OVERVIEW: What every practitioner needs to know

Are you sure your patient has condyloma accuminata ? What should you expect to find?

Most lesions are asymptomatic.
Some patients may experience pruritus or burning.
Psychological distress and anxiety is common.
Lesions typically occur on the external genital skin, including the vulva, penis, scrotum, and perianal area; however, they may also spread to involve the inguinal folds, upper/inner thighs, and suprapubic skin (Figure 1 and Figure 2).
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Condylomata may extend into mucosal sites, such as the vagina, cervix, urethra, or anus/rectum (Figure 3 and Figure 4).
They may also occur on non-genital sites, including the oral mucosa.
Condylomata are typically one to several millimeters in diameter, but they may grow to form large confluent clusters, plaques, or nodules that can be centimeters in diameter.
Individual lesions may be flat, papular, pedunculated, or exophytic with a surface that varies from smooth to verrucous.
Lesions vary in color from flesh colored to hyperpigmented.
Traumatized lesions may become macerated, superinfected, or ulcerated.

Penile condylomata: Verrucous hyperpigmented papules on the penile shaft

Extensive peri-anal condylomata. There would be definite concern for rectal involvement in this patient. The lesions are also macerated, possibly secondary to prior treatment.

How did the patient develop condyloma accuminata? What was the primary source from which the infection spread?

Genital condylomata are caused by infection with human papillomavirus (HPV) and are acquired through intimate/sexual contact with individuals who have clinical or subclinical HPV infection. Microtrauma during intercourse/sexual contact may play a role in acquisition of the infection.

Which individuals are at greater risk of developing condylomata accuminata?

HIV infected and organ transplant patients may have condylomata that are more persistent and progressive.
CD4 T-cell depletion and high HIV viral loads are important risk factors for significant disease.
Anal condylomata, anal infection with HPV virus, and progressive anal disease to malignancy are most common in HIV-positive men who have sex with men (MSM).

Beware: there are other diseases that can mimic condyloma accuminata

The differential diagnosis of condyloma accuminata includes:

Giant condyloma of Buschke-Lowenstein: This is a large verrucous genital tumor caused by HPV infection with potential for expansile and destructive growth, as well as malignant degeneration to squamous cell carcinoma.
Bowen’s Disease (intraepithelial neoplasia): This usually occurs as a solitary erythematous or red-brown patch or plaque, which sometimes has superficial scale; histologically, there is full thickness keratinocytic atypia without invasion into the underlying dermis; on the genital skin, these are usually related to HPV infection (Figure 5).
Squamous cell carcinoma: Chronic infection with HPV on the genital skin, particularly in combination with HIV infection and a low CD4 nadir, can lead to development of squamous cell carcinoma at the site of mucocutaneous HPV infection (i.e., anus, vulva, penis). Malignant degeneration can occur within long standing cutaneous lesions of genital HPV; uncircumcised men with HIV and HPV infection are at particularly high risk of invasive penile cancer, and regular physical examinations should be conducted. HIV infected MSM are at significantly higher risk of anal cancer than the general population (Figure 6).
Bowenoid papulosis: These are red-brown to tan papules that occur on the external genitals and may be difficult to distinguish from condyloma clinically. Histologically, they show full thickness keratinocytic atypia of the epidermis. The typical clinical course is for them to occur in crops and have spontaneous regression within months; however, they can be persistent and require treatment.
Molluscum contagiosum: These are caused by a poxvirus and clinically present as 1-3 mm shiny dome shaped papules with a central umbilication. They have the same typical distribution as genital warts, although they do not involve mucosal sites (Figure 7).
Angiokeratomas: These are benign lesions that most commonly present as hyperkeratotic violaceous to purple papules on the scrotum of men or the external genitalia of women; they are usually dispersed symmetrically across the involved area.
Pearly penile papules: These are typically 1-2 mm flesh colored dome shaped papules that occur most commonly around the corona of the penis. The female counterpart is known as vestibular papillomatosis and usually occurs at the introitus or labia minora. Histologically, these are angiofibromas.

Bowen’s disease presents as a solitary erythematous or red-brown patch or plaque.

Penile squamous cell carcinoma in a patient with a history of condyloma

Molluscum presents as well circumscribed dome shaped papules with a central umbilication.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Skin biopsy

Condyloma can show a variety of patterns on histology, and the biopsy is often not diagnostic.
Lesions usually show epidermal acanthosis, papillomatosis, and focal parakeratosis.
When present, koilocytosis (viral change within keratinocytes) can help confirm the diagnosis.
Histology of condyloma without koilocytic change can mimic a seborrheic keratosis, which can also occur in the genital skin.

Results that confirm the diagnosis

Immunohistochemistry

HPV immunohistochemical stains can be performed on lesional skin biopsies. In a lesion that shows histology consistent with condyloma, positive HPV immunohistochemical lesional nuclear staining helps to confirm the diagnosis.

Polymerase chain reaction (PCR)

PCR can be performed on lesional skin, and a positive PCR to HPV types known to cause condylomata help to confirm the diagnosis.

What imaging studies will be helpful in making or excluding the diagnosis of condylomata?

Imaging is not useful for the diagnosis of condylomata; however, MRI studies have been used to evaluate the extent of expansile growth in Buscke-Lowenstein tumors.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has condyloma accuminata, what therapies should you initiate immediately?

Dermatology can help assist in making the diagnosis of condylomata, as well as treating the lesions. If the diagnosis is in doubt clinically or malignant degeneration is suspected, a biopsy can be performed.

Treatment can consist of a single therapy or a combination of therapies, which include topical medications, destructive methods, and surgery. Combination therapy usually yields the best results, especially in extensive or refractory cases. The treatments discussed only refer to treatment of external condylomata.

1. Anti-infective agents (Table I)

Table I.

Type of treatment	Treatment	Dose/procedure	Evidence level/Comments
Topical	Imiquimod 5% cream	Patient applied: apply to lesions three times per week for up to 16 weeks.	Evidence level ACan be combined with destructive methods, such as cryotherapy; however, the patients should not apply the imiquimod until the skin is healed from the procedure.
Topical	Podofilox 0.5% gel or solution	Patient applied: apply twice daily for 3 days in a row, then stop for 4 days; this 7 day cycle can be repeated up to four times.	Evidence level AThis is patient applied, as opposed to podophyllin, which is more potent and physician applied only.
Topical	Sinecatechin green tea extract 15% ointment	Patient applied: Apply to lesions three times daily for 16 weeks.	Evidence level A
Topical	Podophyllin 10-25%	Physician applied: apply to condylomata and allow to dry, then the patient will wash off in 4 hours.	Evidence level BTreatment area should be limited to < 0.5mL of podophyllin per session.
Destructive	Cryotherapy	Physician applied: liquid nitrogen is sprayed or applied to lesions once every 1-2 weeks.	Evidence level BLesions will potentially blister, crust, or ulcerate after treatment; patients should be told to apply vaseline for wound healing.
Destructive	Trichloroacetic acid (TCA) 80%	Physician applied: a small amount is applied to lesions, let air dry until white frost develops; this can be applied weekly.	Evidence level BIf TCA is applied to non-lesional skin, it should be neutralized using talc or sodium bicarbonate.
Destructive	Surgery	Curettage, shave removal, or excision	Evidence level BMay be combined with imiquimod after the site heals.

2. Next list other key therapeutic modalities.

Laser treatment, including pulsed dye and CO₂, has been described as an effective treatment of condylomata (Evidence level B).
Intralesional interferon alpha (twice weekly for up to 8 weeks) has also demonstrated efficacy (Evidence level A).

What complications could arise as a consequence of condyloma accuminata?

What should you tell the patient about prognosis?

HIV infected patients often have larger and more numerous warts that are more refractory to treatment. They also have a higher co-infection with oncogenic HPV types, which may lead to the development of anal, vulvar, or penile carcinoma. In addition, large untreated warts can become macerated, superinfected with bacteria, painful, and obstructive.

Patients with HIV and a history of a low CD4 count have a more refractory course of condylomata. They may be more persistent and refractory to treatment, which leads to continual spread onto the surrounding skin or mucosal surfaces. HIV patients with clinical signs of HPV infection are also at risk for malignant change, and they should be closely monitored. Immunocompetent patients are generally more responsive to standard treatment options.

How do you contract condyloma accuminata and how frequent is this disease?

Genital condylomata are caused by infection with human papillomavirus (HPV) and are acquired through intimate/sexual contact with individuals who have clinical or subclinical HPV infection.
Basal keratinocytes are the targets of HPV infection, and the virus usually gains entry through sites of minor trauma or maceration of the epidermis.
It is estimated that 1-2% of all sexually active adults in the United States have condylomata, and the incidence has been rising steadily over the past 50 years.

What pathogens are responsible for this disease?

Human papillomavirus types 6 and 11 are responsible for the development of the majority of condylomata. Immunocompromised patients, particularly those with HIV infection, may have numerous other HPV types associated with these lesions, including the oncogenic types, such as HPV 16.

How do these pathogens cause condyloma accuminata?

Genital condylomata are caused by infection with human papillomavirus (HPV) and are acquired through intimate/sexual contact with individuals who have clinical or subclinical HPV infection.
Basal keratinocytes are the targets of HPV infection, and the virus usually gains entry through sites of minor trauma or maceration of the epidermis.
Productive infection and hyperproliferation of virus occurs when the virus enters proliferating basal keratinocytes.
Persistent papillomavirus is common, indicating that the virus can evade immune detection.
Natural immunity to HPV requires strong cell mediated immunity, which is deficient in HIV infected patients. This allows increased reactivation of latent virus and hastening the course of established cutaneous HPV infections.

How can condyloma accuminata be prevented?

Condoms and other barrier methods during sexual activity can help to prevent the acquisition of HPV viral infections and, thus, condylomata.
Effective prophylactic vaccines are now available, including a quadrivalent vaccine that protects against HPV types 6, 11, 16, and 18. Initially, it has been recommended for girls/women 9-26 years of age and has been expanded to include boys and young men of the same age range. It is given in three separate intramuscular injection doses over a 6-month period.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Ahmed, AM, Madkan, V, Tyring, SK.. “Human papillomaviruses and genital disease”. Dermatol Clinics. vol. 24. 2006. pp. 157-65. (This is a good overview of HPV and condylomata, and it also provides estimates of incidence of disease in the United States.)

Arima, Y, Winer, RL, Feng, Q. “Development of genital warts after incident detection of human papillomavirus infection in young men”. J Infect Dis. vol. 202. 2010 Oct 15. pp. 1181-4. (This study investigated the rate at which men develop genital warts after infection with alpha genus human papillomavirus (HPV) types. They conducted a cohort study of 18-21-year-old men who underwent tri-annual genital examinations. The 24-month cumulative genital wart incidence was 57.9% among men with incident detection of HPV-6 or HPV-11 infection, 2.0% among men with incident detection of infection with other HPV types, and 0.7% among men who tested negative for HPV.)

Berman, B, Amini, S, Huo, R., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Anogenital warts”. Treatment of skin disease comprehensive therapuetic strategies. 2010. pp. 44-6. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A: Double-blind studies, B: Clinical trial with greater than or equal 20 subjects, C: Clinical trial with less than 20 subjects, D: Case series of more than 4 subjects, and E: Anecdotal case reports.)

Dinh, TH, Sternberg, M, Dunne, EF, Markowitz, LE.. “Genital warts among 18- to 59-year-olds in the United States, national health and nutrition examination survey, 1999-2004”. Sex Transm Dis. vol. 35. 2008 Apr. pp. 357-60. (Overall, 5.6% of 18-to 59-year olds reported having ever been diagnosed with genital warts. The percentage was higher in women than in men. History of genital wart diagnosis peaked among 25- to 34-year-old women and 35- to 44-year-old men. Sex, age, race/ethnicity, number of lifetime sex partners, and cocaine/street drug use were associated with genital warts in multivariate analysis.)

Gormley, R, Kovarik, C.. “Dermatologic manifestations of HPV in HIV-infected individuals”. Curr HIV/AIDS Rep. vol. 6. 2009 Aug. pp. 130-8. (This article reviews the evidence behind skin manifestations of HPV infection in HIV-positive patients and includes recommendations for diagnosis and treatment.)

Giuliano, AR, Lee, JH, Fulp, W. “Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study”. Lancet. vol. 377. 2011 Mar 12. pp. 932-40. (In 1159 men, the incidence of a new genital HPV infection was 38.4 per 1000 person months. Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners and number of male anal-sexual partners)

Kirnbauer, R, Lenz, P, Okun, MM., Bolognia, JL, Jorizzo, JL, Rapini, RP. “Human papillomavirus”. Dermatology. 2008. pp. 1183-98. (This is an outstanding review of human papillomavirus, including its relationship to patients immunocompromised by HIV infection, diagnosis, and treatment strategies.)

Palefsky, JM, Holly, EA, Ralston, ML, Jay, N.. “Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men”. J Infect Dis. vol. 177. 1998 Feb. pp. 361-7. (In HIV infected men who have sex with men (MSM), anal swabs were positive for HPV DNA in 93%, compared to 60% of HIV negative MSM.)

King, EM, Oomeer, S, Gilson, R, Copas, A. “Oral Human Papillomavirus Infection in Men Who Have Sex with Men: A Systematic Review and Meta-Analysis”. PLoS One. vol. 11. 2016 Jul 6. pp. e0157976(This study clarifies many aspects of the epidemiology of HPV infection in HIV positive, as well as HIV negative homosexual men.)

Walling, EB, Benzoni, N, Dornfeld, J, Bhandari, R. “Interventions to Improve HPV Vaccine Uptake: A Systematic Review”. Pediatrics. vol. 138. 2016 Jul. pp. e20153863(Vaccines against HPV are under-utilized, particularly in boys. This review identifies effective measures to increase vaccine uptake.)

DRG CODES and expected length of stay

078.11: Condyloma acuminatum

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Condyloma accuminata and other genital lesions due to human papilloma virus