Verruciform epidermodysplasia B07.x

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

generalized verrucosis; Lewandowsky-Lutz syndrome

History
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Lewandowsky and Lutz, 1922

Definition
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Rare, hereditary, HPV-induced (oncogenic and non-oncogenic human papillomaviruses) genodermatosis with a tendency to form generalized wart infections and non-melanoma skin cancers in about 50% of patients.

Pathogen
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Human papilloma viruses, especially HPV types 5, 8, 9, 12, 14, 15, 17, 19, 20, 21-25, 36, 38, 47, 50.

Etiopathogenesis
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Causally discussed is the autosomal recessive (X-linked) inherited mutation of the EVER1 gene (TMC6 gene) (EVER = acronym for Epidermodysplasia Verruciformis Endoplasmatic Reticulum Gene) or the EVER2 gene (TMC8 gene), both of which are mapped side by side on gene locus 17q25. These mutations lead to a disruption of integral membrane proteins of the endoplasmatic reticulum and increase the sensitivity to infection with human papillomavirus.

TMC6 encodes the "transmembrane channel-like protein 6", TMC8 the "transmembrane channel-like protein 8". Both proteins cooperatively form a complex with the zinc transporter 1 (SLC30A1). This complex is located in the endoplasmic reticulum, but also in the Golgi apparatus. It has been shown that zinc is a necessary cofactor for many viral proteins and that the biological activity of the transcription products of TMC6/TMC8 can reduce the availability of zinc for foreign proteins (i.e. viral proteins) and thus prevent viral growth and spread of the viruses. The mutations lead to inactivation of these integral membrane proteins and increase susceptibility to infection with human papilloma viruses (types 3, 5a, 5b, 8-10, 12, 14, 15, 17, 19-21, 23-26, 37, 38, 47 and others). In about 30% of the cases, familial occurrence is described.

To what extent polymorphisms of the interleukin-10 gene promoter, which lead to a reduced production of this cytokine, are etiopathogenetically significant remains unclear. Interleukin 10 induces a downregulation of proinflammatory cytokines such as TNF-alpha, IL-1, IL-6 (possible explanation for the specific tolerance to HPV viruses in EV).

Manifestation
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Congenital (8-10%), in infancy or childhood (50-70%), during puberty (10-25%).

Localization
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Skin areas exposed to light, such as the forehead, ears, back of the hands, but also palms of the hands and soles of the feet.

Clinical features
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Disseminated sowing up to 1.0 cm in size, yellowish or yellow-brown, smooth or warty, papular or plaque-like papillomas which occur in localized or beet-like aggregation. They are often combined with(pityriasis versicolor-like) pigment spots. Diagnostic criteria:

  • Occurrence of disseminated skin lesions on the trunk, extremities and face, resembling mainly verrucae planae but also flat verrucae seborrhoicae.
  • In 25-30% of cases, mainly in the light-exposed areas, malignant transformation and development of Bowen's disease or Bowen's carcinoma occurs (Shruti F et al. 2017).
  • The general condition of the patients is good.

Histology
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Depending on the bioptate localization and the duration of the disease, different histological images may be available. In advanced stages, irregularly configured acanthotic surface epithelium with different hypergranulosis and distinct orthhyperkeratosis are visible. Sometimes swollen keratinocytes with fine-vacuolar cytoplasm, cell nuclei of different sizes, sometimes also blistered. In the dermis unspecific, mostly perivascular round cell infiltrates.

Complication(s)
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Carcinomatous degeneration (often from the age of 30) depending on the HPV type and other factors (UV exposure, underlying diseases). In larger studies (147 patients) about 1/3 of the patients developed carcinomas after 24 years of illness.

Therapy
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A causal therapy is not known. Careful clinical monitoring is mandatory. Regular removal of suspicious lesions by curettage, laser or cryosurgery.

Consistent light protection is required to avoid the additive carcinogenic UV effect.

Positive therapeutic effects could be achieved by long-term therapy with isotretinoin (initial 70mg/day, permanent 0.3mg/kgKG) (Troyanova-Slavkova S et al. 2018).

External therapy
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  • External therapy attempts with ointments containing vitamin A acid, even under occlusion, are usually unsuccessful.
  • In a single case study a good effect could be achieved with Imiquimod (5% Imiqimod cream 2-3 times/week over 12 weeks).

Radiation therapy
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Successful therapy trials with photodynamic therapy (off-label use) are described on the basis of individual case reports.

Internal therapy
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Therapy trials with retinoids such as acitretin (neotigason) starting with 0.5-1 mg/kg bw/day and after improvement with 0.3-0.5 mg/kg bw/day and interferons ( interferon alfa-2a 1-3 times/week 1-3 million IU s.c. or peginterferon alfa-2b 1 μg/kg bw/week s.c.) are described and lead to an improvement of the clinical picture, but not to a complete healing. Remissions after discontinuation of therapy.

Temporary success according to case studies: trial with cimetidine (Tagamet) 40 mg/day/kg bw.

Operative therapie
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Excision for suspected carcinoma.

Aftercare
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Regular dermatological checks, as malignant degeneration can occur.

Note(s)
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Currently unanswered is the question of the extent to which the combination with primary lymphedema represents a separate entity.

Literature
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  1. Alpsoy E et al (2002) Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease? Br J Dermatol 146: 503-507
  2. Boxman IL et al (2001) Association between epidermodysplasia verruciformis-associated human papillomavirus DNA in plucked eyebrow hair and solar keratoses. J Invest Dermatol 117: 1108-1112
  3. Carre D et al (2003) Epidermodysplasia verruciformis in a patient with HIV infection: no response to highly active antiretroviral therapy. Int J Dermatol 42: 296-300
  4. De Oliveira W et al (2003) Clinical aspects of epidermodysplasia verruciformis. J Eur Acad Dermatol Venereol 17: 394-398
  5. Feltkamp MC et al (2003) Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 63: 2695-2700
  6. Heratizadeh A et al (2010) Successful symptomatic therapy of an epidermodysplasia verruciformis with Imiquimod 5% cream. Dermatologist 61: 1052-1055
  7. Kreuter A et al (2008) A human papillomavirus-associated disease with disseminated warts, depressed cell-mediated immunity, primary lymphedema, and anogenital dysplasia. Arch Dermatol 144: 366-372
  8. Lewandowsky F, Lutz W (1922) A case of skin disease (epidermodysplasia verruciformis) not yet described. Arch Derm Syph (Berlin) 141: 193-202
  9. Masini C et al (2003) Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals. Arch Dermatol 139: 890-894
  10. Majewski S, Jablonska S (1992) Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancers: the role of local immunosurveillance. On J Med Sciences 304: 174-179
  11. Majewski S et al (2002) Do epidermodysplasia verruciformis human papillomaviruses contribute to malignant and benign epidermal proliferations? Arch Dermatol 138: 649-654
  12. Pereira de Oliveira WR et al (2003) Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis. J Dermatol 30: 203-209
  13. Ramoz N et al (2002) Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 32: 579-581
  14. Roncalli W et al (2003) Polymorphisms of the interleukin 10 gene promoter in patients from Brazil with epidermodysplasia verruciformis. J Am Acad 49: 639-643
  15. Rübben A (2011) Clinical algorithm for the therapy of cutaneous, extragenital HPV-induced warts. Dermatologist 62: 6-16
  16. Shruti S et al(2017) Epidermodysplasia verruciformis: three case reports and a brief review.
    Acta Dermatovenerol Alp Pannonica Adriat 26:59-61.
  17. Szeimies RM et al (2002) Non-oncologic indications for ALA-PDT. J Dermatolog Treat 13(Suppl 1): S13-18
  18. Troyanova-Slavkova S et al (2018) Low-dose prophylactic oral isotretinoin treatment for 18 years in a patient with epidermodysplasia verruciformis and numerous squamous cell carcinomasDermatologist
    69):1033-1038.

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 29.10.2020