Epidermodysplasia Verruciformis Workup

  • Author: Grace F Kao, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 26, 2012
 

Laboratory Studies

  • Human papillomaviruses (HPVs) can be detected by in situ hybridization, using anti-HPV antibodies on formalin-fixed skin tissue specimens. Unfortunately, this viral typing is not readily available on a commercial basis. Typing can also be performed by polymerase chain reaction on fresh or frozen tissue specimens.[18]
  • EVER1 and EVER2 mutational analysis can be evaluated using single-stranded conformational 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.
  • Defective cell-mediated immunity can be detected by the following studies:
    • Keratinocytes isolated from premalignant lesions of patients with epidermodysplasia verruciformis with HPV type 5 genomes show inhibition to natural cell-mediated cytotoxicity by normal peripheral blood mononuclear cells, whereas normal keratinocytes do not.
    • Patients with mixed HPV or HPV type 3 infection may demonstrate cutaneous anergy to locally applied contact sensitizers, such as dinitrochlorobenzene.
    • A normal number of antigen-presenting Langerhans cells are found in patients with epidermodysplasia verruciformis. However, the possibility of a genetically determined defective functionality of these cells, leading to abnormal presentation and recognition of HPV antigens, has been considered.
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Histologic Findings

Biopsy is performed for early detection of premalignant and malignant lesions and for the identification of epidermodysplasia verruciformis–associated HPVs. The most characteristic findings are seen within the epidermis. The classic histologic manifestation of epidermodysplasia verruciformis is a verruca plana–like lesion with mild hyperkeratosis and acanthosis, in which the keratinocytes contain perinuclear halos and blue-gray pallor, as is demonstrated in the image below. Perinuclear halos are a specific cytopathic effect, that is, clear cells in the granular and spinous layers with occasional enlarged, hyperchromatic, atypical nuclei, are present.

Mild acanthosis, bridging of rete ridges, prominenMild 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).

The nucleoplasm is clear, and keratohyalin granules of various sizes and shapes are present. The keratin layer is loose, with a basket weave–like appearance. In premalignant tumors, the normal keratinocyte maturation is preserved. In contrast, in malignant lesions, the normal surface maturation of keratinocytes is lost. HPV can be detected in infected keratinocyte nuclei by in situ hybridization, particularly in the upper layers of the epidermis, as demonstrated in the image below.

Left: Photomicrograph of a precancerous, verrucousLeft: 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.

Premalignant lesions display features similar to actinic keratosis, with prominent atypical, dyskeratotic cells. The cytopathic effects of viral warts are often absent, although large amounts of HPV DNA can be detected, as is shown in the image by using immunostains on a skin lesion

Dense deposits of human papillomavirus (HPV) DNA aDense 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).

Invasive malignant tumors most commonly show squamous and occasionally adnexal differentiation. A well-differentiated squamous cell carcinoma seen in an epidermodysplasia verruciformis–associated skin cancer is shown in the image below.[19]

A photomicrograph shows an invasive well-differentA 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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Contributor Information and Disclosures
Author

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, and International Society of Dermatopathology

Disclosure: Nothing to disclose.

Coauthor(s)

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 and American Academy of Dermatology

Disclosure: Nothing to disclose.

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, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Nothing to disclose.

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

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

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

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

Disclosure: Nothing to disclose.

References

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

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  9. 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. Mar 2008;128(3):732-5. [Medline].

  10. 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. Oct 2005;141(10):1323-5. [Medline].

  11. 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. Oct 2003;49(4):639-43. [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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