AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Epidermodysplasia verruciformis (EV) is a rare inherited disease. It is a lifelong, viral-mediated, autosomal recessive (Sex-linked¹ and autosomal dominant inheritance patterns have also been reported.) disorder affecting the skin. The disease is characterized by chronic infection with human papillomavirus (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.

The lesions may transform into malignant skin tumors (carcinomas), usually after age 30 years. Skin cancers initially appear on sun-exposed areas, such as the face and the ear lobes. Patients with EV are usually infected with multiple types of HPV, including "common" types affecting normal individuals (HPV -3,10) and those unique to EV, that are so named "EV HPVs." More than 30 EV HPVs, such as types 4, 5a, 5b, 8-9, 12, 14, 15, 17, 19-21, 23-26, 36-38, 47, and 50 have been identified in EV lesions. The EV HPVs are detected in up to 20% of the normal population, and they are only pathogenic in EV patients. HPV-5 and HPV-8 have been isolated in more than 90% of EV-associated squamous cell carcinomas.

Pathophysiology

The pathophysiology of EV is linked to defective cell-mediated immunity, with recent 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 their role in the pathogenesis of EV 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. The exact mechanism by which cancer frequently occurs in patients with EV is unclear. The role of HPV in cancer development is supported by the identification of viral DNA within EV-induced malignancies. Carcinogenic cofactors, such as ultraviolet B and x-ray irradiation, are likely involved in the progression from benign warts (verrucae) to cancer.

The papillomavirus genus is a member of the Papovaviridae family. HPVs are small, nonenveloped viruses measuring about 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 about 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 identified on the basis of their DNA homology.

Patients with EV have a defective cell-mediated immune response to HPV infection. Many of the HPV types found in EV lesions are nonpathogenic to the general population. 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 EV 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 EV is thought to be a result of an immunogenetic defect, which determines the generation of several cytokines capable of down-regulating cell-mediated immunity. It has been reported that patients with EV showed an increased rate of low-production genotypes of interleukin 10 compared with control subjects. Patients with EV and skin cancer are more likely to have low-production interleukin 10 genotypes than patients with benign forms of EV.⁴

In EV tumors, transcripts of E6 and E7 (the early region of viral genes) gene products are detected. Within the early region of the HPV genome, E6 and E7 code for the 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. Collaboratively, they cause immortalization or failure of programmed cell death, resulting in transformation of normal human keratinocytes to malignant cells.

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, which 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 disposition for somatic mutations and malignant transformation in patients with EV.

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

Frequency

United States

The exact frequency of this skin disorder is unknown.

International

The largest series reported in the literature included 195 cases, mainly in Eastern Europe, Poland, and Latin America.

Mortality/Morbidity

Malignant skin tumors develop during the fourth and fifth decades of life in approximately one third of patients. These tumors are numerous and 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. Tumors are locally destructive without treatment. No disease-related fatality has been reported.

Race

The disease is universal and affects all races.

Sex

No sexual preference is noted, although sex-linked¹ and autosomal dominant inheritance have been described.

Age

Patients typically present early in childhood with flat wart-like lesions of the dorsal hands, extremities, face, and neck. The disease manifests as a congenital form in infancy (about 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The disease usually begins in infancy or early childhood with the development of various types of warts and confluent plaques on the skin.
• The lesions may progress to form verrucous plaques and nodules, or they may transform into squamous cell carcinomas.
• The clinical course 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 EV should be suspected in the clinical setting of numerous verrucous lesions or when lesions are recalcitrant to appropriate therapy.

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 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 (see Media File 1). 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.
• 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. 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.

Causes

• EV-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 EV-associated skin cancers contain these viruses.
  • 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 EV include the following:
• • An autosomal recessive mode of inheritance is supported by the finding that, in 10% of patients with EV, it originated from 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 recently been identified.^{2, 3}
  • Major histocompatibility complex (MHC) class II alleles (DR-DQ) were recently found in a large series of patients with EV from Europe, Africa, and America.
  • Neither chromosomal abnormalities nor the relationship to any specific MHC class I antigens has been found in patients with EV.
  • The exact mechanisms involved in the keratinocytic transformation within EV skin lesions are unclear. Transcripts of the early region of viral genomes (E6 and E7 gene proteins) have been detected in EV 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 an oncogenic viral infection further enhances the disposition for somatic mutations and malignant transformation in patients with EV.
  • 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 EV skin lesions is a characteristic feature of EV.
  • Chronic sun-exposure coupled with immunologic defects in patients with EV 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 EV is known to be related to overproduction of immunosuppressive cytokines, such as tumor necrosis factor a (TNF-a), transforming growth factor b (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 EV, thus suggesting other cells cause immunotolerance to EV-associated HPVs.
  • Lesions of EV have been associated with common variable immunodeficiency and graft versus host disease.⁶

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Benign papillomas
Verruca plana

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• HPVs can be detected by in situ hybridization using anti-HPV antibodies on formalin-fixed skin tissue specimens. Unfortunately, this viral typing is not readily available on a commercial basis. Typing can also be performed by polymerase chain reaction on fresh or frozen tissue specimens.
• Defective cell-mediated immunity can be detected by the following studies:
• • Keratinocytes isolated from the premalignant lesions of patients with EV found to harbor HPV type 5 genomes show inhibition to natural cell-mediated cytotoxicity by normal peripheral blood mononuclear cells, whereas normal keratinocytes do not.
  • Patients with mixed HPV and HPV type 3 infection may demonstrate cutaneous anergy to locally applied contact sensitizers, such as dinitrochlorobenzene.
  • A normal number of antigen-presenting Langerhans cells are found in patients with EV. However, the possibility of a genetically determined defective function of these cells, leading to abnormal presentation and recognition of HPV antigens, has been considered.

Histologic Findings

Biopsy is performed for early detection of premalignant and malignant lesions and for the identification of EV-associated HPVs. The most characteristic findings are within the epidermis. The classic histologic manifestation of EV is a verruca plana–like lesion with mild hyperkeratosis and acanthosis, in which the keratinocytes contain perinuclear halos and blue-gray pallor. Perinuclear halos are a specific cytopathic effect, that is, the presence of clear cells in the granular and spinous layers with occasional enlarged, hyperchromatic, atypical nuclei, is present (see Media File 2 [left image]).

The nucleoplasm is clear, and keratohyalin granules of various sizes and shapes are present. The keratin layer is loose with a basket weave–like appearance. In premalignant tumors, the normal keratinocyte maturation is preserved. In contrast, in the malignant lesions, the normal surface maturation of keratinocytes is lost. HPV can be detected in the infected keratinocyte nuclei by in situ hybridization, particularly in the upper layers of the epidermis (see Media File 2 [right image]).

The premalignant lesions display features similar to actinic keratoses with prominent atypical, dyskeratotic cells. The cytopathic effects of viral warts are often missing, although large amounts of HPV DNA can be detected as is shown by using immunostains on a skin lesion (see Media File 3).

Invasive malignant tumors most commonly show squamous and occasionally adnexal differentiation. A well-differentiated squamous cell carcinoma seen in an EV-associated skin cancer is shown in Media File 4.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

No therapy for EV is definitive. Treatment of EV includes preventive measures, the most important of which is strict sun avoidance and protection, beginning as soon as the diagnosis is made.

• Nonsurgical therapies for the management of skin cancers include  topical imiquimod and 5-fluorouracil, systemic retinoids, interferon, and 5-aminolevulinic acid photodynamic therapy.^{7, 8, 9}
• In advanced HPV-related carcinomas, an experimental therapy involves treatment with a combination of 13-cis retinoic acid and interferon alpha or cholecalciferol analogues.¹⁰
• For localized multiple malignant lesions, autotransplantation of skin from uninvolved skin has been reported with success in preventing further development of cancers.
• UV-B exposure, UV-A exposure, and x-ray irradiation should be avoided because radiation therapy often promotes the recurrence of more aggressive skin cancers.

Surgical Care

Surgical and electrosurgical removal and cryotherapy are used in the treatment of benign and premalignant skin lesions. Surgery is also indicated for treatment of malignant lesions. If skin grafting is necessary, the graft should be from sun-protected skin.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Malignant transformation of skin lesions has been observed in more than one half of the patients followed up for 20-30 years. Malignant tumors are typically found after age 30 years, usually during the fourth and fifth decades of life.

Prognosis

• EV tumors evolve progressively, from childhood through adolescence, to adulthood.
• Fatality due to metastasizing invasive squamous cell carcinoma arising in conjunctiva has been occasionally reported.¹¹

Patient Education

• For excellent patient education resources, visit eMedicine's Warts Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Warts, Skin Cancer, and Skin Biopsy.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to perform a skin biopsy for early detection of premalignant and malignant skin lesions and for the identification of EV-associated HPVs is a pitfall.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Eruptive, polymorphic, warty papules and plaques on the lower extremities of a patient with epidermodysplasia verruciformis. Courtesy of Professor S. Jablonska and Professor S. Majewski.
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Media type:  Photo

Media file 2:  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 darker, spherical-to-ovoid shaped positive nuclear staining. These are sites of HPV DNA.
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Media type:  Photo

Media file 3:  Large amounts of human papillomavirus (HPV) DNA are demonstrated by immunostaining a 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 the sites of HPV DNA (in situ hybridization, original magnification X450).
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Media type:  Photo

Media file 4:  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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• 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].
3. Sun XK, Chen JF, Xu AE. A homozygous nonsense mutation in the EVER2 gene leads to epidermodysplasia verruciformis. Clin Exp Dermatol. Sep 2005;30(5):573-4. [Medline].
4. de Oliveira WR, Rady PL, Grady J, Hughes TK, Festa Neto C, Rivitti EA, et al. Polymorphisms of the interleukin 10 gene promoter in patients from Brazil with epidermodysplasia verruciformis. J Am Acad Dermatol. Oct 2003;49(4):639-43. [Medline].
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8. Anadolu R, Oskay T, Erdem C, Boyvat A, Terzi E, Gürgey E. Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. J Am Acad Dermatol. Aug 2001;45(2):296-9. [Medline].
9. 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].
10. Majewski S, Skopinska M, Bollag W, Jablonska S. Combination of isotretinoin and calcitriol for precancerous and cancerous skin lesions. Lancet. Nov 26 1994;344(8935):1510-1. [Medline].
11. 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. Nov 2003;49(5 Suppl):S262-4. [Medline].
12. Azzimonti B, Mondini M, De Andrea M, Gioia D, Dianzani U, Mesturini R, 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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17. Joblonska S. Epidermodysplasia verruciformis. In: Friedman RJ, ed. Skin Cancers. Philadelphia, Pa: WB Saunders; 1991:101-13.
18. Kao G, et al. Cutaneous carcinogenesis: Etiologic Factors-Viruses. In: Miller S, Mahoney M, eds. Cutaneous Oncology: Pathophysiology, Diagnosis, and Treatment. London, England: Blackwell Science; 1997:148-57.
19. Kunishige JH, Hymes SR, Madkan V, Wyatt AJ, Uptmore D, Lazar AJ, et al. Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J Am Acad Dermatol. Nov 2007;57(5 Suppl):S78-80. [Medline].
20. Lane JE, Bowman PH, Cohen DJ. Epidermodysplasia verruciformis. South Med J. Jun 2003;96(6):613-5. [Medline].
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22. Lutzner MA, Blanchet-Bardon C, Orth G. Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dermatol. Jul 1984;83(1 Suppl):18s-25s. [Medline].
23. 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].
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. Nuovo GJ, Ishag M. The histologic spectrum of epidermodysplasia verruciformis. Am J Surg Pathol. Oct 2000;24(10):1400-6. [Medline].
26. Ortak T, Uysal AC, Alagoz MS, Orbay H, Sensoz O. Epidermodysplasia verruciformis: an unusual presentation. Dermatol Surg. Feb 2006;32(2):302-6. [Medline].
27. Orth G, Favre M, Majewski S, Jablonska S. Epidermodysplasia verruciformis defines a subset of cutaneous human papillomaviruses. J Virol. May 2001;75(10):4952-3. [Medline].
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Article Last Updated: Nov 13, 2007