The Clinical Implication of Incidental Epidermodysplasia Verruciformis

To the Editor: Epidermodysplasia verruciformis (EV) is a condition clinically characterized by disseminated flat-topped verruca plana–like papules or pityriasis versicolor–like macules found predominantly on sun-exposed sites.1 This disorder is a rare inherited autosomal recessive genodermatosis, with most cases being a result of mutations in the EVER1/TMC6 or EVER2/TMC8 genes resulting in susceptibility to certain human papillomavirus (HPV) subtypes.2 It presents during early infancy or childhood, and approximately 30%–50% of these patients develop nonmelanoma skin cancers (NMSCs), primarily squamous cell carcinoma (SCC).3 These occur as early as the second decade of life, primarily on sun-exposed skin.3 The risk of developing NMSCs depends on the subtype of HPV present, with 5 and 8 having the highest oncogenic potential.4 A second form of EV, known as “acquired EV” occurs later in life as a result of immunosuppression, most often in patients with HIV or solid organ transplant recipients.5 Histopathologic examination of lesions of EV shows enlarged keratinocytes in the upper layers of the epidermis with abundant distinct blue-grey cytoplasm, coarse keratohyalin granules, and large nuclei with peripheralized chromatin. There is typically mild associated acanthosis. Incidental foci of EV-like changes are occasionally noted in skin biopsies. A study of these detected EV HPV DNA by polymerase chain reaction in the majority, suggesting that these foci of EV-like changes are because of EV HPV, despite the absence of clinical EV.6 To the best of our knowledge, a larger cohort and a comprehensive review of the clinical history of patients with these incidental foci has not been published. We identified 19 instances of incidental EV over a 6-year period (July 2014–April 2020) from a pool of 23,400 dermatopathology cases at a single laboratory in Vancouver, Canada. A chart review was performed to identify any history of immunodeficiency or skin cancer. All cases except 1 had another primary diagnosis (Table 1). Representative photomicrographs are shown in Figure 1. The mean age was 75 years (range, 44–96). Eleven (58%) of the cases were located on the head and neck, and an additional 3 (16%) were on the forearm. Eleven (58%) patients had a history of skin cancer (either melanoma or NMSC) in the current or a previous biopsy. Seven (37%) of the cases were found within biopsies of a malignancy. Four (21%) of the patients had a history of iatrogenic immunosuppression. TABLE 1. - Case Information of Patients With Foci of Incidental EV Case Gender Age Site Immunosuppression Diagnosis Other Skin Diagnoses 1 F 96 Chin No BCC AK, BCC 2 F 72 Cheek No Venous lake Squamous papilloma 3 F 82 Vulva No Lichen sclerosus None 4 M 58 Calf No Common blue nevus MIS (×2) and melanocytic nevus 5 M 70 Back No EC Cutaneous lymphoid hyperplasia, EC, and spindle cell lipoma 6 M 78 Ear Follicular lymphoma, diagnosed 1 yr before Lentigo maligna AK (×2), BCC, dysplastic nevi (×2), ISSM, mycosis fungoides, and SK 7 F 82 Forearm No BCC None 8 M 74 Scalp Renal transplant Desmoplastic ISCC AK (×3), GA, KA, and ISCC (×4), 9 M 67 Chin Renal transplant Prurigo nodularis SCCIS (×3) 10 M 80 Back No ISSM None 11 F 70 Vulva No Normal skin EC, SK 12 M 75 Ear No Hypertrophic AK SK 13 M 75 Face On imatinib Pigmented AK EC (×2) and folliculitis 14 F 44 Forearm No BAP-1-inactivated nevus Congenital melanocytic nevus, intradermal nevus 15 M 80 Neck No Dysplastic nevus AK, BCC (×5), MIS, and ISCC 16 M 81 Neck No Lentigo maligna melanoma AK (×3), BCC (×13), LSC, ISCC (×3), and SCCIS (×3) 17 F 85 Scalp No Desmoplastic SCC BCC and ISCC 18 M 89 Neck No SK AK, BCC, and ISCC 19 M 66 Forearm No Verruca vulgaris None AK, actinic keratosis; BCC, basal cell carcinoma; BMT, bone marrow transplant; EC, epidermoid cyst; GA, granuloma annulare; ISCC, invasive squamous cell carcinoma; ISSM, invasive superficial spreading melanoma; KA, keratoacanthoma; LSC, lichen simplex chronicus; MIS, melanoma in situ; SCCIS, squamous cell carcinoma in situ; SK, seborrheic keratosis. FIGURE 1.: Representative H&E stained images of biopsies with incidental focal changes of epidermodysplasia verruciformis (EV). (A) (×100) and (B) (×200) depict a blue nevus, and (C) (×100) and (D) (×200) depict a venous lake. Both cases show overlying foci of the characteristic appearance of EV cytopathic effect with enlarged keratinocytes having abundant blue–grey cytoplasm.In our cohort of patients, a history of NMSCs was noted in 8 patients with 4 patients having invasive SCC and BCC, 1 having invasive SCC alone, 3 with BCC alone, and 1 with SCC in situ alone. EV HPV DNA has been detected in biopsies of the clinically normal skin and found to be significantly associated with a history of NMSCs in a case series that included both immunocompetent and immunosuppressed patients, suggesting that it may be predictive of NMSC risk.7 Furthermore, 5 (26%) patients in our series had a history of melanoma, either invasive (n = 3) or in situ (n = 2), and there were 3 cases in which the foci of EV were contiguous with the melanoma. The presence of EV associated with a melanoma may be because of a shared role of UV irradiation as a predisposing factor. It has also been suggested in the literature that the occurrence of EV directly within a melanoma may reflect a record of EV HPV involvement in melanoma initiation or progression rather than simply reflecting coincidental UV exposure,8,9 and this area may warrant further investigations. We identified that 14 (74%) of the cases were found on chronically sun-exposed sites, paralleling the clinical development of EV on sun-exposed areas. Our findings contribute to the growing evidence of a relationship between EV HPV and the development of both NMSC and melanoma. We propose it is important to even note incidental findings of EV in the pathology report because it may provide an indication to follow these patients more closely. Finally, it is important to be aware of the characteristic appearance of incidental EV in practice to avoid mistaking it for pathologic simulants such as verruca plana or SCC in situ.

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