Epidermodysplasia verruciformis

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Epidermodysplasia verruciformis

Slawomir Majewski and Stefania Jablonska

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Epidermodysplasia verruciformis (EV) is a rare genetic disease characterized by an impaired immune response to human papillomavirus (HPV) and HPV-associated cutaneous oncogenesis. Chronic infection occurs with potentially oncogenic HPV types 5 and 8 as well as non-oncogenic types. Flat warts and pityriasis versicolor-like lesions begin to appear in early childhood and become widespread. In the fourth and fifth decades many patients begin to develop multiple cutaneous malignancies. It has been established that EV is mostly associated with mutations of genes EVER1 and EVER2, coding transmembrane proteins located in the endoplasmic reticulum and involved in zinc transportation.

A new and important problem is the occurrence of the EV phenotype in immunosuppressed individuals, especially in association with HIV, which has been called ‘acquired epidermodysplasia verruciformis.’ This differs in response to therapies and outcome. Two varieties of acquired EV are described: a generalized verrucosis associated with large common warts mainly of HPV-3 type (sometimes referred to as benign EV), and a variety associated with diverse HPVs of types not usually related to EV.

The high risk of malignant transformation in genetic EV seems to be reduced in the acquired variety.

Management strategy

No compound acts directly on HPV, and no therapy produces a complete and sustained clearing of both benign wart-like and keratotic lesions associated with oncogenic EV HPVs. A most important aspect of the management of EV is protection from ultraviolet radiation, which is a cancer cofactor. Light-avoiding behavior and topical sunblock creams (sun protection factor >50) are indicated. Other cancer cofactors (radiotherapy, immunosuppressants) must be avoided. Premalignant and troublesome benign lesions can be treated by a variety of destructive techniques: surgical (cryotherapy, shave excision, curettage, laser, full excision) or chemical (trichloroacetic acid, 5% 5-fluorouracil).

For more widespread lesions, with signs of premalignancy or malignancy, agents that modify keratinization are indicated, such as oral or topical retinoids, vitamin D₃ analogs, interferons, and imiquimod. Photodynamic therapy (PDT) can be useful for early malignancy. Larger malignancies can necessitate skin autografts.

Specific investigations

Family history and examination of other family members

HPV typing to identify potentially oncogenic and non-oncogenic HPV types

Evaluation of immune status and the presence of factors producing or enhancing immunosuppression: HIV, congenital immunodeficiency syndromes, iatrogenic immunosuppression

Human papillomavirus-associated tumors of the skin and mucosa.

Majewski S, Jablonska S. J Am Acad Dermatol 1997; 36: 659–88.

A CME article on HPV-associated tumors. The histology of verrucous lesions demonstrates a highly characteristic cytopathic effect, with clarification of cytoplasm and nucleoplasm, and prominent keratohyaline granules.

Common variable immunodeficiency syndrome associated with epidermodysplasia verruciformis.

Vu J, Wallace GR, Singh R, Diwan H, Prieto V, Rady P. Am J Clin Dermatol 2007; 8: 307–10.

Epidermodysplasia verruciformis in the setting of graft-versus-host disease.

Kunishige JH, Hymens SR, Madkan V, Wyatt AJ, Uptmore D, Lazar AJ. J Am Acad Dermatol 2007; 58: S78–80.

In addition to HIV, other causes of immunosuppression may give rise to a similar clinical picture.

Generalized verrucosis: a review of the associated diseases, evaluation, and treatments.

Sri JC, Dubina MI, Kao GF, Rady PL, Tyring SK, Gaspari AA. J Am Acad Dermatol 2012; 66: 2292–311.

Generalized verrucosis and distinct diseases (including EV), associated with generalized warts are defined. The indications for histopathologic examination, HPV typing, and other laboratory tests as well as potential treatment options are discussed. Generalized verrucosis may not show immunological abnormalities.

First-line therapies

Sun avoidance/protection	E
Cryotherapy with liquid nitrogen	E
Topical retinoic acid 0.05–0.1% for benign, flat, cosmetically troublesome lesions	E
Topical 5% 5-fluorouracil cream for keratotic lesions	E
Shave excision of flat lesions	E
Surgical excision of malignant lesions	E

Second-line therapies

Interferon-α with retinoids (acitretin)	E
Systemic isotretinoin	E
Imiquimod 5% cream	E
Topical 15% glycolic acid lotion	C
HAART in HIV positive patients	E

Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a.

Anadolu R, Oskay T, Erdem C, Boyvat A, Terzi E. J Am Acad Dermatol 2001; 45: 296–9.

A patient treated with oral acitretin 50 mg daily and systemic interferon-α_2a, 3 MU subcutaneously three times weekly for 6 months. Improvement was followed by relapse after discontinuation of treatment, and the same regimen was re-introduced. The interferon was then discontinued after 4 months and the acitretin reduced to 25 mg for 3 months, then stopped. Improvement was maintained during the subsequent 12-month follow-up. Used as monotherapy, interferon-α has only a slight effect and is not recommended.

Systemic low-dose isotretinoin maintains remission status in epidermodysplasia verruciformis.

Rallis E, Papatheodorou G, Bimpakis E, Buutanska D, Menounos P, Papadakis P. J Eur Acad Dermatol Venereol 2008; 22: 523–5.

In this case isotretinoin 0.8 mg/kg/day for 6 months produced complete clearance, with relapse 4 months after discontinuation of medication. Maintenance treatment with 20 mg/day resulted in sustained remission. EV in this case was associated with HPV-3, i.e., a more benign variant responsive to therapy.

Treatment of a patient with epidermodysplasia verruciformis carrying novel EVER2 mutation with imiquimod.

Berthelot C, Dickerson MC, Rady P, He Q, Niroomand F, Tyring SK, Pandya AG. J Am Acad Dermatol 2007; 56: 882–6.

Epidermodysplasia verruciformis, unsuccessful therapeutic approach with imiquimod.

Janssen K, Lucker GP, Houwing RH, van Rijssel R. Int J Dermatol 2007; 46 (Suppl 3): 45–7.

Favorable results are reported in some cases treated with imiquimod.

Acquired epidermodysplasia verruciformis syndrome in HIV-infected pediatric patients: prospective treatment trial with topical glycolic acid and human papillomavirus genotype characterization.

Moore RL, de Schaetzen V, Joseph M, Lee IA, Miller-Monthrope Y, Phelps BR, et al. Arch Dermatol 2012; 148: 128–30.

Topical 15% glycolic acid lotion had a good effect in HIV infected children; the therapy was regarded as safe and efficacious.

Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy.

Jacobelli S, Laude H, Carlotti A, Rozenberg F, Deleuze J, Morini JP, et al. Arch Dermatol 2011; 147: 590–6.

In many cases acquired EV is associated with HIV infection. Although there is no evidence-based therapy for acquired EV in HIV positive patients, symptomatic treatments for HPV induced lesions combined with HAART therapy could be partially effective. In most cases this therapy failed, although there was some improvement due to diminished viral load, and increased CD4 cell count.

Third-line therapies

Photodynamic therapy	E
CO₂ laser for malignant and premalignant lesions	E
Skin autografts	E

Photodynamic therapy for human papillomavirus-related diseases in dermatology.

Szeimies RM. Med Laser Appl 2003; 18: 107–16.

Topical PDT using 20% 5-aminolevulinic acid was reported to yield excellent results in a case of epidermodysplasia verruciformis associated with HPV-5, -8, -36, and other strains. Twelve months after PDT the lesions started to reappear, but resolved after repeated treatments. The authors suggest annually repeated PDT is safe and will control EV lesions.

CO₂ laser treatment of warts in immunosuppressed patients.

Lauchli S, Kempf W, Dragieva G, Burg G, Hafner J. Dermatology 2003; 206: 148–52.

Alternative therapies for recalcitrant HPV-induced cutaneous warts in EV may include CO₂ laser or neodymium laser. Laser therapy of recalcitrant warts proved to be efficacious in both immunosuppressed and immunocompetent individuals.

Skin autografts in epidermodysplasia verruciformis: human papillomavirus-associated cutaneous changes need over 20 years for malignant conversion.

Majewski S, Jablonska S. Cancer Res 1997; 57: 4214–16.

For very widespread, constantly developing new lesions not responding to any therapy, the only effective method is removal of the most involved skin area (usually on the forehead) and its replacement with skin from non-exposed inner aspects of arms.

Related

Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e