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Therapies for Treatment of Warts, LGAIN, HGAIN

Office-based Therapies

  1. Trichloracetic acid (TCA) 80-90% Solution. This is an acid that works by destroying the wart on contact. It is applied to the wart with a cotton tip applicator. Very small lesions can be treated using the wooden tip of the applicator. The surrounding skin should be covered with a barrier cream or gel to protect healthy skin from any spills or drips. TCA will burn with the initial application but discomfort is usually short-term. It will cause a burning sensation, and the wart will eventually fall off, sometimes leaving an ulceration. TCA can be used for internal or external warts. It usually requires several treatments. External warts can be treated weekly but internally warts should be treated 2-3 weeks apart in order to allow healing of the anal mucosa. If a wart is not successfully treated by the fourth application, an alternative method should be found. Thick, large lesions may be difficult to treat with TCA because the acid may not penetrate to treat the entire wart. A similar agent, bichloroacetic acid or BCA, is also used.
    Indication: Internal or external, warts, LSIL and HSIL, limited disease.
  2. Cryotherapy. External warts can also be treated by freezing with liquid nitrogen, nitrous oxide, or carbon dioxide. Liquid nitrogen is applied by spraying or direct contact with a swab; nitrous oxide is connected to a closed cryo-system and applied with a probe to produce an iceball. The freezing causes necrosis of the wart. This may also cause mild irritation, and may be uncomfortable during the process. Discomfort can be reduced by applying lidocaine spray or gel prior to freezing. Cryotherapy causes the wart to fall off within a few days and may leave a shallow ulceration, which generally heals without scarring. It may require several applications. These treatments can be 1-2 weeks apart. Like TCA, the lesion must be completely treated. If the warts have not been successfully treated by the fourth application, an alternative method should be sought.
    Indication: External warts, LGAIN or HGAIN. Limited disease. Safe during pregnancy.
    A combination of cryotherapy and TCA can sometimes produce more rapid clearance of the warts. However, the double application can cause more severe discomfort than either alone.
  3. Podophyllin is an extract from the podophyllum plant. It can be prepared as a 10% - 25% tincture. It causes the warts to erode approximately 3-5 days after treatment. It is applied to the external warts and must be washed off four hours later. There are several problems associated with podophyllin including low efficacy, potential for toxicity and it may be carcinogenic. It is therefore no longer recommended.
    Indication: External warts; should not exceed 3-4 treatments. Should not be used in pregnancy.
  4. Electrocautery. Lesions can be treated by application of an electric needle to cauterize or burn the warts. Local anesthesia should be used. Small lesions can be treated in a clinic setting, but larger and more extensive lesions usually require treatment in an outpatient surgery setting. The cauterization destroys the warts or lesions. Bleeding and discomfort following the procedure is common and can last for several days or weeks depending on the extent of treatment. However, the warts and lesions are more completely treated in one application and generally do not require multiple treatments. Even so, warts may recur with electrocautery as with any treatment modality.
    Indications: Internal or external warts, LGAIN, HGAIN. Safe during pregnancy. Office procedure limited to the tolerance of the patient; treats more extensive disease than what can be treated by TCA, less extensive than disease requiring outpatient surgery.
  5. Infrared Coagulation (IRC): IRC was developed for the treatment of external anal warts, hemorrhoids and tattoo removals. More recently it has been shown to be an effective treatment for internal anal HGAIN and warts. The treatment involves the application of a heat-guided probe directly to the lesions. The heat is at a lower range compared to laser or electric cauterization. It does not burn the lesions but rather destroys the tissue, similar to a sunburn blister, which can than be removed. It can be done as an office therapy with minimal discomfort both during and after the procedure. Patients are anesthetized pre-treatment with lidocaine gel followed by the injection of 1% lidocaine into the areas to be treated. The treatment can take up to an hour (or more if very extensive) but post-treatment recovery is brief and there are none of the risks of surgical intervention. Following treatment there is frequently bleeding with bowel movements for up to 2-3 weeks. Post-procedure pain may require medication for 1-3 days but for most patients it is minimal although noticeable and most of the pain is associated with bowel movements. The pain can be minimized by frequent soaking in hot water, especially following bowel movements. Care should be taken to increase fluids at this time to avoid constipation. Although the procedure takes longer than the application of TCA, the lesions are usually completely treated in one procedure. Extensive disease may require an additional treatment. We generally schedule a follow-up exam three months following the procedure. If there is too much to treat in one session, we complete the treatment with an additional procedure two to three months later.
    Indications: Internal and external LGAIN and HGAIN; can effectively treat more extensive areas (50-70% circumference of the anal canal or perianus) but may require 2 treatments if extensive.
  6. Laser Therapy: Clinicians trained in laser therapy can apply this technique for perianal disease as well. There are also case reports of laser therapy for intra-anal lesions and it has become a more common practice in some offices. It appeared to be effective in some studies,4,12,13 but there were significant recurrences of the group treated with laser in another study2. More extensive treatments, or those done in conjunction with ablation of cervical, vaginal or vulvar warts, are often done in an operating room. It is done in conjunction with the colposcope for guidance in finding the areas to treat. Laser treats the lesions by destroying them with the heat from the laser light. The laser controls the depth of treatment, which can help minimize scarring. Extensive treatments can be painful and can be managed with hydrocodone/acetaminophen. The pain may be minimal for the first few days since the nerve endings may be burnt initially, but can last for 2-3 weeks. Soaking in warm water especially following bowel movements will be soothing and can facilitate healing. It can take up to two months for the area to heal completely.
    Indications: Warts, LGAIN or HGAIN, more commonly used for external disease but internal disease can be treated as well.

Patient-applied Therapies

  1. Aldara™ (5% imiquimod cream). This is an immune response modulating treatment, which acts to produce a local interferon response. This stimulates the immune system to recruit immune cells to the area and causes the warts to regress. It is applied to the warts and rubbed in 3x/weekly at bedtime and rinsed off in the morning. The treatment continues for 12-16 weeks. Local irritation is expected and is a sign that the treatment is working. It can take 3-4 weeks for the treatment to start working. Occasionally the reaction is severe and the cream should be stopped until the inflammation goes away, or reduced to twice weekly. It is sometimes used post-operatively to prevent recurrence of warts. Once the warts are clear, it may be used continuously 2x/week to prevent recurrences. It has been used experimentally intra-anally14. One study showed it reduced recurrences of anal warts following surgery15 and was also effective as a primary treatment for anal HGAIN16.
    Indications: External anal warts, especially primary outbreaks. The patient must be able to adequately reach the affected areas. Patients should be shown how to apply the cream correctly in the office. Safety in pregnancy is not established. Safety for internal disease is not established.
  2. Condylox™ (.15% podophyllotoxin cream) or Podofilox™ (.5% podophyllotoxin gel, solution, or cream). These are purified extracts of the podophyllum plant. They are applied twice daily for three consecutive days, followed by 4-7 days without treatment. The treatment can be repeated for 4 to 8 cycles. Warts that have not responded after 4 treatments should be treated with an alternative treatment. The treatment can cause burning, tenderness, and swelling and the warts will erode after a few days. If the discomfort is severe the treatment should be stopped.
    Indications: External anal warts. The patient must be able to adequately reach the affected areas. Patients should be shown how to apply the gel correctly in the office. Safety in pregnancy is not established. Safety for internal disease is not established.
  3. Veregen 15% ointment. Approved by the FDA for treatment of external genital warts in 2006. It is a purified green tea extract mixed in an inert ointment. It is applied three times daily (does not need to be 8 hours apart) to affected areas for up to 16 weeks. A different treatment should be used if the warts have had no response within 4 weeks. The ointment may first cause the warts to increase in size, they will then ulcerate and disappear. Most people report some discomfort, it should be tolerable and if not a different therapy should be used. Soaking in warm water or applying lidocaine gel can help with the discomfort.
    Indications: External anal warts. Should not be used in pregnancy. Safety for immune-compromised individuals has not been established.
  4. Efudex™ 5% cream has been suggested for treatment of anal warts but has not been studied. It is occasionally used for treatment of anal warts that are confluent with vulvar warts, and when all other therapies have failed. For a therapy that has been available for several decades it is surprising how little research has been published regarding its efficacy. Several studies reported its use alone or adjunctively in the treatment of intra-urethral, penile, and vulvar warts17,18 . It was effective in treatment of women with extensive vulvar condyloma in two studies evaluating different treatment regimens10,19 . Several small studies of women with vaginal or vulvar intraepithelial neoplasia showed efficacy rates of 41% to 91%10,20,21,22 . It was also shown to prevent recurrence of cervical SIL in HIV-seropositive woman following laser treatment11. A small non-randomized trial showed improvement in 10 of 11 patients using the cream BID for perianal HGAIN8. When used intravaginally patients are taught to carefully protect the normal vulvar mucosa from burns with Efudex™ as it can cause ulcerations of normal skin, and careful follow-up is recommended. When used externally, a thin layer is put on the areas of treatment with generally little adverse effects seen.
    Indications: Unknown efficacy. Possibly for external anal warts, LGAIN or HGAIN. Unknown effects for internal disease. Used for treatment of extensive vaginal warts and vulvar warts, but no longer recommended by the CDC.

Out-Patient Surgery

Patients are referred for outpatient surgery when the warts or lesions are not responsive to other treatments, for very large volume of disease, or if there is any suspicion for cancer or HGAIN that cannot be found due to the presence of large amounts of warts. Although the procedures are technically simple, the usual risks for surgery must be considered. It also has significant post-operative recuperation requiring up to two weeks of generally severe discomfort. It also may be the best option for people who prefer to have it “over and done with” in one treatment, as well as for those who cannot tolerate a long procedure in the clinic room. There are people for whom sedation is necessary and an office procedure would not be easily tolerated. There are several techniques used in surgery, but like the clinic procedures all have the same goal – eradication of the lesions. Surgical fulguration involves treating the lesions with an electric needle and is the most commonly used surgical intervention.

See the Surgery section for more details.

Novel Treatments

There is surprisingly little that is new for treatment of anal warts and LGAIN or HGAIN. A web search reveals only a few alternative therapies. There are homeopathic remedies, Traditional Chinese Medicine, and other alternative-based therapies. Even duct tape has been claimed to effectively treat warts. None of these have been studied in scientific controlled studies. It is also important to remember that treatment of anal warts is different than treatment of skin warts. The anus and surrounding perianal area are mucous membranes. This type of tissue is sensitive and easily absorbs chemicals. Care should be taken in using products that have not been tested for treatment of mucous membranes.

A few therapies which may be prove to be valuable in the future are the following:

  1. Indole 3 carbinol (I3C) is found in cruciferous vegetables. It has been shown to have antiestrogen effects and to be effective in treating cancers in studies with mice. There have been only initial trials of I3C in treatment of CIN (cervical dysplasia), and the results were modestly encouraging23. It has not been studied in relation to anal disease. However, it is occasionally recommended in doses of 200mg BID if tolerated, adjunctively for treating warts or HSIL when other therapies are not working or feasible.
  2. Cidofovir is a cytidine nucleotide analogue that has been found to have some antiviral activity. It has been used intravenously, interlesionally, and topically on external genital warts. Topical application of a 1% gel or cream has been used in a treatment cycle of five days sequentially, repeated in two-week cycles. Several small studies reported response rates between 32% -76%24,25,26,27. It has also been used in combination with surgical removal of warts28. Although it was tolerated with few problems in most patients, reversible renal failure was reported in one patient with prior renal insufficiency29. There are no published studies using Cidofovir for treatment of HGAIN although it has been used for treatment of vulvar intraepithelial neoplasia30.
  3. Interferon alpha 2a and 2b has been administered by injection into the lesions as a primary treatment or used following surgery to prevent recurrence. There was reduced recurrence compared to placebo in one study in combination with surgery31 but no improvement in another32. In another study there was only 6.1% recurrence in patients treated for genital warts with adjunctive interferon compared to 20.7% recurrence without interferon following either Efudex™ or laser33.
  4. Photodynamic Therapy uses a photosensitizing drug such as aminolevulinic acid, which is applied systemically or topically. When light is applied to the lesion, destruction of the tissue occurs which activates immune defenses. Case reports or several small studies reported complete or partial response in patients treated for external anal LGAIN or HGAIN 34,35,36. Similar results were reported for treatment of vulvar disease37,38 and it has been used for cervical disease as well39.
  5. Treatment Vaccines. There has been a lot of exciting new research into the use of vaccines either to prevent or treat HPV-associated diseases including anal disease. Prophylactic vaccines are aimed at preventing LSIL or HSIL by inducing antigens to HPV and have been developed using L1 virus-like proteins (VLP). Prophylactic vaccines are targeted at populations before exposure to the virus, similar to hepatitis vaccination. The vaccine induces virus-neutralizing antibodies, which protect the host when subsequently exposed to the particular HPV strain. Therapeutic vaccines target existent HSIL or SCC for treatment usually through targeting specific proteins (E6 or E7) which have been shown to be expressed in HSIL or cancers. They intend to induce the cellular immune system to recognize and attack cells infected with HPV. In each case the vaccine is directed against a particular viral type such as HPV 16. An ideal vaccine will be multivalent (directed against multiple HPV types) and immunize against a range of common HPV types and these are in development. Most research has focused primarily on prevention or treatment of cervical disease with scant data regarding anal disease. Two trials of therapeutic vaccines for anal HSIL have been completed40,41. The vaccines were tolerated without significant adverse events, but there was incomplete response and further testing is warranted.

Office-based Therapies
Patient-applied Therapies
Out-Patient Surgery
Novel Treatments
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