatic control, whereas elimination of dysplastic lesions is the goal for squamous intraepithelial lesions (SILs).[4] The risk of transmission is reduced by debulking genital warts, but it does not disappear. Topical treatment options include imiquimod, podofilox, sinecatechins, and interferon alpha, as well as cryotherapy, surgical removal, and trichloroacetic or bichloroacetic acid.[31] Strongly urge sexually active patients to use condoms and other barrier contraceptive methods to reduce transmission.[31]
Pap smear courtesy of Flickr/Ed Uthman.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
High-Risk HPV
High-risk HPV infection with strains 16 and 18 accounts for most cases of cervical, penile, vulvar, vaginal, anal, and oropharyngeal cancers and precancerous lesions.[3] Of these, cervical cancer is the most important,[31] as it is the fourth most common cancer in women—with the fourth highest mortality rate among cancers in women—worldwide.[33] Seventy percent of all cervical cancers are caused by HPV 16 and 18.[3,7]
Most cases of cervical carcinoma are preventable by routine screening and by treatment of precancerous lesions.[7] Therefore, it is important for women between the ages of 21 and 65 years to undergo screening with regular Papanicolaou (Pap) testing every 3-5 years to detect any abnormalities in the cervical epithelium and the presence of any precursor lesions to cervical cancer.[34] Combined with molecular tests that detect DNA of oncogenic HPV types, Pap smear results can guide the need for further evaluation, such as colposcopy and/or cervical biopsy. Biopsy findings can guide treatment and future rescreening schedules.[35,36]
The biologic consequences of HPV on the anus are analogous to those of the cervix, both of which involve squamous epithelium.[37] HPV 16 is detected in 95% cases of anal cancer and over 50% of oropharyngeal cancers.[3] Men who have sex with men as well as men and women with human immunodeficiency virus (HIV) infection are at particular risk for developing HPV-related premalignant lesions; these individuals can undergo screening for dysplasia with anal Pap smears or liquid cytology.[37]
The image shows a ThinPrep liquid-based Pap smear. Normal squamous cells are on the left side of the image, whereas HPV-infected cells with mild dysplasia (low-grade SILs [LSILs]) are on the right side.
Image courtesy of Katano A, Takenaka R, Okuma K, Yamashita H, Nakagawa K. J Med Case Rep. 2015;9:114. [Open access.] PMID: 25985999, PMCID: PMC4453232.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The histologic image reveals uterine cervical adenocarcinoma. Note the presence of small cells arranged in a dense papillary or tubular growth pattern. A portion of the tumor cells remains regular glands. (Hematoxylin and eosin stain, low power.)
HPV vaccination
Undergoing HPV vaccination prior to the onset of sexual activity can reduce the risk of specific types of HPV infection[3]; it can also produce a more robust immune response to the virus in the preteen years.[5] It is particularly important to educate patients and their families that vaccination should begin prior to initiation of sexual activity, because the vaccines are inactive against existing HPV infection. The vaccines significantly reduce the risk of transmission and, subsequently, the risk of developing anogenital cancers, especially cervical cancer.
Therefore, all children aged 11 or 12 years should receive the three-dose HPV vaccine, as well as teenagers who did not complete or did not previously receive the HPV vaccine regimen. HPV vaccine can be administered to young men through age 21 years; those who can be vaccinated through age 26 years include (1) young women, (2) any man who has sex with men, and (3) immunocompromised men who did not receive the HPV vaccine when they were younger.[5]
Three HPV vaccines are available in the United States: bivalent (HPV2) (Cervarix), quadrivalent (HPV4) (Gardasil), and nonavalent (HPV9) (Gardasil 9) vaccines.[38] They all protect against infection with high-risk HPV types 16 and 18; however, HPV4 additionally protects against low-risk HPV 6 and 11, and HPV9 provides further protection against not only HPV 6 and 11 but also high-risk HPV strains 31, 33, 45, 52, and 58.[38] A 2-dose regimen of HPV9 has also been approved for children aged 9 through 14 years.[38]
Image courtesy of the Centers for Disease Control and Prevention (CDC)/James Gathany.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
HPV vaccine underutilization
HPV vaccination is safe and effective.[5,39-45] Over a 9-year period (2004-2013) in the United States, the rate of genital warts decreased by 2% in low-income minority girls and 0.7% in their male counterparts[39]; even more dramatically, within 6 years of HPV vaccine introduction, there was a 64% decrease in HPV 6, 11, 16, and 18 infections in girls aged 14-19 years and a 34% decrease in women aged 20-24 years.[40]
Yet, despite its decade-long proven safety and efficacy, HPV vaccination remains controversial and underutilized.[39,41-44] The primary factor contributing to vaccine underuse is pediatricians and primary care physicians not recommending the vaccines, possibly due in part to a perceived lack of urgency, lack of knowledge about the vaccine and/or how to discuss the vaccine with parents/patients, and lack of knowledge about its efficacy against cervical and other cancers.[41-45] However, parental barriers also exist, including misunderstandings and fears, such as suspicion about the need for and/or efficacy of the vaccine, wariness over the association between HPV and sexual activity (and, thus, fear that the vaccine could promote promiscuity), lack of knowledge about the vaccine, concern over long-term health effects, and belief the vaccine is a "money grab" by pharmaceutical companies.[41,42] False, misleading, and/or unfounded Internet reports also play a role in against HPV vaccination.
Studies have not shown an increase in early initiation of sexual activity, sexual promiscuity, and/or risky sexual behaviors following the introduction of the HPV vaccine.[46-48]
Image courtesy of Skowronska-Piekarska U, Koscinski T. BMC Surg. 2015;15:41. [Open access.] PMID: 25885184, PMCID: PMC4399229.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Giant condyloma acuminatum of Buschke and Lowenstein
Giant condyloma acuminatum of Buschke and Lowenstein, often referred to as Buschke-Lowenstein tumor, is a slow growing but clinically aggressive verrucous carcinoma; it typically presents as a keratotic papule/plaque that progresses into a cauliflowerlike, exophytic, fungating mass in the anogenital region (most commonly on the glans penis in uncircumcised men), often associated with fistulae and abscesses.[11,20,49-51] Although this subtype of SCC may infiltrate the local adjacent tissue and has a high recurrence rate, it rarely metastasizes.[11,50]
The pathogenesis of verrucous carcinoma remains unclear. However, HPV 6 and 11 have been isolated from these tumors[11,20]; in addition, HPV 16, 18, 33[50] and, more recently, HPV 52 have also been detected.[52,53]
Micrograph of giant condyloma courtesy of Niazy F, Rostami K, Motabar AR. World J Plast Surg. 2015;4(2):159-62. [Open access.] PMID: 26284185, PMCID: PMC4537608.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
On histopathologic evaluation, it is often difficult to differentiate giant condyloma from condyloma acuminata due to a lack of malignant and dysplastic features.[51] Giant condyloma may be differentiated from typical condyloma acuminata by the presence of a thicker stratum corneum and an endophytic downgrowth, as well as a greater depth of invasion and displacement of surrounding tissues.[10] Foci of SCC correlate with a higher recurrence rate and a higher risk for metastasis. Accurate identification of characteristic histopathology requires sufficiently large and deep biopsies.[10]
Owing to the rarity of this and other verrucous carcinomas, the optimal treatment remains a matter of debate.[51] However, the mainstay of therapy has been wide surgical excision.[10,49-51] Other treatment modalities have had mixed success, including oral and topical chemotherapy, immunotherapy, and radiotherapy.[10]
Images courtesy of Dalirsani Z, Falaki F, Mohtasham N, Vazifeh Mostaan L. Iran J Otorhinolaryngol. 2015;27(79):159-63. [Open access.] PMID: 25938088, PMCID: PMC4409961.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The images were obtained in a middle-aged patient with oral florid papillomatosis. The intraoral view on the left shows an exophytic lesion with a granular surface and purple discoloration in the anterior portion. The panoramic radiograph on the right demonstrates a well-defined radiolucency with sclerotic borders between the left first molar and the right first premolar.
Oral florid papillomatosis (Ackerman tumor)
Oral florid papillomatosis, also known as Ackerman tumor, is another rare subset of verrucous carcinoma. It presents as multiple squamous papillary nodules in the oral cavity but can also involve the esophagus, larynx, pharynx, sinus mucosa, bronchus, and genital tract.[9] As with other forms of verrucous carcinoma, it is characterized as a low-grade SCC with the potential for local invasion and destruction but rarely metastasizes.[54] A wide range of mucosal HPV strains have been isolated from the lesions, including low-risk HPV 6 and 11, as well as HPV types 13, 30, 32, 45, 52, 55, 59, 69, 72, and 73.[9,55] Use of snuff and chewing tobacco as well as cigarette smoking have also been associated with oral florid papillomatosis.[9,55]
The lesions appear as whitish, nonulcerated papillomas on the oral mucosa, often on a background of chronic irritation or leukoplakia; local invasion as well as bone infiltration may occur.[54] Histologically, oral verrucous carcinoma consists of papillomatous, acanthotic, and partially keratinized epithelium with elongated rete ridges[55]; the lesions generally lack high-grade dysplastic features, which may lead to their misdiagnosis as benign disease such as verruca vulgaris rather than SCC.[9] As with giant condyloma acuminatum of Buschke and Lowenstein, the mainstay of treatment has been wide surgical excision, with or without radiotherapy.[9,54,55]
Image courtesy of Mohamed M, Belhadjali H. Pan Afr Med J. 2014;18:306. [Open access.] PMID: 25469199, PMCID: PMC4247901.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
Epithelioma cuniculatum
Epithelioma cuniculatum (or carcinoma cuniculatum, plantar epithelioma cuniculatum) is another rare, slow-growing form of verrucous carcinoma and an SCC variant that has a tendency toward local recurrence but rarely metastasizes.[56,57] The lesion mainly affects men in their 50s and 60s, occurs primarily on the ball of the foot (shown), and is characterized by a fungating, exophytic mass with numerous keratin-filled abscesses and sinuses, which may cause pain on ambulation.[56-58] Lesions may also be found near the toes and heels,[56,57] or palms.[57]
The tumor often begins as a nonhealing plantar wart on the sole of the foot that continues to grow, with local invasion and potential involvement of the fascia and metatarsal bones; it does not respond to treatment regimens that are effective for regular plantar warts.[57,58]
HPV types 1-4, 6, 11, and 18[57] as well as trauma and chronic irritation have been implicated as possible etiologies,[56-58] but the exact pathogenesis remains poorly understood. Wide surgical excision is the treatment of choice.[57,58]
Images courtesy of Yoshida R, Kato T, Kawase M, Honda M, Mitsuishi T. BMC Dermatol. 2014;14:12. [Open access.] PMID: 25048734, PMCID: PMC4110534.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The images were obtained in two sisters with epidermodysplasia verruciformis. The top images in the elder sister show asymptomatic, slightly erythematous, and hypopigmented pityriasis versicolorlike lesions on the neck (A) and numerous round pigmented macules with slight scale on the left upper arm (B). The histologic image (C) shows epidermal hyperplasia and distinct homogeneous intracytoplasmic inclusion bodies in the large clear cells of the epidermis (arrows) (scale bar = 100 µm). Image D reveals multiple brown, flat wartlike lesions on the face of the younger sister.
Epidermodysplasia verruciformis
Epidermodysplasia verruciformis is a rare autosomal recessive disorder linked to mutations in the EVER1 and EVER2 genes.[6,11,20,59] This condition typically begins in early childhood with the appearance of flat to papillomatous, wartlike lesions and reddish-brown pigmented plaques that are often mistaken for tinea versicolor. Epidermodysplasia verruciformis predisposes affected individuals to widespread HPV infection and cutaneous SCCs in adulthood. The HPV infections lead to the growth of multiple verrucous papules that can occur anywhere on the body, most notably on sun-exposed areas such as the hands, feet, ears, and face.[6,11,20,59]
Over 30 HPV strains specific for epidermodysplasia verruciformis (ß-papillomaviruses) have been implicated (eg, HPVs 4, 5, 8, 9, 12, 14, 15, 17, 19-25, 36-38, 47), most of which do not affect those with normal immune function.[11,20,59] Malignant transformation to SCC occurs in 35%-50% of patients and is predominantly (90%) associated with HPV 5 and 8.[20,59] In situ and invasive SCCs can occur, generally in middle age (40s-50s).[59]
Image courtesy of Wikimedia Commons/Monirul Alam.
HPV Diseases: From Cutaneous to Anogenital to Epidermodysplasia Verruciformis
Michael J Payette, MD, MBA; Kristen Russomanno, BA, MS-IV | April 21, 2017 | Contributor Information
The image shows a Bangladeshi man who underwent surgery for one of the world's most severe cases of epidermodysplasia verruciformis.
No cure currently exists for epidermodysplasia verruciformis; medical therapy is aimed at cancer prevention.[20] Counsel patients regarding strict sun protection and the importance of undergoing regular dermatologic surveillance. They should receive appropriate therapy for any skin cancers or precursor lesions that may arise. For localized malignancies, surgical intervention is the mainstay.[20]
Nonsurgical treatments include retinoid agents, imiquimod and other immune modulators, interferons, electrodesiccation, and cryotherapy[20,60]; however none of these have been shown to be consistently effective.[60]
Prompt recognition of herpes simplex infection and early initiation of therapy are of utmost importance in the management of the disease. Test your knowledge of HSV and other herpesviruses with our slideshow.Slideshows, July 2016
Commenting is limited to medical professionals. To comment please Log-in.
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Close
Contributor Information
Authors
Michael J Payette, MD, MBA
Assistant Professor
Associate Residency Program Director
Department of Dermatology
University of Connecticut Health Center
Farmington, Connecticut
Disclosure: Michael J. Payette, MD, MBA is a consultant for AbbVie, Amgen, and Lilly.
Kristen Russomanno, BA, MS-IV
MD Candidate, Class of 2017
University of Connecticut School of Medicine
Farmington, Connecticut
Disclosure: Kristen Russomanno, BA, MS-IV, has disclosed no relevant financial relationships.
Editor
Olivia Wong, DO
Section Editor
Medscape Drugs & Diseases
New York, New York
Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.
Close
References
Stanley M. Pathology and epidemiology of HPV infection in females. Gynecol Oncol. 2010 May; 117(2 suppl):S5-10. PMID: 20304221
Karolinska Institute. International Human Papillomavirus Reference Center. Modified: May 24, 2016. Available at: http://www.hpvcenter.se/html/refclones.html. Accessed April 14, 2017.
Gearhart PA, Randall TC, Buckley RM Jr, Higgins RV. Human papillomavirus. Medscape Drugs & Diseases from WebMD. Updated: January 5, 2017.Available at: http://emedicine.medscape.com/article/219110-overview. Accessed April 14, 2017.
Centers for Disease Control and Prevention. Human papillomavirus (HPV). For parents and public: What is HPV? Questions and answers. Updated: November 28, 2016. Available at: http://www.cdc.gov/hpv/parents/questions-answers.html. Accessed April 14, 2017.
Paller AS, Mancini AJ. Viral diseases of the skin. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 5th ed. Canada: Elsevier; 2016: chapter 15.
World Health Organization. Human papillomavirus (HPV) and cervical cancer. Fact sheet no. 380. Updated: June 2016. Available at: http://www.who.int/mediacentre/factsheets/fs380/en/. Accessed April 14, 2017.
Goldenberg G. Spotting verrucous carcinoma. Medscape Dermatology Clinic. December 29, 2011. Available at: http://www.medscape.com/viewarticle/756117. Accessed April 14, 2017.
Kauffman CL, Alexandrescu DT. Giant condylomata acuminata of Buschke and Lowenstein. Medscape Drugs & Diseases from WebMD. Updated: July 21, 2016. Available at: http://emedicine.medscape.com/article/1132178-overview. Accessed April 14, 2017.
Mittal A, Mehta S. Human papillomavirus and hepatitis A, B, and C infections. In: Singal A, Grover C, eds. Comprehensive Approach to Infections in Dermatology. New Delhi, India: Jaypee Brothers Medical Publishers Ltd; 2015: chapter 9.
Rodriguez-Cerdeira C, Sanchez-Blanco E. Glycolic acid 15% plus salicylic acid 2%: a new therapeutic pearl for facial flat warts. J Clin Aesthet Dermatol. 2011 Sep;4(9):62-4. PMID: 21938272
Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists' guidelines for the management of cutaneous warts 2014. Br J Dermatol. 2014 Oct;171(4):696-712. PMID: 25273231
Al-Obaidi HK. Topical 5-fluorouracil versus topical tretinoin 0.05% in treatment of plane wart; a randomized controlled comparative therapeutic trial. GJBB. 2013;2(3):368-72. Available at: http://www.scienceandnature.org/GJBB_Vol2(3)2013/GJBB-V2(3)2013-15.pdf. Accessed April 14, 2017.
Jablonska S, Obalek S, Favre M, Golebiowska A, Croissant O, Orth G. The morphology of butchers' warts as related to papillomavirus types. Arch Dermatol Res. 1987;279 suppl: S66-72. PMID: 2821930
Hall JC, Hall BJ, eds. Skin Infections: Diagnosis and Treatment. New York, NY: Cambridge University Press; 2009: chapters 2, 16.
Urbina Gonzalez F, Cristobal Gil MC, Aguilar Martinez A, Guerra Rodriguez P, Sanchez de Paz F, Garcia-Perez A. Cutaneous toxicity of intralesional bleomycin administration in the treatment of periungual warts. Arch Dermatol. 1986 Sep;122(9):974-5. PMID: 2427037
Gregg LJ. Intralesional bleomycin and Raynaud's phenomenon. J Am Acad Dermatol. 1992 Feb;26(2 pt 1):279-80. PMID: 1372624
Mayeaux EJ, Khan MJ. Nongenital human papillomavirus disease. Obstet Gynecol Clin North Am. 2013 Jun:40(2):317-37. PMID: 23732034
Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. Otolaryngol Clin North Am. 2012 Jun: 45(3):671-694, vii-ix. PMID: 22588043.
Goon P, Sonnex C, Jani P, Stanley M, Sudhoff H. Recurrent respiratory papillomatosis: an overview of current thinking and treatment. Eur Arch Otorhinolaryngol. 2008 Feb;265(2):147-51. PMID: 18046565
Chesson HW, Dunne EF, Hariri S, Markowitz LE. The estimated lifetime probability of acquiring human papillomavirus in the United States. Sex Transm Dis. 2014 Nov;41(11):660-4. PMID: 25299412
Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health And Nutrition Examination Survey, 2003-2006. J Infect Dis. 2011 Aug 15;204(4):566-73. PMID: 21791659
Centers for Disease Control and Prevention. Anogenital warts. 2015 Sexually transmitted diseases treatment guidelines. Updated: June 4, 2015. Available at: http://www.cdc.gov/std/tg2015/warts.htm. Accessed April 14, 2017.
Hariri S, Dunne E, Saraiya M, Unger E, Markowitz L. Chapter 5: Human papillomavirus. Manual for the Surveillance of Vaccine-Preventable Diseases. Updated: April 1, 2014. Available at: http://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.html. Accessed April 14, 2017.
International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed April 14, 2017.
US Food and Drug Administration. Vaccines, blood & biologics: approved products. Human papillomavirus vaccine. Updated: September 12, 2016 (Gardasil); October 20, 2016 (Gardasil 9); March 13, 2017 (Cevarix). Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm172678.htm. Accessed April 14, 2017.
Perkins RB, Legler A, Hanchate A. Trends in male and female genital warts among adolescents in a safety-net health care system 2004-2013: correlation with introduction of female and male human papillomavirus vaccination. Sex Transm Dis. 2015 Dec;42(12):665-8. PMID: 26562694
Markowitz LE, Liu G, Hariri S, Steinau M, Dunne EF, Unger ER. Prevalence of HPV after introduction of the vaccination program in the United States. Pediatrics. 2016 Mar;137(3):e20151968. PMID: 26908697
Suryadevara M, Handel A, Bonville CA, Cibula DA, Domachowske JB. Pediatric provider vaccine hesitancy: An under-recognized obstacle to immunizing children. Vaccine. 2015 Nov 27;33(48):6629-34. PMID: 26529071
Berkowitz Z, Malone M, Rodriguez J, Saraiya M. Providers' beliefs about the effectiveness of the HPV vaccine in preventing cancer and their recommended age groups for vaccination: Findings from a provider survey, 2012. Prev Med. 2015 Dec;81:405-11. PMID: 26598805
Rubin R. Why the "no-brainer" HPV vaccine is being ignored. JAMA. 2015 Apr 21;313(15):1502-4. PMID: 25898032
Bednarczyk RA, Davis R, Ault K, Orenstein W, Omer SB. Sexual activity-related outcomes after human papillomavirus vaccination of 11- to 12-year-olds. Pediatrics. 2012 Nov;130(5):798-805. PMID: 23071201
Jena AB, Goldman DP, Seabury SA. Incidence of sexually transmitted infections after human papillomavirus vaccination among adolescent females. JAMA Intern Med. 2015 Apr;175(4):617-23. PMID: 25664968
Mullins TL, Widdice LE, Rosenthal SL, Zimet GD, Kahn JA. Risk perceptions, sexual attitudes, and sexual behavior after HPV vaccination in 11-12 year-old girls. Vaccine. 2015 Jul 31;33(32):3907-12. PMID: 26116249
Fanget F, Pasquer A, Djeudji F, Chabanon J, Barth X. Should the surgical management of Buschke-Lowenstein tumors be aggressive? About 10 cases. Dig Surg. 2016 Dec 10. PMID: 27941342
Spinu D, Radulescu A, Bratu O, Checherita IA, Ranetti AE, Mischianu D. Giant condyloma acuminatum - Buschke-Lowenstein disease - a literature review. Chirurgia (Bucur). 2014 Jul-Aug;109(4):445-50. PMID: 25149605
Pinto AR, Guedes-Martins L, Marques C, Cabral JM. Buschke-Lowenstein tumor. Acta Med Port. 2012 Sep-Oct;25(5):345-7. PMID: 23211208
Ishibuchi T, Shimizu A, Kato M, et al. Detection of human papillomavirus type 56 in giant condyloma acuminatum. Acta Derm Venereol. 2014 Jul;94(4):482-3. PMID: 24287806
Diani M, Boneschi V, Ramoni S, Gadda F, Del Gobbo A, Cusini M. Rapidly invasive Buschke-Löwenstein tumor associated with human papillomavirus types 6 and 52. Sex Transm Dis. 2015 Oct;42(10):547-8. PMID: 26366507
Kallarakkal TG, Ramanathan A, Zain RB. Verrucous papillary lesions: dilemmas in diagnosis and terminology. Int J Dent. 2013;2013:298249. PMID: 24223590
Rinker MH, Fenske NA, Scalf LA, Glass LF. Histologic variants of squamous cell carcinoma of the skin. Cancer Control. 2001 Jul-Aug;8(4):354-63. PMID: 11483889
Schein O, Orenstein A, Bar-Meir E. Plantar verrucous carcinoma (epithelloma cuniculatum): rare form of the common wart. Isr Med Assoc J. 2006 Dec;8(12):885. PMID: 17214114
Ray R, Bhagat A, Vasudevan B, Sridhar J, Madan R, Ray M. A rare case of plantar epithelioma cuniculatum arising from a wart. Indian J Dermatol. 2015 Sep-Oct;60(5):485-7. PMID: 26538697
Please do not use this form to submit personal or patient medical information or to report adverse drug events. You are encouraged to report adverse drug event information to the FDA.
Comments