- Author: Anthony A Gaspari, MD; Chief Editor: Dirk M Elston, MD more...
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. 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.
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. 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.
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. 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. 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. 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. 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. 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. 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.
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.
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.
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.
The exact frequency of epidermodysplasia verruciformis is unknown.
The largest series of epidermodysplasia verruciformis reported in the literature includes 195 cases, mainly from Eastern Europe, Poland, and Latin America.
Epidermodysplasia verruciformis is universal and affects persons of all races.
No sexual preference is noted for epidermodysplasia verruciformis, although sex-linked and autosomal dominant inheritance have been described.
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%.
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. 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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