IMAGES IN DERMATOPATHOLOGY

Am J Clin Dermatol 2005; 6 (4): 239-243 1175-0561/05/0004-0239/$34.95/0 2005 Adis Data Information BV. All rights reserved.

Genital Warts
Current and Future Management Options
Colm OMahony
Department of Sexual Health, Countess of Chester Hospital NHS Foundation Trust, Chester, England

Abstract

Genital warts are a cosmetic nuisance. They are caused by low-risk human papillomavirus types, have no oncogenic potential and are not linked to cervical cancer. However, they often cause significant psychological morbidity. Treatments are aimed at eradicating the unsightly lesions and stimulating the immune system to generate clearance and prevent recurrence. Commonly used physical treatment methods include cryotherapy, trichloroacetic acid, laser, and electrocautery. However, many patients respond extremely well to home therapies with either podophyllotoxin or imiquimod. Patients prefer the comfort and dignity of home treatment, and this should be the first-line of treatment for the majority of patients. A routine screen for sexually transmitted infections is appropriate in most cases. Detailed explanation and reassurance are of paramount importance in reducing the psychological distress associated with this unpleasant genital condition.

Genital warts are a cosmetic nuisance. They are not linked to genital cancer. You are no more likely to develop cervical cancer than someone who has never had warts. Time and time again we use these words to try and reassure upset patients that the lumps below are just an unpleasant nuisance and have no long-term significance. But Ive just read in magazine that the wart virus causes cancer, is often the reply. With such patients, it is important to explain that there are certain types of wart virus that have a cancer causing potential but that these viruses do not cause clinically obvious genital warts. However, many individuals are exposed to and infected with these oncogenic types and in some cases persistence of the virus, coupled with other factors, leads to pre-malignant change and eventually to cancer. That is why there are national cervical cancer screening programs (Pap smear) and, if managed properly, such programs are very effective. Thus, the management of patients presenting with genital warts requires a great deal of discussion and reassurance, which must be skillfully carried out if the patient is not to be left feeling guilty, ashamed and anxious.[1] Many individuals perception of themselves as sexually attractive and desirable has been irrevocably damaged by poor management of what is (medically speaking) a harmless cosmetic nuisance.

1. Risk Factors for Genital Cancer There are >80 different types of wart virus and only a few have been linked to genital cancer. Types 16, 18, and 33 are the most frequently found in cancer tissue. Integration and persistence of viral genome in host cell genome precedes cancer development. Despite intensive research, the factors that facilitate carcinogenesis are still undetermined, but cigarette smoking has been shown to produce a 2-fold risk.[2] 2. Epidemiology Most people come into contact with genital wart virus sooner or later. Many studies show human papillomavirus DNA in genital samples of patients who have never had clinically obvious genital warts.[3] Less than 1% of people infected with wart virus actually develop clinically obvious warts. Transmission can occur, therefore, from someone who does not appear to have warts. This explains the often-encountered difficult scenario where, in an apparently stable monogamous relationship, one partner presents with genital warts. The incubation period is also uncertain, and although generally considered to range from weeks to 23 months, can be much longer. In some cases, loss of immune suppression allows the virus to emerge years later as clinically obvious warts (e.g. HIV infection or post-transplant).

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3. Diagnosis The diagnosis of genital warts is by clinical examination. There can be some uncertainty in the early stages of infection when the warts are small, and some patients often mistake the pearly penile papules on the corona glandis (figure 1), or Fordyce spots (figure 2), as warts. In addition to subtle presentations, some may be quite large (figure 3). Even when patients have warts it is important to point out these normal variants so that if they are treating themselves at home they do not treat these variants in error. 4. Treatment The aim of treatment is eradication of the clinically obvious warts and stimulation of the immune system to recognize the virus and suppress further growth. Many factors are taken into consideration when discussing which treatment option is best for the patient. Patient preference is of major importance and the majority of patients attending our clinic want a treatment they can apply in the comfort and dignity of their own home, as opposed to frequent clinic visits.[4] Our clinic has a protocol for the treatment of genital warts (figure 4). The algorithm is very flexible and it is possible that several different treatment methods may be appropriate in one patient. In general, however, warts on dry skin are keratinized and require ablation by physical means, and/or an immune response modifier. All therapies have their advantages and disadvantages, and clinics would normally have an array of therapies from which to choose. In the past, most treatment regimens would have been based on personal preference, but some evidence-based recommendations have emerged. These are comprehensively reviewed in three sets of guidelines.[5-7] Very large warts (figure 3) are best removed surgically under general anesthetic. Any residual lesions or recurrence can then be treated easily. Podophyllotoxin, a purified extract of podophyllum resin, is extracted from the roots of the Podophyllum plant. The predominant effect of podophyllotoxin is blocking of the polymerization of tubulin into micro-tubules and it therefore blocks mitosis. It causes

Fig. 2. Normal glands, i.e. Fordyce spots alongside a wart.

destruction of wart tissue within a few days, but can also cause damage to normal skin. Podophyllotoxin preparations are cheap and relatively fast acting, making them first-line treatment options for soft fleshy warts in our clinic. Figure 5 shows a typical case of soft fleshy warts and the response to podophyllotoxin therapy at 1 and 2 weeks. Imiquimod is an immune response modifier that is applied topically three times per week for up to 3 months or longer if necessary (figure 6). Imiquimod has no direct antiviral effect. However, it stimulates immune mediated pathways by elevating levels of cytokines, thereby creating a chemical gradient that attracts inactivated immune cells. As it is the hosts immune response that clears the warts, recurrence rates are very low, around 10% (i.e. similar to that of spontaneous clearance).[8] Meatal warts are best treated with cryotherapy (figure 7). However, recurrences are common and we have used imiquimod off-license for meatal warts on occasions following initial debulking with cryotherapy. Keratinized warts can be treated with imiquimod from the outset, and we commonly use this agent as first-line treatment for anal and perianal warts.[9] One month of treatment is given initially

Fig. 1. Normal glands on the corona glandis, often called pearly penile papules.
2005 Adis Data Information BV. All rights reserved.

Fig. 3. Extensive perianal warts.

Am J Clin Dermatol 2005; 6 (4)

 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (4)

Genital Warts

Soft/moist/non-keratinized

Dry/keratinized or both moist and dry

Single

Few (25)

Multiple (6) or extensive

Single or few (15)

Multiple (6)

Extensive

Cryotherapy x4 treatments

PDX solution/cream cryotherapy or imiquimod or TCA

Cryotherapy x4 treatments

Imiquimod cream

Review at 4 weeks Non-clearance If unsatisfactory progress (<50% response) 1. If on cryotherapy or TCA change to PDX 2. If on PDX change to imiquimod 3. If on imiquimod continue If satisfactory progress (>50% response) Continue on present treatment 1. Consider imiquimod 2. If on imiquimod may continue for up to 16 weeks with 4-weekly review 3. Consult doctor

Review at 4 weeks

If unsatisfactory progress (<50% response) 1. If on imiquimod continue treatment 2. If no response to cryotherapy give imiquimod

If satisfactory progress (>50% response) Continue on present treatment

Review at 4 weeks

Review at 4 weeks

If clear, discharge IMPORTANT Pregnancy: cryotherapy is first-line therapy Patient choice: clinic or home-based treatment

If clear, discharge Recurrence: If successful treatment in previous episode then refer to algorithm. If previous therapy failure give imiquimod Perianal warts: Consider imiquimod

Fig. 4. Algorithm for treatment of anogenital warts used in the authors clinic (Genito-Urinary Medical Clinic, Countess of Chester Hospital, Chester, England). PDX = podophyllotoxin; TCA = trichloroacetic acid.

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Fig. 5. Genital wart successfully treated with podophyllotoxin (PDX). (a) Soft fleshy wart suitable for treatment with PDX. (b) Wart reduction and erythema after 1 week. (c) Wart cleared after 2 weeks.

and patients are warned that the treated area can become inflamed as the immune system becomes activated.[10] Despite the often alarming appearance, the affected area is not usually painful and resolves in a few days after interrupting therapy. Patients need to be warned not to increase the frequency of application of imiquimod just because they do not see any apparent effect. Excessive use like this can result in a dramatic and exaggerated immune response with significant excoriation and ulceration (figure 8). Anorectal warts can be treated with application of imiquimod by suppositories (anal tampons). One study reported successful prevention of recurrences after surgical ablation using this technique.[11] Small areas of keratinized warts can be frozen, cauterized, or treated with 95% trichloroacetic acid. With practice, trichloroacetic acid is easy to apply neatly without damaging the surrounding skin (figure 9). While there is no advantage associated with using a laser for treatment, clinics that have spent money on lasers obviously use it as the ablative method of choice. Vaginal warts can be treated with cryotherapy, but such treatment can be painful. Generally, there are also external warts that can be treated and cleared, and usually the immune recognition

that develops from that also clears the vaginal warts. A similar approach applies to cervical warts, but the UK national guidelines recommend colposcopy when cervical warts are seen.[6] This can cause problems in young patients, as colposcopy can unearth cervical intraepithelial neoplasia changes that would have regressed spontaneously by the time the patient entered the cervical screening program at 20 years of age. After reviewing the evidence, the national screening program in the UK has now decided that the age of first cervical smear should be delayed until 25 years of age in an effort to prevent over-diagnosis and treatment of transient cervical intraepithelial neoplasia. It is appropriate to consider checking for other sexually transmitted infections and most patients understand the rationale for this. Indeed, they may be too embarrassed to ask for this and appreciate it being offered. In the UK, it is routine to offer a full sexually transmitted infection screen (including HIV) to almost all attendees at genito-urinary medical clinics. 5. Conclusion With the range of therapies now available, most patients with genital warts can be managed with just one or two clinic visits. A

Fig. 6. Genital warts successfully treated with imiquimod. (a) Extensive gland and prepuce warts. (b) After 1 month of imiquimod. (c) After 2 months of imiquimod.
2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (4)

Genital Warts

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Fig. 7. Meatal wart frozen with cryoprobe.

Fig. 9. Accurate application of trichloroacetic acid.

as the mainstay of treatment. This is good for the patient and for optimizing efficient use of specialized clinic staff and time. Acknowledgments
Dr OMahony has received lecture fees from Steifel manufacturers of Warticon (podophyllotoxin) and 3M Pharmaceuticals manufacturers of Aldara (imiquimod).

References
1. Wilson J. Treatment of genital warts: whats the evidence? Int J STD AIDS 2002; 13: 216-20 2. Szarewski A, Cuzick J. Smoking and cervical neoplasia: a review of the evidence. J Epidemiol Biostat 1998; 3: 229-56 3. Koutsky L, Galloway DA, Holmes KK. Epidemiology of genital human papilloma virus infection. Epidemiol Rev 1988; 10: 122-63 4. OMahony C, Law C, Gollnick HPM, et al. New patient-applied therapy for anogenital warts is rated favourably by patients. Int J STD AIDS 2001; 12: 565-70 5. von Krogh G, Lacey CJ, Gross G, et al. European guideline for the management of anogenital warts. Int J STD AIDS 2001; 12 Suppl. 3: 40-7 6. Clinical Effectiveness Group (Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases). National Guidelines for the management of anogenital warts. Sex Transm Infect 1999; 75 Suppl. 1: 71-5 7. Centres for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep 2002; 51: 53-7 8. Miller RL, Gerest JF, Owens ML, et al. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 1999; 21: 1-14 9. OMahony C. Difficult wart cases: use of imiquimod cream 5%. Int J STD AIDS 2001; 12: 400-3 10. OMahony C. Management of imiquimod induced erythema. HPV Today 2004; 4: 15 11. Kaspari M, Gutsmer R, Kaspari T, et al. Application of imiquimod by suppositories (anal tampons) efficiently prevents recurrences after ablation of anal canal condyloma. Br J Dermatol 2002; 147: 757-9

b
Fig. 8. Effects of overuse of imiquimod. (a) Severe excoriation and erythema after overuse of imiquimod. (b) Resolution 1 week after stopping therapy (the warts have also disappeared).

recent audit in our clinic showed that out of all patients attending with genital warts, 70% required two visits or less. In contrast with the situation only a few years ago, home therapies have taken over

Correspondence and offprints: Dr Colm OMahony, Department of Sexual Health, Countess of Chester Hospital NHS Foundation Trust, Liverpool Road, Chester, CH2 1UL, England. E-mail: Colm.OMahony@coch.nhs.uk

2005 Adis Data Information BV. All rights reserved.

Am J Clin Dermatol 2005; 6 (4)