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Epidermodysplasia Verruciformis

  • Author: Anthony A Gaspari, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Jun 08, 2016
 

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,[5] sporadic, sex-linked, and autosomal dominant inheritance have been described. In those cases of autosomal recessive inherence, there may be a history of consanguinity in the parents of the afflicted individual. In those cases of atypical inheritance, there may be an association with chronic lymphopenias. Regardless of the mode of inheritance, the phenotype of 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, which reflects the high-risk nature of the HPV infection. Skin cancers initially appear on sun-exposed areas, such as the face, neck, chest, and arms, reflecting the role of ultraviolet light and HPV infection in the promotion of skin cancer development. Patients with epidermodysplasia verruciformis are usually infected with multiple types of HPV, including common types that affect individuals without epidermodysplasia verruciformis (eg, HPV types 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, 6] 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.[7] 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.[8]  

Sporadic reports have described patients with the epidermodysplasia verruciformis phenotype who exhibit mutations in other genes. In 2012, two siblings who were homozygous for a mutation that created a stop codon in the Ras homolog gene family member H (RHOH) gene exhibited an epidermodysplasia verruciformis phenotype and their T cells exhibited impaired T-cell receptor (TCR) signaling.[9] A report also described a 19-year-old with an autosomal recessive MST1 (or STK4, serine/threonine kinase 4) deficiencyf8b} who exhibited the epidermodysplasia verruciformis phenotype as well as a global immune deficiency with susceptibility to other bacterial and viral infections.[10] MST1 deficiency leads to naive T-cell lymphopenia and an impaired egress of mature T lymphocytes from the thymus to secondary lymphoid organs, associated with an impaired chemotactic response to several chemokines, including the CCR7 ligands CCL19 and CCL21.[10] Lastly, a report describes three siblings who lacked EVER1/EVER2 mutations and exhibited atypical epidermodysplasia verruciformis, but who exhibited a homozygous splicing deficiency in the gene encoding LCK (lymphocyte specific kinase), resulting in a deletion of three exons of this gene.[11] These three siblings exhibited T-cell defects and epidermodysplasia verruciformis phenotype, including skin cancers.

These reports indicate that there are multiple genetic defects that can be associated with an epidermodysplasia verruciformis phenotype, and that genes resulting in T-cell defects play a permissive role in allowing the epidermodysplasia verruciformis‒associated HPV to cause skin lesions.

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.[12] In cases of the acquired epidermodysplasia verruciformis phenotype, such as HIV infection or organ transplantation, the status of EVER1 or EVER2 has not been evaluated. Whether these patients harbor previously silent mutations, epigenetic changes, or splice variants of EVER1 or EVER2 is not known, but it is clear that in these cases, global immune suppression allows the phenotype to develop. 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.[13] 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.[14]

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. In classic, autosomal recessive epidermodysplasia verruciformis, the immune defect is very specific, as these patients do not exhibit global defects in cell-mediated immunity, and there is no evidence that there are any defects in controlling other types of viral infections or bacterial or fungal challenges. 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.[15]

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.[16]

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.[17, 18, 19, 20]

Renal transplant recipients and immunosuppressed patients have an increased risk of developing lesions of epidermodysplasia verruciformis.[8]

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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,[21] and Latin America.

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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Prognosis

Epidermodysplasia verruciformis tumors evolve progressively, from childhood through adolescence, into adulthood. Fatality due to metastasizing invasive squamous cell carcinoma arising in conjunctiva has occasionally been reported.[22]  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.

 

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Patient Education

For excellent patient education resources, visit eMedicineHealth's Skin Conditions and Beauty Center and Cancer Center. Also, see eMedicineHealth's patient education articles Warts, Skin Cancer, and Skin Biopsy.

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Contributor Information and Disclosures
Author

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, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

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

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

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

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

Disclosure: Nothing to disclose.

Additional Contributors

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, International Society of Dermatopathology

Disclosure: Nothing to disclose.

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: Women's Dermatologic Society, American Contact Dermatitis Society, Medical Dermatology Society, Dermatology Foundation, Alpha Omega Alpha, American Academy of Dermatology

Disclosure: Nothing to disclose.

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, American Academy of Dermatology

Disclosure: Nothing to disclose.

References
  1. 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].

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

  3. Patel T, Morrison LK, Rady P, Tyring S. Epidermodysplasia verruciformis and susceptibility to HPV. Dis Markers. 2010. 29(3-4):199-206. [Medline].

  4. 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].

  5. 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].

  6. 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].

  7. 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].

  8. 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].

  9. 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].

  10. 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].

  11. 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].

  12. 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].

  13. 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].

  14. 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].

  15. 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].

  16. 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.

  17. 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].

  18. 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].

  19. 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].

  20. 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].

  21. 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].

  22. 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].

  23. 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].

  24. Nuovo GJ, Ishag M. The histologic spectrum of epidermodysplasia verruciformis. Am J Surg Pathol. 2000 Oct. 24(10):1400-6. [Medline].

  25. 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].

  26. 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].

  27. 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].

  28. Hoffner MV, Camacho FM. Surgical treatment of epidermodysplasia verruciformis. Dermatol Surg. 2010 Mar. 36(3):363-7. [Medline].

  29. 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].

  30. 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].

 
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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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