Epidermodysplasia verruciformis is an HPV–associated skin lesion characterized by multiple warty rashes. The main foci are located on the face, hands, forearms, shins, soles, in the perineum. The elements are represented by flat warts covered with a horny mass of gray-black color. Diagnostic criteria are histological examination data, a positive PCR test for etiologically significant serotypes of papillomavirus. Treatment consists in general and local interferon therapy, removal of wart-like elements using cryodestruction, laser, surgical method.
Warty (verruciform) Levandowski-Lutz epidermodysplasia is a papillomavirus infection of the skin that develops in genetically predisposed individuals. The disease is also known as disseminated (generalized) verrucosis, congenital dyskeratotic warts. Skin pathology was studied in detail by dermatologists F. Levandovsky and W. Lutz in 1922. To date, more than 200 cases of the disease have been described. Verrucose elements appear already in childhood or adolescence, persist throughout life, have a high potential for malignancy, which determines the relevance of epidermodysplasia verruciformis in clinical dermatology.
Warty epidermodysplasia is a genodermatosis of papillomavirus etiology. In most patients, defects are detected in the EVER1 and EVER2 genes located on the long arm of chromosome 17 and encoding endoplasmic transmembrane proteins. Gene mutations increase the vulnerability of the skin to papillomavirus of certain serotypes.
In patients with epidermodysplasia verruciformis, about 20 types of HPV are identified, including HPV-3, 5, 8, 9, 10, 12, 14, 15, 19, 20, 21, 25, 36, 47, 49 and others (sometimes several serotypes are detected simultaneously). Approximately 80% of patients are diagnosed with HPV-5 and HPV-8, which have high oncogenic activity. Infection occurs through microtrauma, inflamed skin and mucous membranes.
Most cases of genodermatosis are sporadic, a quarter of cases have autosomal recessive transmission, sometimes autosomal dominant and X-recessive inheritance is traced. Occasionally, the disease is not hereditary, but acquired in nature, develops in patients with secondary immunodeficiency of various origins: HIV-infected, who have undergone organ transplantation and are receiving immunosuppressive therapy.
The EVER1/EVER2 genes encode proteins that form a complex with the zinc carrier protein ZnT-1 in the membrane of the endoplasmic reticulum (ER) of keratinocytes. Zinc is an important cofactor necessary for the synthesis of viral proteins, and the normal activity of the EVER1/EVER2 genes apparently prevents the papillomavirus from accessing trace element reserves in the nuclei of host cells, preventing it from replicating.
Mutational variability leads to an increase in the susceptibility of the macroorganism to HPV of the beta genus, an increase in the expression of viral genes, which is accompanied by a violation of the differentiation of epithelial cells and the appearance of disseminated flat warts. Inhibition of cellular immunity plays a significant role in pathogenesis, but at the moment it has not been established whether it is a consequence of infection or hereditary predisposition.
The histological picture of disseminated verrucosis corresponds to that of flat warts: the epidermis is thickened, coilocytes are found in the granular layer, indicating the cytopathic effect of the virus. Characteristic of verruciform dysplasia is the presence of cells with an increased volume of pale cytoplasm.
Taking into account the type of HPV and the prognosis for wart malignancy, two forms of epidermodysplasia verruciformis are distinguished: simple and dysplastic:
- simple – is a disseminated proliferation of benign flat papules, mainly on the neck and body. Rashes are associated with HPV-3 and HPV-10.
- dysplastic – warty formations appear in early childhood on exposed parts of the body, have a high oncogenic potential. HPV types 5 and 8 are called.
The manifestation of the disease can be observed in infancy (7.5%), preschool childhood (61.5%), puberty (22%), adolescence. Skin lesions are polymorphic. The elements are flat warty hypo- and hyperpigmented papules, irregular plaques, foci of hyperkeratosis, dyschromia. Formations reach the size of a pea (3-5 mm), but there are also larger elements. Their color may correspond to the color of ordinary skin or be pinkish, reddish-brown. In addition to verrucose elements, there are “coffee” pigment spots, lentigo.
More often, rashes are located on open areas of the skin: the face, neck, back of the hands, forearms, shins. Sometimes the axillary area, the perineal area, and labia are affected. Alopecia may occur on areas of the scalp affected by rashes. The elements tend to merge and form large conglomerates covered with a grayish-black horny mass. In neglected cases, overgrown warts become like tree branches – hence the colloquial name of the pathology “arboreal man syndrome”.
In oncodermatology, verruciform epidodysplasia refers to precancerous conditions. Papillomavirus genodermatosis can be complicated by Bowen’s disease, bovenoid papulosis. Approximately 25-30% (according to some data, 60%) of patients aged 30-40 years develop non–melanoma skin cancer, more often squamous cell carcinoma, sometimes basal cell carcinoma.
Skin cancer associated with verruciform epidodysplasia is characterized by perineural and lymphatic invasion, aggressive clinical course, distant metastasis, leading to death.
The diagnosis of verruciform epidemiodysplasia is made on the basis of clinical data confirmed by the results of laboratory tests. Consultations of a dermatovenerologist and an immunologist are necessary. To verify the pathology is carried out:
- Biopsy of the cutaneous elements. Sampling and histological examination of samples reveals typical changes: mild hyperkeratosis, hypergranulosis, acanthosis, epidermis, perinuclear vacuolization of keratinocytes, pallor of the cytoplasm.
- Detection of the pathogen. The PCR method allows not only to detect papillomavirus in tissue material, but also to type it, which is extremely important for predicting the risk of malignancy. In addition, methods of fluorescent hybridization and immunohistochemistry are used to detect the pathogen.
- Genetic counseling. Medical and genetic counseling of patients and their close relatives is necessary to calculate the probability of having children with a similar pathology.
Differential diagnosis should be carried out with other skin diseases accompanied by generalized warty rashes. With the help of molecular genetic and morphological studies, the following are excluded:
- viral warts;
- genital warts;
- Hopf ‘s verruciform acrokeratosis;
- follicular vegetative dyskeratosis (Darye’s disease);
- congenital poikiloderma with warty hyperkeratosis;
- pigmented xeroderma;
- other genodermatoses.
Methods of gene therapy of congenital dyskeratotic warts have not been developed. To date, only medicines and surgical methods are available to reduce the manifestations of warty epidermodysplasia with temporary success. The optimal therapy, its duration and frequency of courses are selected by a dermatologist. In practice , they are used:
Systemic and topical medications. Inside, immunomodulators, vitamin A, retinoids, interferon preparations are prescribed. Externally, ointments with keratolytic action, local retinoids, 5-fluorouracil ointment are used. The positive effects of photodynamic therapy with 5-aminolevulinic acid are described.
Destruction of elements by physical methods. To achieve an acceptable cosmetic and functional result, warty growths are removed using cryotherapy, laser coagulation, electrocoagulation, surgical excision. As a rule, repeated repeated procedures for the destruction of warts are required.
Prognosis and prevention
Currently, there are no methods for the complete cure of verruciform epidermodysplasia. Despite periodic medication courses and surgical removal of warty elements, relapses cannot be avoided. Even with a benign course, the disease significantly worsens the quality of life.
Much attention in the management of patients with dysplastic variant of the disease is paid to the prevention of malignancy of elements. To do this, it is recommended to undergo regular dermatological screening, protect the skin from direct sunlight with clothing and SPF creams. Preventive vaccination against HPV is considered impractical, since existing vaccines do not protect against those types of HPV that cause Levandowski-Lutz verruciform epidermodysplasia.