Epidermodysplasia verruciformis

J Cutan Pathol. 2008 Mar;35(3):259-72. Abstract quote

BACKGROUND: 'Human papillomavirus (HPV) vulvitis' is a disputed entity where most studies examining for genital-mucosal (GM) HPV have been negative.

METHODS: Using degenerate and type specific primers for cutaneous (CU), GM and epidermodysplasia verruciformis (EV) HPV types, the prevalence of specific HPV types was investigated in biopsy specimens from 19 women with 'HPV vulvitis', seven with asymptomatic vulvar squamous papillomatosis (ASxVSP), and controls of vulvar fibroepithelial polyps (FEP) (15), vulvar condyloma (10) and normal vulva (NV) (10).

RESULTS: HPV DNA/EV HPV/GM HPV/CU HPV were detected in 84/74/47/5% of vulvitis patients, 78/71/0/28% of ASxVSP, 47/20/20/7% of FEP, 10/10%/0/0 of NV and 100/0/100/10% of condyloma. Fourteen putatively novel HPV genotypes were detected in vulvitis and ASxVSP patients, but not in controls. The two most frequent novel EV HPV, Alb-4 and DL285, were detected in 9/19 (47%) and 5/19 (26%) of vulvitis cases and were persistently identified in serial biopsies. HPV co-infection and Alb-4 infection occurred significantly more frequently in vulvitis patients, particularly those complaining of 'burning' (62/62% vs. 17/7%, p < or = 0.004). Koilocytosis was identified significantly more frequently in vulvitis compared with non-condyloma controls (81% vs. 40%, p = 0.0001), and its presence correlated with detection of HPV DNA (r = 0.3, p = 0.002).

CONCLUSION: The high frequency of novel EV HPV in HPV vulvitis and correlation of clinicopathologic findings with HPV DNA suggests that HPV vulvitis may indeed exist.

Epidemiology
Disease Associations
Pathogenesis
Histopathological Features and Variants
Prognosis
Treatment
Commonly Used Terms
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EPIDEMIOLOGY	CHARACTERIZATION
AGE RANGE-MEDIAN	25-58 years Mean 39 years

DISEASE ASSOCIATIONS	CHARACTERIZATION
Immunocompromised states	Organ transplantation AIDS
NEUROFIBROMATOSIS
Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease? Alpsoy E, Ciftcioglu MA, Keser I, De Villiers EM, Zouboulis CC. Department of Dermatology, Akdeniz University School of Medicine, 07070 Antalya, Turkey.	Br J Dermatol 2002 Mar;146(3):503-7 Abstract quote We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1). The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen's disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, cafe-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing. Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood. The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17.
VULVITIS
'HPV vulvitis' revisited: frequent and persistent detection of novel epidermodysplasia verruciformis-associated HPV genotypes. Lin MT, Rohwedder A, Mysliborski J, Leopold K, Wilson VL, Carlson JA. Division of Dermatology and Dermatopathology, Department of Pathology, Albany Medical College, Albany, NY 12208, USA.	J Cutan Pathol. 2008 Mar;35(3):259-72. Abstract quote BACKGROUND: 'Human papillomavirus (HPV) vulvitis' is a disputed entity where most studies examining for genital-mucosal (GM) HPV have been negative. METHODS: Using degenerate and type specific primers for cutaneous (CU), GM and epidermodysplasia verruciformis (EV) HPV types, the prevalence of specific HPV types was investigated in biopsy specimens from 19 women with 'HPV vulvitis', seven with asymptomatic vulvar squamous papillomatosis (ASxVSP), and controls of vulvar fibroepithelial polyps (FEP) (15), vulvar condyloma (10) and normal vulva (NV) (10). RESULTS: HPV DNA/EV HPV/GM HPV/CU HPV were detected in 84/74/47/5% of vulvitis patients, 78/71/0/28% of ASxVSP, 47/20/20/7% of FEP, 10/10%/0/0 of NV and 100/0/100/10% of condyloma. Fourteen putatively novel HPV genotypes were detected in vulvitis and ASxVSP patients, but not in controls. The two most frequent novel EV HPV, Alb-4 and DL285, were detected in 9/19 (47%) and 5/19 (26%) of vulvitis cases and were persistently identified in serial biopsies. HPV co-infection and Alb-4 infection occurred significantly more frequently in vulvitis patients, particularly those complaining of 'burning' (62/62% vs. 17/7%, p < or = 0.004). Koilocytosis was identified significantly more frequently in vulvitis compared with non-condyloma controls (81% vs. 40%, p = 0.0001), and its presence correlated with detection of HPV DNA (r = 0.3, p = 0.002). CONCLUSION: The high frequency of novel EV HPV in HPV vulvitis and correlation of clinicopathologic findings with HPV DNA suggests that HPV vulvitis may indeed exist.

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Moderate acanthosis and hyperkeratosis with characteristic enlargement of the keratinocytes with blue-gray pallor, occasional perinuclear halos, and irregular granular zone
VARIANTS	May have wide variation in histology similar to the spectrum of changes of HPV in the genital tract
The Histologic Spectrum of Epidermodysplasia Verruciformis Gerard J. Nuovo, M.D.; Mona Ishag, M.D. From the Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, U.S.A.	Am J Surg Pathol 2000;24:1400-1406 Abstract quote The classic histologic presentation of epidermodysplasia verruciformis is a verruca plana-type lesion with minimal hyperkeratosis and acanthotic areas where the cells contain perinuclear halos and blue�gray pallor. Whereas these lesions have a high malignant potential, it is important to elucidate the histologic spectrum of this entity and to differentiate it from its mimics. Fifteen skin biopsies from people with multiple cutaneous warts clinically suspicious for epidermodysplasia verruciformis were analyzed both histologically and for human papillomavirus (HPV) deoxyribonucleic acid (DNA) by in situ hybridization. Ten of the lesions contained HPV DNA, either type 5 (n = 6), type 8 (n = 3), or type 51 (n = 1). Only three of these lesions showed typical verruca plana. The histologic marker of HPV DNA in the other seven viral-positive cases was rare perinuclear halos in association with an irregular granular layer. The other five cases, which were also negative for viral DNA after polymerase chain reaction in situ hybridization, rarely demonstrated the abrupt variation in keratohyaline granules and concomitant perinuclear halos. The authors conclude that there is a wide spectrum of histologic changes in epidermodysplasia verruciformis and that viral testing in conjunction with the histologic and clinical findings can differentiate this premalignant entity from its mimics.
The histologic spectrum of epidermodysplasia verruciformis in transplant and AIDS patients. Morrison C, Eliezri Y, Magro C, Nuovo GJ. Department of Pathology, Ohio State University Medical Center, Center for Dermatologic Surgery, New York, NY, USA.	J Cutan Pathol 2002 Sep;29(8):480-9 Abstract quote BACKGROUND: The purpose of this study was to correlate the histologic findings of skin lesions clinically suspicious for epidermodysplasia verruciformis with the viral findings in patients with organ transplants or AIDS. METHODS: Thirty-seven skin biopsies from 17 patients (six with AIDS and 11 with transplants) were studied as a non-randomized, controlled, unblinded case series by in situ hybridization for HPV DNA. RESULTS: Nineteen (51%) of these biopsies were HPV-positive by in situ hybridization either for HPV type 5 (five cases), type 8 (10 cases), type 16 (four cases) or HPV 31 (one case, with one case of dual infection). Only eight of the 19 HPV-positive tissues (42%) showed the classic histologic features of verruca planae. The more common histologic feature significantly associated with HPV detection was a focally thickened and disrupted granular layer (13/19 [68%] vs. 8/18 [44%], p < 0.04). Dysplasia was evident in 12/19 HPV-positive tissues (63%), which was significantly greater than in patients with congenital epidermodysplasia verruciformis (20%). CONCLUSIONS: Oncogenic HPV types are detected in about one-half of skin biopsies from immunocompromised patients with a clinical presentation suspicious for epidermodysplasia verruciformis. Many of these lesions lack the histologic features of verruca planae, a focally thickened granular layer is a marker for viral detection, and the risk for dysplasia in such lesions is much higher than in epidermodysplasia verruciformis not associated with acquired immunosuppression.
EV ACANTHOMA
Changes of epidermodysplasia verruciformis in benign skin lesions: the EV acanthoma. Ko CJ, Iftner T, Barr RJ, Binder SW. Yale-New Haven Hospital, New Haven, CT, USA.	J Cutan Pathol. 2007 Jan;34(1):44-8. Abstract quote Foci of histological changes of epidermodysplasia verruciformis (EV) were noted in five benign skin lesions. These skin lesions included an intradermal nevus, a pigmented seborrheic keratosis, an isolated papule on the forearm, a perianal lesion, and an acantholytic acanthoma. Because the changes resembled true EV so strongly despite the absence of clinical EV in these patients, we searched for EV-human papilloma virus (HPV) types in these skin lesions. Polymerase chain reaction (PCR) analysis on the formalin-fixed, paraffin-embedded blocks was performed. As a positive control, we included tissue from two HIV-positive patients with clinical EV proven by biopsy. Studies were also performed on five other archived biopsies that did not show changes of EV on multiple tissue sections. A nested PCR method detected EV-HPV types in three of the five benign skin lesions showing EV changes as well as in the positive controls. EV changes and EV-HPV can be found incidentally on biopsy in the absence of clinical EV; when such changes are the major histopathological finding in an isolated skin lesion, the lesion should be termed an EV acanthoma.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Squamous cell carcinoma develops in 30-50% of cases
TREATMENT
Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a Rana Anadolu, MD, etal	J Am Acad Dermatol 2001;45:296-9 Abstract quote Epidermodysplasia verruciformis (EV) is an autosomal recessive disease characterized by the lifelong eruption of disseminated verrucae-like lesions. Numerous treatment modalities have been used to treat EV without benefit. Recently, retinoid and interferon therapies have been found to be of value in the treatment of EV. We present a case of EV that was treated with a combination of acitretin and interferon alfa-2a.