eMedicine Specialties > Dermatology > Viral Infections

Epidermodysplasia Verruciformis

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
Coauthor(s): Susannah E McClain, MD, Resident Physician, Department of Dermatology, University of Maryland School of Medicine; Anthony A Gaspari, MD, Professor, Department of Dermatology, University of Maryland School of Medicine
Contributor Information and Disclosures

Updated: Dec 16, 2009

Introduction

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 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.

Pathophysiology

The pathophysiology of epidermodysplasia verruciformis is linked to defective cell-mediated immunity, with elucidation of mutations in EVER1 and EVER2 genes (band 17q25).^2,3 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.⁴ 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.⁵
 
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. 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.⁶ 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.⁷

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.⁸

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.⁹
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.^10,11,12,13

Renal transplant recipients and immunosuppressed patients have an increased risk of developing lesions of epidermodysplasia verruciformis.⁵

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,¹⁴ 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-linked¹ 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%.

Clinical

History

• 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.

Physical

• 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.
• 
  

  

  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.

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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.

• 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.
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  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).

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  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).

• 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.
• 
  

  

  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.

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  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.

• Cutaneous lesions induced by EV-HPVs vary from flesh-colored warts (verruca vulgaris) to red, reddish-brown, and brown plaques.

Causes

• 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.¹ A clear mode of inheritance is not evident in all cases.
  • Pathogenic mutations in 2 adjacent genes, EVER1 and EVER2, have been identified.^2,3
  • 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.
  • Lesions of epidermodysplasia verruciformis have been associated with common variable immunodeficiency and graft versus host disease.⁶

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