Epidermodysplasia Verruciformis 

  • Author: Grace F Kao, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 26, 2012
 

Background

Epidermodysplasia verruciformis (EV) is a rare, inherited disorder that predisposes patients to widespread human papillomavirus (HPV) infection and cutaneous squamous cell carcinomas.[1, 2, 3, 4] Although epidermodysplasia verruciformis is most commonly inherited in an autosomal recessive manner, sporadic, sex-linked, and autosomal dominant inheritance have been described. The disease is characterized by chronic infection with HPV. Widespread skin eruptions of flat-to-papillomatous, wartlike lesions and reddish-brown pigmented plaques on the trunk, the hands, the upper and lower extremities, and the face are typical.

Malignant skin tumors (carcinomas), especially squamous cell carcinoma (in situ or invasive), develop frequently in these patients (30–70%), most commonly in sun-exposed areas starting between the ages of 20 and 40 years. Skin cancers initially appear on sun-exposed areas, such as the face, neck, chest, and arms. Patients with epidermodysplasia verruciformis are usually infected with multiple types of HPV, including common types that affect individuals without epidermodysplasia verruciformis (eg, HPV type 3 and 10) and those unique to epidermodysplasia verruciformis, the so called epidermodysplasia verruciformis–associated HPVs (EV-HPVs).

More than 30 EV-HPVs, such as types 4, 5a, 5b, 8,9, 12, 14, 15, 17, 19-25, 36-38, 47, and 50, have been identified in epidermodysplasia verruciformis lesions. Some EV-HPVs are detected in up to 20% of the non–epidermodysplasia verruciformis population, but they are only pathogenic in epidermodysplasia verruciformis patients. HPV-5 and HPV-8 have been isolated in more than 90% of epidermodysplasia verruciformis–associated squamous cell carcinomas.

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Pathophysiology

The pathophysiology of epidermodysplasia verruciformis is linked to defective cell-mediated immunity, with elucidation of mutations in EVER1 and EVER2 genes (band 17q25).[2, 5] Their gene products are integral membrane proteins localized to the endoplasmic reticulum.

Although the role of EVER1 and EVER2 genes in the pathogenesis of epidermodysplasia verruciformis remains unclear, one hypothesis is that they are involved in the control of HPV infection within keratinocytes, or they play a role in the immune response to the infection itself. Intracellular zinc homeostasis regulated by a complex of EVER proteins and zinc transporter proteins may play a role in inhibiting EV-HPV expression.[6] However, an estimated 25% of patients with epidermodysplasia verruciformis lack mutations in EVER1 and EVER2, with the genetic defect in these patients not yet elucidated.[7]

Several epidermodysplasia verruciformis variants have been described, and the majority of these cases occur in association with immunosuppression, such as HIV infection, organ transplantation, or idiopathic lymphopenia.[8] Zavattaro et al reported a rare case of an epidermodysplasia verruciformis patient who had clinical features of epidermodysplasia verruciformis but lacked the EVER1 or EVER2 mutation.[9] This patient was older at diagnosis and had no premalignant or malignant lesions upon examination. Defective Fas protein function (CD95, apoptosis receptor) was identified along with perforin gene variations, suggesting that this combination resulted in increased susceptibility to HPV infection owing to defective viral clearance.

In addition, a profound CD8+ T-cell lymphocytopenia was identified, a finding also described by Azzimonti et al in a patient who also had a clinical diagnosis of epidermodysplasia verruciformis but who lacked EVER1 or EVER2 mutations.[10]

The papillomavirus genus is a member of the Papovaviridae family. HPVs are small, nonenveloped viruses, measuring approximately 55 nm in diameter. Their icosahedral capsid is composed of 72 capsomers, with a 56,000-d major protein, which is the genus-specific antigenic determinant of the virus, and a 76,000-d minor protein. The HPV genome contains a double-stranded circular DNA of approximately 7900 base pairs, functionally divided into an early region (E) of 5-7 open reading frames E1-E7, a late region (L) of open reading frames L1 and L2, and a noncoding upstream regulatory region. The HPV types are primarily classified on the basis of their DNA homology.

Patients with epidermodysplasia verruciformis have a defective cell-mediated immune response to HPV infection. Many HPV types found in epidermodysplasia verruciformis lesions are nonpathogenic to the general population. The exact mechanism by which cancer occurs frequently in patients with epidermodysplasia verruciformis is unclear. The role of HPV in cancer development is supported by the identification of viral DNA within epidermodysplasia verruciformis–induced malignancies. Carcinogenic cofactors, such as ultraviolet B and x-ray irradiation, are probably involved in the progression from benign warts (verrucae) to cancer. Cells with early signs of malignant transformation have been found closely connected with virus-infected epidermal regions.

The exact mechanisms involved in the malignant transformation of keratinocytes in skin lesions of patients with epidermodysplasia verruciformis are still unclear. Studies have shown that interactions occur between oncogenic HPVs and antioncogene proteins, such as p53 and pRb, in cell cycle regulation, DNA repair, and the execution of programmed cell death (apoptosis).

The persistence of HPV infection in epidermodysplasia verruciformis is thought to be the result of an immunogenetic defect, which generates several cytokines capable of down-regulating cell-mediated immunity. Patients with epidermodysplasia verruciformis reportedly show an increased rate of low-production genotypes of interleukin 10 compared with control subjects. Patients with epidermodysplasia verruciformis and skin cancer are more likely to have low-production interleukin 10 genotypes than patients with benign forms of epidermodysplasia verruciformis.[11]

In epidermodysplasia verruciformis tumors, gene products transcripts of E6 and E7 (the early region of viral genes) are detected. Within the early region of the HPV genome, E6 and E7 code for major oncoproteins responsible for the oncogenic potential of HPV. These viral proteins are crucial for tumorigenesis. In cancerous lesions, the high-risk HPV types, such as HPV types 5, 8, and 47, selectively retain and express the E6 and E7 portions of the viral genome. Working together, these E6/E7 regions cause cell immortalization, or failure of programmed cell death, resulting in transformation of normal human keratinocytes into malignant cells.[12]

Both E6 and E7 are multifunctional proteins that promote cell growth via multiple mechanisms. Each has the ability to neutralize an antioncogene product, specifically p53 and pRb, that is essential for intracellular defense mechanisms against the development of neoplasms. However, the exact mechanism of carcinogenesis of E6 and E7 oncoproteins and the effects of these oncoproteins on p53 and pRb are unclear.

Failure of programmed cell death to eliminate cells with DNA damage may play an important role in malignant transformation of squamous epithelium. A decrease in UV-induced DNA repair synthesis, coupled with an oncogenic viral infection, further enhances the susceptibility toward somatic mutations and malignant transformation in patients with epidermodysplasia verruciformis.[13, 14, 15, 16]

Renal transplant recipients and immunosuppressed patients have an increased risk of developing lesions of epidermodysplasia verruciformis.[7]

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Epidemiology

Frequency

United States

The exact frequency of epidermodysplasia verruciformis is unknown.

International

The largest series of epidermodysplasia verruciformis reported in the literature includes 195 cases, mainly from Eastern Europe, Poland,[17] and Latin America.

Mortality/Morbidity

Malignant skin tumors develop during the fourth and fifth decades of life in approximately one third of patients. Epidermodysplasia verruciformis tumors are numerous, and they initially progress as noninvasive in situ carcinomas. Approximately 30-60% of patients with lesions develop invasive cancers. Most cancers remain local, and metastasis is extremely uncommon. Epidermodysplasia verruciformis tumors are locally destructive without treatment. No disease-related fatality has been reported.

Race

Epidermodysplasia verruciformis is universal and affects persons of all races.

Sex

No sexual preference is noted for epidermodysplasia verruciformis, although sex-linked[1] and autosomal dominant inheritance have been described.

Age

Patients with epidermodysplasia verruciformis typically present early in childhood with flat wartlike lesions of the dorsal hands, extremities, face, and neck. The disease manifests as a congenital form in infancy (approximately 7.5%), during childhood (61.5% in children aged 5-11 y), or at puberty (22.5%). Malignant tumors typically appear during the fourth and fifth decades of life. The reported frequency of malignant change ranges from 30-60%.

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Contributor Information and Disclosures
Author

Grace F Kao, MD  Clinical Professor of Dermatopathology, Department of Dermatology, University of Maryland School of Medicine and George Washington University Medical School; Director, Dermatopathology Section, Department of Pathology and Laboratory Medicine, Veterans Affairs Maryland Healthcare System, Baltimore, Maryland

Grace F Kao, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and International Society of Dermatopathology

Disclosure: Nothing to disclose.

Coauthor(s)

Susannah E McClain, MD  Resident Physician, Department of Dermatology, University of Maryland School of Medicine

Susannah E McClain, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Anthony A Gaspari, MD  Professor, Department of Dermatology, University of Maryland School of Medicine

Anthony A Gaspari, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American Contact Dermatitis Society, American Medical Association, Clinical Immunology Society, Dermatology Foundation, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Kathryn Schwarzenberger, MD  Associate Professor of Medicine, Division of Dermatology, University of Vermont College of Medicine; Consulting Staff, Division of Dermatology, Fletcher Allen Health Care

Kathryn Schwarzenberger, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, American Dermatological Association, Dermatology Foundation, Medical Dermatology Society, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Lester F Libow, MD  Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References
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  2. 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. Apr 2007;127(4):817-20. [Medline].

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  9. 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. Mar 2008;128(3):732-5. [Medline].

  10. 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. Oct 2005;141(10):1323-5. [Medline].

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  16. Kunishige JH, Hymes SR, Madkan V, et al. Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J Am Acad Dermatol. Nov 2007;57(5 Suppl):S78-80. [Medline].

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  21. Gubinelli E, Posteraro P, Cocuroccia B, Girolomoni G. Epidermodysplasia verruciformis with multiple mucosal carcinomas treated with pegylated interferon alfa and acitretin. J Dermatolog Treat. Sep 2003;14(3):184-8. [Medline].

  22. Majewski S, Jablonska S. Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancer of the skin. Arch Dermatol. Nov 1995;131(11):1312-8. [Medline].

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  24. 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. Sep 2003;34(9):886-92. [Medline].

  25. 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. Dec 2008;30(6):582-5. [Medline].

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Epidermodysplasia verruciformis cutaneous lesions with flat macules that vary from flesh-colored to reddish brown or brown plaques, with slightly scaly surfaces and irregular borders present on the forehead of an 8-year-old boy, who is one of the 2 sons of the epidermodysplasia verruciformis patient shown in the next image.
Verrucous or seborrheic keratosis–like lesions of epidermodysplasia verruciformis; they are commonly seen on sun-exposed skin. Lesions are present on dorsum of hands of a 34-year-old man who had 2 affected sons (previous image).
A 41-year-old white woman with a 25-year history of numerous flat warts on her bilateral upper and lower extremities. Shave biopsy of a leg papule showed findings consistent with verruca plana.
Mild acanthosis, bridging of rete ridges, prominent granular layer, and rare koilocytotic keratinocytes, as is seen in lesions of verruca plana, are present in this lesion of epidermodysplasia verruciformis (hematoxylin and eosin; X150).
Left: Photomicrograph of a precancerous, verrucous skin lesion from a patient with epidermodysplasia verruciformis depicts the characteristic microscopic features of specific cytopathic effect, that is, the presence of clear cells and an occasional enlarged, hyperchromatic, atypical nucleus (center of the field) in the epidermis. These changes are seen in human papillomavirus (HPV)-associated epithelial lesions (hematoxylin-eosin stain, original magnification X250). Right: Photomicrograph of the same skin lesion shows positive staining of keratinocytes infected with HPV type 8 (in situ hybridization, original magnification X250). Note the darker, spherical-to-ovoid shaped positive nuclear staining. These are sites of HPV DNA.
Dense deposits of human papillomavirus (HPV) DNA are demonstrated by immunostaining the skin biopsy of a warty lesion of epidermodysplasia verruciformis. Note prominent vacuolation of the cytoplasm of the infected cells (koilocytosis), typical of lesions associated with HPV infection. The darker positive staining areas are sites of HPV DNA (in situ hybridization, original magnification X450).
A photomicrograph shows an invasive well-differentiated squamous cell carcinoma, that arose in a warty lesion on sun-exposed skin of a middle-aged patient with epidermodysplasia verruciformis. Notice the atypical, neoplastic squamous cancer cells with irregular, hyperchromatic nuclei, and an occasional bizarre mitotic figure (shown near the 12-o'clock position in this field) invading into the dermis. A moderate host lymphocytic inflammatory response is present within the tumor (hematoxylin-eosin stain, original magnification X300). Squamous cell carcinoma is the most common type of skin cancer found in patients with epidermodysplasia verruciformis.
 
 
 
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