Epidermodysplasia Verruciformis Clinical Presentation
- Author: Anthony A Gaspari, MD; Chief Editor: Dirk M Elston, MD more...
Epidermodysplasia verruciformis usually begins in infancy or early childhood, with the development of various types of flat, wartlike lesions and confluent plaques on the skin, especially on dorsal hands, extremities, face, and neck. Patients may also develop tinea versicolor–like lesions on the trunk.
Epidermodysplasia verruciformis lesions may progress to form verrucous plaques and nodules, or they may transform into invasive squamous cell carcinomas, most commonly between the ages of 20 and 40 years.
The clinical course of epidermodysplasia verruciformis is protracted. As the disease progresses, some lesions disappear, while new lesions may appear on other areas of the body. The rate of appearance of new lesions varies considerably.
The diagnosis of epidermodysplasia verruciformis should be suspected in the clinical setting of numerous verrucous lesions or when lesions are resistant to appropriate therapy.
Epidermodysplasia verruciformis variants may be suspected when a patient has the typical clinical presentation in the setting of epidermodysplasia verruciformis–associated HPV but lacks nonmelanoma skin cancers at a young age or has late-onset disease.
Pertinent physical findings are limited to the skin and rarely occur on the mucosa.
Primary skin lesions manifest as 2 types, although they generally are polymorphic. The first type is flat, wartlike lesions resembling verruca plana; they are flat-topped papules with scaly, hyperpigmented or hypopigmented, sometimes confluent patches or plaques. Flat macules and reddish brown plaques with slightly scaly surfaces and irregular borders are also noted, as shown in the image below. These lesions may resemble tinea versicolor. Papules on the knees, the elbows, and the trunk may coalesce into large plaques.
The second type is verrucous or seborrheic keratosis–like lesions; they are commonly seen on sun-exposed skin, including dorsum of hands, as shown in the image below.
The wartlike lesions are mostly localized on sun-exposed areas, mainly distributed on the hands, the feet, and the face, sometimes in a linear arrangement, as demonstrated in the image below. The pigmented plaques preferentially involve the trunk, the neck, and the proximal extremities. The lesions may be found on the palms and the soles, in the axillae, and on the external genitalia. The mucous membranes (conjunctiva and oral cavity) are rarely affected.
Cutaneous lesions induced by EV-HPVs vary from flesh-colored warts (verruca vulgaris) to red, reddish-brown, and brown plaques.
Epidermodysplasia verruciformis–associated HPVs can be divided into 2 groups. One group has high oncogenic potential (HPV types 5, 8, 10, and 47). More than 90% of epidermodysplasia verruciformis–associated skin cancers contain these virus types. The other group has low oncogenic potential (HPV types 14, 20, 21, and 25). These types are usually detected in benign skin lesions.
Proposed mechanisms for the development of epidermodysplasia verruciformis include the following:
An autosomal recessive mode of inheritance is supported by the finding that 10% of patients with epidermodysplasia verruciformis are offspring of consanguineous marriages. X-linked inheritance has rarely been reported.  A clear mode of inheritance is not evident in all cases.
Pathogenic mutations in 2 adjacent genes, EVER1 and EVER2, have been identified. [2, 6]
Major histocompatibility complex (MHC) class II alleles (DR-DQ) have been found in a large series of patients with epidermodysplasia verruciformis from Europe, Africa, and America.
Neither chromosomal abnormalities nor the relationship to any specific MHC class I antigens has been found in patients with epidermodysplasia verruciformis.
The exact mechanisms involved in the keratinocytic transformation within epidermodysplasia verruciformis skin lesions are unclear. Transcripts of the early region of viral genomes (E6 and E7 gene proteins) have been detected in epidermodysplasia verruciformis tumors. However, in most carcinomas, viral sequences are not integrated into the host genome.
Studies have shown that interactions occur between oncogenic HPVs and the antioncogene products, p53 and pRb, in cell cycle regulation, DNA repair, and the execution of programmed cell death (apoptosis). Failure of programmed cell death to eliminate cells with DNA damage may play an important role in the malignant transformation of squamous epithelium, with resultant proliferation, disruption of epithelial structural order, and development of cellular atypia. A decrease in UV-induced DNA repair synthesis, coupled with antioncogenic viral infection, further enhances the disposition for somatic mutations and malignant transformation in patients with epidermodysplasia verruciformis.
A specific defect of cell-mediated immunity, manifested by the inhibition of natural cytotoxicity and the proliferation of T lymphocytes against HPV-infected squamous cells in epidermodysplasia verruciformis skin lesions, is a characteristic feature of epidermodysplasia verruciformis.
Chronic sun-exposure coupled with immunologic defects in patients with epidermodysplasia verruciformis is likely to induce mutations of the tumor suppressor gene protein (p53), leading to the development of malignant skin cancer in adult patients.
UV-B–induced local immunosuppression on the skin of patients with epidermodysplasia verruciformis is known to be related to overproduction of immunosuppressive cytokines, such as tumor necrosis factor-alpha (TNF-a), transforming growth factor-beta (TGF-b), interleukin 4, and interleukin 10, as well as excessive formation of cis- urocanic acid.
Studies have implicated a defect within keratinocytes. The activity of Langerhans cell antigen presentation appears normal in epidermodysplasia verruciformis, thus suggesting other cells cause immunotolerance to epidermodysplasia verruciformis–associated HPVs.
Androphy EJ, Dvoretzky I, Lowy DR. X-linked inheritance of epidermodysplasia verruciformis. Genetic and virologic studies of a kindred. Arch Dermatol. 1985 Jul. 121(7):864-8. [Medline].
Gober MD, Rady PL, He Q, Tucker SB, Tyring SK, Gaspari AA. Novel homozygous frameshift mutation of EVER1 gene in an epidermodysplasia verruciformis patient. J Invest Dermatol. 2007 Apr. 127(4):817-20. [Medline].
Patel T, Morrison LK, Rady P, Tyring S. Epidermodysplasia verruciformis and susceptibility to HPV. Dis Markers. 2010. 29(3-4):199-206. [Medline].
Toyoda H, Ido M, Nakanishi K, Nakano T, Kamiya H, Matsumine A, et al. Multiple cutaneous squamous cell carcinomas in a patient with interferon gamma receptor 2 (IFN gamma R2) deficiency. J Med Genet. 2010 Sep. 47(9):631-4. [Medline].
Yoshida R, Kato T, Kawase M, Honda M, Mitsuishi T. Two sisters reveal autosomal recessive inheritance of epidermodysplasia verruciformis: a case report. BMC Dermatol. 2014 Jul 21. 14(1):12. [Medline]. [Full Text].
Sun XK, Chen JF, Xu AE. A homozygous nonsense mutation in the EVER2 gene leads to epidermodysplasia verruciformis. Clin Exp Dermatol. 2005 Sep. 30(5):573-4. [Medline].
Lazarczyk M, Pons C, Mendoza JA, Cassonnet P, Jacob Y, Favre M. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med. 2008 Jan 21. 205(1):35-42. [Medline].
McDermott DF, Gammon B, Snijders PJ, et al. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation. Pediatr Dermatol. 2009 May-Jun. 26(3):306-10. [Medline].
Crequer A, Troeger A, Patin E, Ma CS, Picard C, Pedergnana V, et al. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest. 2012 Sep. 122 (9):3239-47. [Medline].
Crequer A, Picard C, Patin E, D'Amico A, Abhyankar A, Munzer M, et al. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS One. 2012. 7 (8):e44010. [Medline].
Li SL, Duo LN, Wang HJ, Dai W, Zhou EH, Xu YN, et al. Identification of the LCK mutation in an atypical epidermodysplasia verruciformis family with T cell defects and virus-induced squamous cell carcinoma. Br J Dermatol. 2016 Apr 18. [Medline].
Jacobelli S, Laude H, Carlotti A, Rozenberg F, Deleuze J, Morini JP, et al. Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. Arch Dermatol. 2011 May. 147(5):590-6. [Medline].
Zavattaro E, Azzimonti B, Mondini M, et al. Identification of defective Fas function and variation of the perforin gene in an epidermodysplasia verruciformis patient lacking EVER1 and EVER2 mutations. J Invest Dermatol. 2008 Mar. 128(3):732-5. [Medline].
Azzimonti B, Mondini M, De Andrea M, et al. CD8+ T-cell lymphocytopenia and lack of EVER mutations in a patient with clinically and virologically typical epidermodysplasia verruciformis. Arch Dermatol. 2005 Oct. 141(10):1323-5. [Medline].
de Oliveira WR, Rady PL, Grady J, et al. Polymorphisms of the interleukin 10 gene promoter in patients from Brazil with epidermodysplasia verruciformis. J Am Acad Dermatol. 2003 Oct. 49(4):639-43. [Medline].
Kao G, et al. Cutaneous carcinogenesis: Etiologic Factors-Viruses. Miller S, Mahoney M, eds. Cutaneous Oncology: Pathophysiology, Diagnosis, and Treatment. London, England: Blackwell Science; 1997. 148-157.
Vu J, Wallace GR, Singh R, et al. Common variable immunodeficiency syndrome associated with epidermodysplasia verruciformis. Am J Clin Dermatol. 2007. 8(5):307-10. [Medline].
Morrison C, Eliezri Y, Magro C, Nuovo GJ. The histologic spectrum of epidermodysplasia verruciformis in transplant and AIDS patients. J Cutan Pathol. 2002 Sep. 29(8):480-9. [Medline].
Berthelot C, Dickerson MC, Rady P, et al. Treatment of a patient with epidermodysplasia verruciformis carrying a novel EVER2 mutation with imiquimod. J Am Acad Dermatol. 2007 May. 56(5):882-6. [Medline].
Kunishige JH, Hymes SR, Madkan V, et al. Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J Am Acad Dermatol. 2007 Nov. 57(5 Suppl):S78-80. [Medline].
Majewski S, Skopinska M, Bollag W, Jablonska S. Combination of isotretinoin and calcitriol for precancerous and cancerous skin lesions. Lancet. 1994 Nov 26. 344(8935):1510-1. [Medline].
Partridge ME, Pariser RJ. Ocular and cutaneous squamous cell carcinoma in an African American man with epidermodysplasia verruciformis resulting in blindness and death. J Am Acad Dermatol. 2003 Nov. 49(5 Suppl):S262-4. [Medline].
de Koning M, Struijk L, Feltkamp M, ter Schegget J. HPV DNA detection and typing in inapparent cutaneous infections and premalignant lesions. Methods Mol Med. 2005. 119:115-27. [Medline].
Nuovo GJ, Ishag M. The histologic spectrum of epidermodysplasia verruciformis. Am J Surg Pathol. 2000 Oct. 24(10):1400-6. [Medline].
Anadolu R, Oskay T, Erdem C, Boyvat A, Terzi E, Gurgey E. Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. J Am Acad Dermatol. 2001 Aug. 45(2):296-9. [Medline].
Gubinelli E, Posteraro P, Cocuroccia B, Girolomoni G. Epidermodysplasia verruciformis with multiple mucosal carcinomas treated with pegylated interferon alfa and acitretin. J Dermatolog Treat. 2003 Sep. 14(3):184-8. [Medline].
Majewski S, Jablonska S. Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancer of the skin. Arch Dermatol. 1995 Nov. 131(11):1312-8. [Medline].
Hoffner MV, Camacho FM. Surgical treatment of epidermodysplasia verruciformis. Dermatol Surg. 2010 Mar. 36(3):363-7. [Medline].
Mitsuishi T, Kawana S, Kato T, Kawashima M. Human papillomavirus infection in actinic keratosis and bowen's disease: comparative study with expression of cell-cycle regulatory proteins p21(Waf1/Cip1), p53, PCNA, Ki-67, and Bcl-2 in positive and negative lesions. Hum Pathol. 2003 Sep. 34(9):886-92. [Medline].
Stetsenko GY, McFarlane RJ, Chien AJ, et al. Subungual Bowen disease in a patient with epidermodysplasia verruciformis presenting clinically as longitudinal melanonychia. Am J Dermatopathol. 2008 Dec. 30(6):582-5. [Medline].