Epidermodysplasia Verruciformis Workup

Updated: Mar 08, 2019
  • Author: Anthony A Gaspari, MD; Chief Editor: Dirk M Elston, MD  more...
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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. [46]

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.

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, prominen 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).

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, verrucous 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.

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 a 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).

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. [47]

A photomicrograph shows an invasive well-different 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.