Verruca

Lauren L. Levy

Amanda Zubek

Macrene Alexiades

BACKGROUND

Warts (verrucae) are benign neoplasms affecting the skin and mucosa due to the human papilloma virus (HPV). However, certain HPV serotypes predispose to malignancy and yet others are considered oncogenetic.

PRESENTATION

Patients usually present with painless growths or bumps on the skin, oral mucosa or anogenital area or painful growths on the palms or soles. On the skin they may either be flat and small or may grow into a hard nodule or cauliflower-like bump. On the anogenital area, they may form cauliflower-like growths or brown flat papules.

DIAGNOSIS

Clinical Diagnosis

Warts present clinically as verrucous papules or nodules on the skin, oral mucosa or genitalia or perianal region. They are usually painless and usually slow-growing; though, they may appear suddenly with rapid growth. Plantar warts are often endophytic and painful. A number of subtypes of warts (see Subtypes below) are caused by the different HPV serotypes (Table 11.6.1).

Genital Warts

The white vinegar test reveals subclinical lesions of Bowenoid papulosis as they turn white within several minutes. The workup of genital warts should include a
Pap test and colposcopy (females), anoscopy if perianal, HPV PCR or DNA-based assays, and biopsy.

TABLE 11.6.1 Wart Types, Presentations, and HPV Serotypes

Type	Clinical Presentation	Serotypes
Verruca Vulgaris (Common)	Verrucous papules on skin	2, 4 > 1, 3, 27, 29, 57
Palmoplantar (Myrmecia) verruca	Endophytic verrucous nodules on palms or soles	1 > 2-4, 27, 29, 57
Verruca Plana (Flat)	Planar slightly papillated and often slightly hyperpigmented plaques often on face or hands	3, 10, 28
Condyloma acuminatum (Genital)	Cauliflower like flesh colored, pink papules and nodules anogenital region	Low grade: 6, 11
Condyloma acuminatum (Genital)		High grade:^a 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68
Bowenoid papulosis^b	Hyperpigmented brown papillated plaques anogenital region	16 > 18, 31, 32, 33, 34, 35, 39, 42, 48, 51, 52, 53, and 54
Focal epithelial hyperplasia (Heck’s Disease, Oral)	Multiple flat or dome shaped papules on oral mucosa	13, 32
Epidermodysplasia verruciformis	Widespread skin colored, pink or hypopigmented flat macules or thin papules on arms, legs face, dorsal hands	3, 5, 8 > (9, 10, 12, 14, 15, 17, 19-25, 28, 29, 36-38, 46, 47, 49-51, 59)
Buschke-Löwenstein tumor	Large exophytic cauliflower-like tumor, may have deep invasion, intratumoral abscesses or fistulous tracts	6, 11
^aHigh grade indicates high risk of cervical carcinoma. ^bBowenoid papulosis is midway between genital warts and squamous cell carcinoma; the rate of malignant transformation is low.

Histopathology

Skin biopsy is sometimes warranted to distinguish warts from malignancy. On the skin, HPV has been associated with squamous cell carcinoma, and skin biopsy is necessary to distinguish between the two. On the genitalia, biopsy is necessary to distinguish Bowenoid papulosis from condyloma acuminatum.

Verruca Vulgaris

Common warts are well demarcated exophytic acanthotic papules that exhibit papillomatosis with ortho- and parakeratosis heaped up over the papillomatous projections. The rete ridges are elongated, and there are dilated capillaries seen in the papillary dermis.¹

Palmoplantar Verruca (Myrmecium)

Palmoplantar warts are often endophytic rather than exophytic, with papillomatosis overlying a cup-shaped acanthotic wart. There is hypergranulosis with irregular keratohyalin granules and giant eosinophilic cytoplasmic aggregations. Vacuolated cells overlying the papillae. Similar to verruca vulgaris, dilated capillaries are seen in the papillary dermis, which are sometimes thrombosed.¹,²

Verruca Plana

Flat warts are acanthotic, with “basket-weave” orthokeratosis.

Vacuolization is seen in the spinous layer, with a thickened granular layer, and marked lack of papillomatosis. Occasionally flat warts are inflamed and can spontaneously regress. Histologic features of flat wart regression include keratinocyte apoptosis, spongiosis, lymphocyte exocytosis and a superficial perivascular inflammatory infiltrate.¹,²

Condyloma Acuminatum

Genital warts are exophytic, well demarcated lesions with acanthosis, often rounded papillomatosis. There is hyperkeratosis and parakeratosis, coarse hypergranulosis, koilocytosis and vacuolization of the upper spinous and granular layer.¹,²

Bowenoid Papulosis

Well demarcated dome shaped papule or plaque, with acanthosis, hyperkeratosis and vacuolization of the upper epidermis. There is variable cellular atypia and variable nuclear pleomorphism, variable number of mitoses.²

Focal Epithelial Hyperplasia

Lesions of Heck’s disease exhibit epithelial acanthosis and broad rete ridges that connect. There is mild keratinization seen (normal oral mucosa is not keratinized), superficial koilocytes, and in the lower epidermis degenerating nuclei can be seen with clumped chromatin.²

Epidermodysplasia Verruciformis

These lesions are hyperkeratotic with acanthosis, hypergranulosis and vacuolization of the upper epidermis with a characteristic blue-gray color most notable within the upper granular layer. Atypia is variable and can range from mild to carcinoma in situ-like changes.²

Buschke-Löwenstein Tumor

Histologic features similar to condyloma but much more extensive acanthosis and bulbous endophytic rete, marked lack of cellular atypia.¹,²

Subtypes

Verruca Vulgaris

Verruca Vulgaris or common warts are human papilloma virus mediated growths which may occur on any part of the body including the mucosa. They can be solitary or widespread, the latter is more common in an immunocompromised host. They are hyperkeratotic, cobblestoned or filiform papules which may be friable. Black dots may occur which represents thrombosed capillaries. They tend to be large solitary lesions, biopsy may be necessary to confirm the diagnosis and rule out malignancy.

Verruca Plana

Verruca plana or flat warts are small flat skin colored or pink papules that occur commonly on the face, hands, elbows and knees. In immunocompromised hosts lesions can be quite extensive.

Palmoplantar Verruca

Palmar and plantar warts present as thick keratotic lesions that may be painful. Black dots are usually abundant. Mosaic warts are plantar warts that coalesce into a large plaque and can be a therapeutic challenge.

Periungual Verruca

Periungual verruca are warts of the nail apparatus. They present as keratotic lesions in the paronychium, hyponychium or nail bed. They can be painful and cause significant nail dystrophy.

Condyloma Acuminatum

Anogenital warts are small skin colored to tan discrete filiform papules found on the genitalia, perineum, perianal anal, mons pubis or inguinal folds. They can also spread to effect the vagina, urethra or anal canal. Larger more exophytic lesions can occur. It is important to distinguish anogenital verruca from squamous dysplasia (ie, Bowenoid papulosis and squamous cell carcinoma).

PATHOGENESIS

All verrucae are caused by infection with human papilloma virus, a nonenveloped double stranded DNA virus. Specific viral strains cause the various types of warts (Table 11.6.1). The virus life cycle is completed inside squamous epithelium. The virus invades the basal epithelial cells through initial trauma in the skin and subsequently begins to replicate leading to proliferation of the epithelium. Special attention should be paid to genital warts as the lesions are highly transmissible and represent the most common sexually transmitted infection. High risk HPV is the cause of cervical dysplasia, cervical cancer, and other anogenital malignancies. With the advent of HPV vaccination, there has been a worldwide decrease in the incidence of cervical cancer.³

Non-genital warts occur in approximately 10% of the population and are most common in children and adolescents peaking between ages 12 to 16.⁴ Genital warts have an annual incidence of 1% and rates are highest among males and females ages 20 to 24.⁵ Immunosuppression including cancer, HIV infection, or immunosuppressive medications can increase severity of verruca.

Epidermodysplasia verruciformis is unique in that it is a genetic predisposition to developing flat-wart like lesions, which is why there is such a large variety of HPV types seen. Most common mutations are due to EVER1 and EVER2 gene mutations, which encode proteins that are important for zinc transport in keratinocytes. The mechanism of pathogenesis is unknown, but it is thought that there is a defective T-cell response to HPV infected keratinocytes.²

TREATMENT

Numerous medical and surgical treatment modalities are available (Algorithm 11.6.1). Untreated verruca can spontaneously resolve, as two-thirds of warts clear without treatment in approximately 2 years.⁶ Significant psychological distress can be associated with verruca, especially with anogenital lesions, so aggressive treatment is often desired.

Medical

Medical treatments can also be used either alone or in conjunction with surgical destructive measures. Destructive methods are by far most common and include cryotherapy, application of various acids, curettage, and laser surgery. Oral medications such as cimetidine and zinc sulfate can be used as immunomodulators. Topical and intralesional immunomodulators are also part of the treatment armamentarium as well.

Topical

Occlusion. Duct tape occlusion of warts has been anecdotally reported to be effective, but the reported trials are flawed and it is generally not recommended as a solitary treatment option.⁷

Salicylic Acid. Salicylic acid is a keratolytic chemical that causes destruction of the keratinized layer of epidermis and mild irritant contact dermatitis. Most over the counter formulations (liquid, gel or adhesive patch) are salicylic acid 17%, although via prescription salicylic acid 40% compounded in petrolatum is effective. This method should be used in conjunction with paring and intermittent destructive methods to obtain highest efficacy. Duct tape may be used in conjunction for occlusion. Cure rate is approximately 73% with 6 to 12 weeks of treatment. Resolution is slow, typically requiring up to 12 weeks of continuous treatment.⁷

Trichloroacetic Acid. Trichloroacetic acid(TCA) at the concentrations of 60% to 90% is a very effective treatment of genital warts with clearance rates ranging from 70% to 80% with recurrence rates of approximately 36%.⁸ A small amount of acid is applied to the lesion followed by frosting. TCA can also be used to treat verruca vulgaris. A randomized study compared 35% TCA versus 80% TCA in 62 patients. Treatment continued until clearance for a maximum of 6 applications. At the end of the study, there was significantly more improvement with higher concentration TCA.⁹ A study comparing TCA with concentrations of 10%, 25% and cryotherapy in the treatment of verruca plana showed that all three methods had similar reductions in number of lesions at 8 weeks; however, there was more pain and dyspigmentation with cryotherapy group and more adverse effects with the 25% TCA group.¹⁰ Side effects of TCA include pain, crusting, ulceration, and blistering. Several treatments may be needed for maximal efficacy. Application of TCA can occur after treatment with PDL.

Glycolic acid has been reported beneficial in a case of extensive facial flat warts. Benefits of a glycolic acid peel include low risk for scarring and dyspigmentation.¹¹

Podophyllotoxin. Podophyllotoxin is an extract from the resin of the Podophyllum species plant (common name: mayapple). It has antiproliferative properties and in some studies treatment with podophyllotoxin led to cure rates of genital warts ranging from 37% to 83%. One trial that compared imiquimod (discussed below) to podophyllotoxin showed that they had equivalent efficacy for anogenital warts¹² Podophyllotoxin is well tolerated, dosing is twice daily for anogenital warts three consecutive days a week for up to 4 weeks.

Imiquimod. Imiquimod cream 5% and 3.75% are both Food and Drug Administration approved for the treatment of genital and perianal warts. They are not currently approved for the treatment of other types of warts but can be used off label. This topical agent is an immunomodulator which induces interferon (IFN) production that ultimately leads to viral death. Imiquimod 5% cream is applied for 6 to 10 hours three times a week for up to 16 weeks. Clearance rates are reported as 50% and median time to clearance is between 8 to 12 weeks. Recurrence rates range between 5% to 19%.¹³ The 3.75%

formation is applied nightly for 6 to 8 weeks and has the advantage of being used over a larger areas with more convenient dosing. Clearance rates are not as high as in the 5% formulation, but side effect profile is lower. Side effects of imiquimod include pain, blistering, ulceration in the treated area and rarely systemic symptoms such as malaise, arthralgias, and myalgias may occur.

ALGORITHM 11.6.1 Treatment algorithm for verruca. BCG, Bacillus Calmette-Guerin; CO₂, carbon dioxide laser; ED, electrodessication; HPV, human papilloma virus; IPL, intense pulsed light; MMR, measles mumps rubella vaccine; PDL, pulsed dye laser. (Courtesy of Macrene Alexiades, MD, PhD.)

Although not approved for the treatment of non-genital warts, topical imiquimod cream 5% applied nightly 5 days a week to common warts in children resulted in 56% clearance at 16 weeks.¹⁴ Imiquimod 5% has also shown efficacy in recalcitrant palmoplantar warts in immunosuppressed patients.¹⁵ A study comparing cryotherapy (performed every 2 weeks) for 3 months with imiquimod 5% cream nightly for 5 days of the week for 3 months in plantar warts found imiquimod more effective.¹⁶

Cantharidin. Cantharidin is a blistering agent that is produced by the blister beetle of the Meloidae family. The cantharidin activates proteases in the epidermis that leads to intraepidermal acantholysis and blistering. Side effects are pain, postinflammatory hyperpigmentation, erythema. There is a risk of ring-wart formation at the periphery of the blister. Cantharidin is applied for 8 hours (non-volar surfaces, or pediatric use) up to 24 hours for adult volar use. Occlusion is recommended once the liquid dries and is then is washed off. Estimated efficacy is approximately 80%.¹⁷

Tretinoin. Retinoids are vitamin A derivatives, and are known to increase of epidermal turnover by increasing basal keratinocyte proliferation and keratinocyte differentiation and ultimately desquamation. Retinoids may decrease HPV transcription in infected keratinocytes.¹⁸

Efficacy of topical retinoid treatment of warts has been reported to range from 33% to 85% clearance rates, although in one study the placebo clearance rate was 32%.¹⁹

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