DEFINITION
Epidermodysplasia Verruciformis (EV), also called Lewandowsky-Lutz dysplasia, is a rare inherited genodermatosis characterized by chronic infection with Human Papillomavirus leading to polymorphous cutaneous lesions and high risk of developing non-melanoma skin cancers. The exact prevalence of EV is unknown; more than 200 cases have been reported in the literature so far.
(Acquired epidermodysplasia verruciformis, 2009)
EPIDEMIOLOGY
The disease usually manifests during infancy (7.5% of cases), childhood (61.5% of cases) or puberty (22% of cases), with the development of various types of flat, wart-like lesions and confluent plaques on the skin, especially on dorsal hands, extremities, face and neck. EV lesions may progress into verrucous plaques and nodules, or they may transform into invasive Squamous-cell carcinoma, most commonly between the ages of 20 and 40 years. Most squamous cell carcinomas remain local, metastases are uncommon.
(Development of Aggressive Squamous Cell Carcinoma in Epidermodysplasia Verruciformis Associated with Human Papillomavirus Type 22b)
The clinical course of EV is protracted. As the disease progresses, some lesions disappear, while new ones may appear on other areas of the body. The rate of appearance of new lesions varies considerably.
Black-skinned patients have a much lower incidence of skin cancer.
(Epidermodysplasia verruciformis in Nigerians, 1979)
SYMPTOMS
The disease is characterized by a progressive development of hyperpigmented or hypopigmented flat wart-like papules, irregular reddish brown plaques, seborrheic keratosis-like lesions and Tinea Versicolor like macules on the trunk, neck, face, dorsal hands and feet (sun-exposed skin). Thick visible warts appear all over the body as well as on the inside of the skin.
The skin becomes thick and hardened and as old skin dies new skin is created.
The hands and feet, the extremities, are enlarged and it is difficult to use them. Hands and feet have been described as looking like contorted, yellow-brown branches extending up to 3 feet.
Skin looks like tree bark or tree roots, hence the name Tree-Man Disease or Tree-Man Syndrome (TMS).
(Epidermodysplasia verruciformis: clinical presentation with varied forms of lesions, 2011)
DIAGNOSIS
Diagnosis of EV should be suspected in the clinical setting of numerous verrucous lesions or when lesions are resistant to appropriate therapy. It is based on clinical and histological findings. Skin biopsy shows verruca plana-like lesions with mild hyperkeratosis, hypergranulosis and acanthosis of the epidermis. Keratinocytes of the upper epidermal layers are enlarged with perinuclear vacuolization and a typical blue-gray pallor.
(Acquired Epidermodysplasia Verruciformis Due to Multiple and Unusual HPV Infection Among Vertically-Infected, HIV-Positive Adolescents in Zimbabwe, 2012)
HPVs can be detected in keratinocytes using in situ hybridization or immunohistochemistry with anti-HPV antibodies on formalin-fixed skin tissue specimens. Typing can also be performed by polymerase chain reaction on fresh or frozen tissue specimens.
(Detection of high-risk human papillomavirus subtypes in cervical glandular neoplasia by in situ hybridization, 2013)
EVER1 and EVER2 mutational analysis can be evaluated using single-strand conformation polymorphism analysis, to screen polymerase chain reaction fragments specific to exons for mutation(s) of the EVER1 and EVER2 genes, in a DNA sample from leukocytes.
(Homozygosity for the c.917A → T (p.N306l) Polymorphism in the EVER2/TMC8 Gene of Two Sisters with Epidermodysplasia Verruciformis Lewandowsky-Lutz Originally Described by Wilhelm Lutz, 2011)
Defective cell-mediated immunity can be detected by the following studies:
Keratinocytes isolated from premalignant lesions of patients with EV with HPV type 8 genomes show inhibition to natural cell-mediated cytotoxicity by normal peripheral blood mononuclear cells, whereas normal keratinocytes do not.
(Natural cell-mediated cytotoxicity of peripheral blood lymphocytes against target cells transfected with epidermodysplasia verruciformis-specific human papillomavirus type 8 L1 DNA sequences, 2004)
Patients with mixed HPV or HPV type 3 or HPV 5 infection may demonstrate cutaneous anergy to locally applied contact sensitizers, such as dinitrochlorobenzene.
(T cell defect in patients with epidermodysplasia verruciformis due to human papillomavirus type 3 and 5, 1981)
A normal number of antigen-presenting Langerhans cells are found in patients with EV. However, the possibility of a genetically determined defective functionality of these cells, leading to abnormal presentation and recognition of HPV antigens, has been considered.
(Langerhans cells in epidermodysplasia verruciformis, 1987)
PATHOGENESIS
EV can be caused by loss-of-function mutations in either of the 2 adjacent genes EVER1/TMC6 or EVER2/TMC8, which are located on chromosome 17 (17q25.3) coding for membrane proteins that form a complex with the Zinc transporter protein ZnT-1 in the endoplasmic reticulum (ER) membrane of keratinocytes.
(The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections, 2009)
(Lack of EVER2 Protein in Two Epidermodysplasia Verruciformis Patients with Skin Cancer Presenting Previously Unreported Homozygous Genetic Deletions in the EVER2 Gene, 2012)
The mutations in these genes lead to susceptibility to infection with specific HPV subtypes belonging to the beta genus, including HPV5, 8, 9, 10, 12, 14, 15, 17, 19-25, 36-38, 47 and 49, which are ubiquitous and harmless to healthy individuals. More than 30 EV-HPVs (HPV5 and HPV8 are found in 80% of cases) have been identified in the cutaneous lesions. Patients with EV are usually infected with multiple types of HPV, including common types that affect individuals without EV (eg, HPV type 3 and 10) and those unique to EV, the so called epidermodysplasia verruciformis–associated HPVs (EV-HPVs).
(Epidermodysplasia verruciformis and susceptibility to HPV, 2010)
(Seroreactivity of 38 Human Papillomavirus Types in Epidermodysplasia Verruciformis Patients, Relatives, and Controls, 2010)
(Epidermodysplasia verruciformis associated with HPV 10, 2013)
PATIENT RISK FACTORS
Genetic
Research has shown genetically predisposed deficiencies in cutaneous immunity leave EV patients vulnerable to persistent HPV infection. Mutations in the family of genes, called EVER genes, codifye for proteins whose deficiencies are responsible for these conditions. In most cases, transmission is autosomal recessive but sex linkage and autosomal dominant inheritance patterns have also been reported.
(Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses, 2006)
(Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation, 2009)
Acquired
Different diagnosis include squamous cell carcinoma, acrokeratosis verruciformis, tinea versicolor, and generalized verrucosis of other origin. In addition, an acquired epidermodysplasia verruciformis-like syndrome has been described in patients with impaired cell-mediated immunity, mainly HIV infected subjects and with CD8 T-cell lymphocytopenia or graft versus host disease.
(Epidermodysplasia verruciform-like Lesions in an HIV patient, 2009)
(Epidermodysplasia Verruciformis Associated with Natural Killer/T Cell Lymphoma, 2010)
(Acquired Epidermodysplasia Verruciformis in a Patient With Congenital HIV Infection, 2013)
(Acquired Epidermodysplasia Verruciformis in a Child with the Human Immunodeficiency Virus, 2013)
COMPLICATIONS
About 30 to 60% of patients with EV develop non-melanoma skin cancers, especially squamous cell carcinomas (in situ or invasive), during the fourth or fifth decades of life, mainly on sun-exposed areas, such as face, neck, chest and arms.
UV-B exposure, UV-A exposure, and x-ray irradiation should be avoided because these therapies usually promote more aggressive skin cancers. The prognosis is favourable since skin tumors appear progressively and metastases are uncommon.
(Human papillomavirus infection and UV exposure as epidermoid inclusion cyst risk factors in a patient with epidermodysplasia verruciformis?, 2009)
EV may be a risk factor also for neoplastic conditions as Bowen's disease of skin.
(Epidermodysplasia verruciformis with keratoacanthoma, Bowen's disease and squamous cell carcinoma: isolation of high-risk types of HPV 5 and unknown type of human papillomavirus, 2008)
THERAPY
No therapy for EV is definitive. Treatments of EV include preventive measures, the most important of which are strict sun avoidance and protection, beginning as soon as the diagnosis is made. Described treatment modalities include cryotherapy, topical imiquimod and 5-fluorouracil, systemic retinoids, interferon alpha, and 5-aminolevulinic acid photodynamic therapy.
Surgical excision is the treatment of choice for Squamous cell carcinomas. For localized multiple malignant lesions, autotransplantation of skin from uninvolved areas has been reported with success in preventing further development of cancer.
(Surgical Treatment of Epidermodysplasia Verruciformis, 2010)
(Autosomal dominant epidermodysplasia verruciformis: A clinicotherapeutic experience in two cases, 2010)
(Successful symptomatic treatment of epidermodysplasia verruciformis with imiquimod 5% cream, 2010)
(Sustained clinical resolution of acquired epidermodysplasia verruciformis in an immunocompromised patient after discontinuation of oral acitretin with topical imiquimod, 2013)
(Acquired epidermodysplasia verruciformis: a comprehensive review and a proposal for treatment, 2013)
