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Epidermodysplasia Verruciformis in Human Immunodeficiency Virus–Infected Patients A Marker of Human Papillomavirus–Related Disorders Not Affected by Antiretroviral Therapy FREE

Simon Jacobelli, MD; Helene Laude, MD; Agnes Carlotti, MD; Flore Rozenberg, MD, PhD; Jean Deleuze, MD; Jean-Pierre Morini, MD; Nathalie Franck, MD; Isabelle Gorin, MD; Marie-Francoise Avril, MD, PhD; Nicolas Dupin, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Dermatology, UPRES EA1833 (Drs Jacobelli, Deleuze, Morini, Franck, Gorin, Avril, and Dupin), Virology, UPRES EA1833 (Drs Laude and Rozenberg), and Pathology (Dr Carlotti), APHP Cochin Hospital, University Paris Descartes, Paris, France.


Arch Dermatol. 2011;147(5):590-596. doi:10.1001/archdermatol.2010.399.
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Published online

Epidermodysplasia verruciformis (EV) is an autosomal recessive genodermatosis characterized by disseminated dyschromic and squamous skin macules resembling pityriasis versicolor (PV-like macules) and flat warts, predominant on sun-exposed areas.1 Most cases are caused by invalidating mutations in 2 genes, EVER1 and EVER2 located on chromosome 17q25, resulting in a susceptibility to a group of beta human papillomavirus (β-HPV) or EV-associated HPV types. EVER genes encode transmembrane proteins located in the endoplasmic reticulum and are involved in signal transduction.2 It has been demonstrated that EVER proteins regulate zinc homeostasis by interacting with zinc transporter proteins (ZnT1). This interaction is inhibited by the E5 protein of HPV. It has been suggested that loss-of-function mutations in the EVER genes and the lack of E5 protein in β-HPV result in specific susceptibility and host restriction to these viruses.3 Local innate and adaptive immunity to specific HPV types in the infected keratinocytes is likely to be involved.1 This would account for the transition from an abortive to a productive infection by EV-HPV types, which are usually ubiquitous and commensal defective viruses in normal skin.

The oncogenic HPV-5 and HPV-8 are the most frequent HPV types, identified in 90% of patients with EV.1 Approximately 20 other β-HPV types are known, including HPV-9, 12, 14, 15, 17, 19 through 25, 28, 29, 36, and 47. The main histologic features of the disease are the coexistence of epidermal thickening, loose horny layer with a basket weave–like appearance, and presence of large cells in the spinous and granular layers presenting with a large blue-gray cytoplasm. A perinuclear halo can be seen.

Skin eruption usually begins during childhood and progressively spreads. The lesions remain chronic and refractory. As the causal mutations do not confer susceptibility to oncogenic or nononcogenic mucous HPV, the mucous membranes are generally unharmed. Cutaneous nonmelanoma skin cancers develop in 30% to 50% of the patients, within a mean of 25 years after the onset of benign skin lesions.4 These cancers are mostly Bowen's disease and invasive squamous cell carcinomas, growing slowly on areas exposed to the sunlight. The physiopathologic features of cutaneous oncogenesis is suggestive of the combined effects of the oncogenic potential of HPV-5 and HPV-8, an environment of UV-induced keratinocyte mutations, and a specific genetic background.

Susceptibility to HPV infection has been reported in patients with genetic primary immunodeficiencies (WHIM [warts, hypogammaglobulinemia, infections, and myelokathexis] syndrome and severe combined immune deficiency) and in patients with acquired cell-mediated immunodeficiency (HIV-positive patients and immunosuppressive treatment in organ allograft recipients). These patients are at high risk of developing other HPV-related diseases, such as common warts, anogenital condylomas, and mucosal intraepithelial neoplasia, but EV-like eruptions are rarely observed. 59 We studied a series of 11 cases of EV-like syndrome occurring in HIV-infected patients in order to describe the epidemiologic, clinical, virologic, and immunologic characteristics of these patients. A systematic literature review was carried out.

METHODS

STUDY DESIGN

We studied HIV-positive patients seen between 2003 and 2009 in the Department of Dermatology at Tarnier-Cochin Hospital, Paris, France. All patients with clinically evocative and histologically confirmed EV-like syndrome were included in this study. The histological diagnostic features were a combination of a thickened epidermis and the presence of large cells, with an atypical nucleus and a large blue-gray cytoplasm, in the granular and spinous layers (Figure 1). Data collection was standardized. The following demographic and epidemiologic data were recorded: sex, ethnic origin, phototype, age at diagnosis of HIV infection, age at onset, and diagnosis of EV lesions. We also recorded the following clinical signs: existence of flat warts, PV-like macules, lichenoid lesions, topographic abnormalities, history of cutaneous or mucosal HPV-associated infection (warts, condylomas, bowenoid papulosis) and nonmelanoma skin cancer, lymphoproliferative malignant disorders, and viral hepatitis. Timing of lesion onset with respect to the initiation of HAART, CD4 T-cell count, HIV viral load at EV onset and at the time of this report, and HAART efficacy were also recorded. For cases occurring soon after HAART initiation, CD4 T-cell count and HIV viral load at HAART initiation were noted. Results were expressed as percentages or as medians and interquartile ranges for quantitative variables.

Place holder to copy figure label and caption
Figure 1.

Histologic features of epidermodysplasia verruciformis. Epidermal thickening with presence of large cells, sometimes in nests, in the spinous and granular layers presenting with an atypical nucleus and a large blue-gray cytoplasm.

Graphic Jump Location
HPV TYPING
DNA Extraction

Fresh frozen skin biopsy specimens from typical EV lesions were collected after obtaining informed consent. The skin samples were cut and mechanically dissociated. DNA was extracted with the QIAmp DNA extraction kit for tissues (Qiagen Inc, Valencia, California), using a slightly modified version of the manufacturer's protocol. Briefly, the lysis period was extended to 18 hours, with shaking at 56°C, and repeated additions of proteinase K (Qiagen Inc): 400 μg of the enzyme was added every 3 hours during the first 6 hours and 800 μg before overnight lysis. DNA was eluted in 200 μL of elution buffer (Macheret; Macherey-Nagel, Duren, Germany). Concentration and purity were verified by the NanoDrop method (NanoDrop Technology, Wilmington, Delaware). DNA quality was checked by amplifying a 90–base pair (bp) fragment of the human apolipoprotein B (HAPB) gene (GenBank NG_011793) with the following primers and probe: HAPBF, 5′-TGAAGGTGGAGGACATCCCTCTA-3′; HAPBR, 5′-CTGGAATTGGCATTTCTGGTAA-3′; and HAPBP, 5′-VIC-CGAGAATCACCCTGCCAGACTTCCGT-TAMRA-3′. Amplification was performed on 200 ng of DNA with each primer (300nM) and a 100nM probe in 50-μL Taqman Master Mix (Applied Biosystems, Courtaboeuf, France). After a 10-minute denaturation step at 95°C, cycling conditions consisted in 50 cycles of 15 s at 95°C and 1 minute at 60°C on an ABI 7500 platform (Applied Biosystems).

Amplification of HPV DNA by FAP59/62 Consensus PCR and Sequencing

We used the consensus primer pair FAP59/62, described by Forslund et al.10 Amplification was performed in a final volume of 50 μL containing 200 ng of sample DNA, 500 nmol/μL of each consensus primer and 1X Ampli Taq Gold buffer (Applied Biosystems). The polymerase chain reaction (PCR) conditions were as follows: 10 minutes for initial denaturation at 94°C, followed by 45 cycles of 30 s at 94°C, 1 minute at 54°C, and 1 minute at 72°C, with a final 5-minute elongation at 72°C. As a positive control, 10 ng of plasmid containing the whole genome of HPV-5 or HPV-8 was included. Water was used as a negative control. The PCR products were analyzed by subjecting 20 μL of amplicon to electrophoresis in a 2% agarose gel. For positive samples, the bands were isolated from the gel with the QIAQuick Gel extraction kit (Qiagen Inc), according to the manufacturer's instructions, and eluted into a final volume of 50 μL. The purified PCR products were subjected to automated nucleotide sequencing in an ABI 3130XL genetic analyzer (Applied Biosystems). DNA sequences were compared with the sequences stored at the National Center for Biotechnology Information, Bethesda, Maryland.

Specific Amplification of HPV-5 and HPV-8 Sequences for EV Lesions

Sequences of the primers used were HPV5F (5′-AATCGCATTTGGCACTGC-3′) and HP5R (5′-TTGCACGGTGACCTCT-3′) for HPV-5, and HP8F (5′-TTACAATGCTGTGACTTGTGC-3′) and HPV8R (5′-CACTACATTCAGCTTCCAAAATACA-3′) for HPV-8. These primers amplified a 720-bp fragment from HPV-5 and an 840-bp DNA fragment from HPV-8. Amplification was carried out in a final volume of 50 μL containing 200 ng of sample DNA, 500 nmol/μL of each specific primer and 1X Ampli Taq Gold buffer (Applied Biosystems). The PCR conditions were as follows: initial denaturation for 10 minutes at 94°C, followed by 50 cycles of 30 s at 94°C, 1 minute at 50°C, and 1 minute at 72°C, with a final 5-minute elongation at 72°C. As a positive control, 10 ng of HPV-5 or HPV-8 plasmid were included. Water was used as negative control. We then subjected 20 μL of the PCR products to electrophoresis in a 2% agarose gel. The specificity of the amplification was checked by sequencing the purified amplicon.

LITERATURE REVIEW

We searched the MEDLINE electronic database for articles reporting acquired EV during HIV infection. The keywords used were “epidermodysplasia verruciformis” and “HIV.” We selected and reviewed articles in which the reported cases fulfilled the same inclusion criteria used in our study. Data were collected in a standardized manner, as previously described for our own series.

RESULTS

OUR SERIES

Eleven HIV-positive patients fulfilling the inclusion criteria were studied. The main characteristics of these patients are summarized in the Table. There were 6 men and 5 women. Six of the patients were black and originated from an African country. The median age at diagnosis of HIV infection was 27 years (interquartile range [IQR], 22-33 years; range, 20-37 years). The first EV lesions occurred at a median age of 40 years (IQR, 29-43 years; range, 15-45 years). The lesions occurred after HIV diagnosis in 10 cases, with a period of 9 years between HIV diagnosis and lesion onset (IQR, 7-13 years; range, 1-20 years). Patient 1 developed EV lesions before the diagnosis of HIV infection. The median age at diagnosis of EV was 44 years (IQR, 35-46 years; range, 32-50 years). The median delay to EV diagnosis was 4 years (IQR, 3-7 years; range, 0-18 years). At the time of this report, EV lesions have been present for a median of 10 years (IQR, 7-12 years; range, 1-24 years). Median age at the time of this report was 45 years (IQR, 41-50 years; range, 39-51 years). Patients 8 and 9 died at the ages of 45 and 44 years, respectively. Patient 10 was lost to follow-up at the age of 50 years.

Table Graphic Jump LocationTable. Epidemiologic, Clinical, Virologic, and Immunological Characteristics of Present Series

Extensive flat warts were observed in all cases, with associated pityriasis-like macules in 5 cases. In 3 cases, the clinical presentation was lichenoid papules resembling lichen planus (patients 1, 3, and 10). The skin lesions affected the upper trunk in all cases and were generalized in 3 cases (patients 1, 2, and 3) (Figure 2). Fresh frozen skin biopsy specimens taken from EV lesions were not available for 3 patients (patients 8, 9, and 10), for whom PCR for HPV typing could not be carried out. In all the cases studied, EV-associated HPV was detected, and the strains identified included oncogenic HPV-5 and/or HPV-8 in 6 cases. Coinfection with HPV within EV lesions was observed in 4 cases. In patient 3, HPV-3, associated with flat warts, was found. Patient 6 had another 2 HPV subtypes (HPV-38 and 65) not usually associated with EV.

Place holder to copy figure label and caption
Figure 2.

Clinical features of epidermodysplasia verruciformis. Clinical presentation includes lichenoid dyschromic papules (A) and disseminated flat warts and extensive pityriasis versicolor–like macules (B and C).

Graphic Jump Location

Eight patients (73%) currently had or had a history of another HPV-associated cutaneous or mucosal infection: common palmar and/or plantar warts in 4 cases and anogenital bowenoid papulosis and/or condylomas in 7 cases. Associated oncogenic mucosal HPV subtypes were detected in 3 patients (patients 5, 6, and 11). Three of the women in this series had previously undergone treatment for high-grade cervical intraepithelial neoplasia (patients 4, 10, and 11). In patients for whom familial history was available (patients 3, 4, 5, and 6), we found no history of warts or consanguinity in their parents and siblings.

Three patients (patients 3, 5, and 10) developed nonmelanoma skin cancers: 2 cases of Bowen's disease and 1 case of invasive squamous cell carcinoma. None displayed nodal or visceral metastatic progression of the skin cancers. For these skin cancers, HPV typing was not possible. Four patients had a history of lymphoproliferative disorder (patients 3, 8, 9, and 10), which was the cause of death in patients 8 and 9. These lymphoid tumors were not related to EBV. The first EV lesions occurred at the time of diagnosis of human herpesvirus 8–linked multicentric Castleman disease in patient 8 and of a large B-cell lymphoma in patient 10. Current active viral hepatitis was found in 3 patients.

In all cases, HAART was ineffective on the course of skin lesions. The first EV lesions occurred after the initiation of HAART in 7 cases. The time between HAART initiation and EV onset was less than 2 years in 3 cases (patients 2, 4, and 8) and, in 2 other cases, skin eruption occurred in a context of virologic escape (patients 5 and 6). At the onset of EV lesions, median CD4 T-cell count was 170/μL (IQR, 116/μL-326/μL; range, 2/μL-767/μL), and HIV viral load was undetectable in 3 cases (data not available for patient 1). At the time of this report, the median CD4 T-cell count was 495/μL (IQR, 304/μL-615/μL; range, 78/μL-1040/μL), and HIV viral load was undetectable in 8 cases. Patients 2 and 4 displayed a significant increase in CD4 T-cell count and a decrease in HIV viral load on HAART, coinciding with the development of the first skin symptoms. All the patients received topical treatments without any improvement (tretinoin, imiquimod, urea, fluorouracil, and cryotherapy). Patient 3 reported a partial improvement of EV skin lesions during a course of interferon alfa treatment for hepatitis C virus infection.

LITERATURE REVIEW

We identified 17 articles reporting 25 other cases of acquired EV in patients with HIV infection.1127 Most of these cases were published as individual case reports. Even the largest series did not exceed 3 cases. The data for these cases are given in the eTable. Articles reporting other HPV-associated skin eruptions in HIV-positive patients, such as flat warts and common warts28,29 without histological features of EV were not included.

COMMENT

Epidermodysplasia verruciformis–like eruptions have rarely been described in immunodeficient patients, unlike HPV-associated anogenital malignant diseases.59 The EV phenotype and EV-HPV genotypes3032 were first reported in kidney transplant recipients and then in hematological malignant diseases,3335 iatrogenic immunodeficiency,36,37 and CD4+ T lymphocytopenia.38,39 In HIV-positive patients, HAART resulted in a decrease in the incidence of opportunistic infections, but the prolonged survival was associated to the emergence of cutaneous and mucosal HPV-related diseases, especially anogenital intraepithelial neoplasia.5,6,40 The EV-like syndrome provides an example of emerging widespread HPV infections in HIV-positive patients. The present series appears to be the largest reported with clinical, virologic, and immunologic documentation.

We found HIV-positive men and women equally affected by EV. The high frequency of black patients and the lack of pediatric cases are consistent with our recruitment. The first skin lesions mostly occurred in adult patients, after HIV diagnosis, and following a long period of immunosuppression (median of 9 years) and then were chronic and refractory (median duration of 10 years). The onset of HIV infection was unknown for patient 1 but probably occurred during adolescence in Cameroon, at the time of the first skin EV lesions. Then, this patient should be considered as more likely having an acquired EV related to HIV infection than a classic genetic EV. The clinical lesions resembled those of genetic EV, predominantly on the skin exposed to the sun, in accordance with the role of UV in β-HPV–induced lesions. However, the occasional presence of flat warts in sun-protected skin suggests that UV exposure is not always necessary. The presence of lichenoid papules mimicking lichen planus is a clinical feature that has been rarely reported and may account for the long delay of diagnosis (median of 4 years). Pathological examination and HPV typing of these lesions showed typical characteristics of EV and EV-associated HPV that excluded coincidental skin disease associated with viral hepatitis. For virologic results, we increased the sensitivity of HPV typing by amplifying HPV-5 and HPV-8 sequences specifically, in addition to amplifying FAP59/62 sequences, which might identify only the preferentially amplified genotype. β-HPV was found in all skin biopsy specimens and oncogenic HPV-5 or HPV-8 in 75% of specimens, which is similar to that reported for patients with genetic EV1 and in EV-like disorders.32 Gamma HPV-65 and HPV-38 found in patient 6 had previously been described in genetic EV41 and in an immunocompromised patient.34

Unlike patients with genetic EV who are only susceptible to β-HPV, HIV-positive patients with EV often displayed other HPV-related diseases including mucosal HPV in 64% of cases. Most of these mucosal HPV were oncogenic, highlighting the risk of intraepithelial cervical neoplasia observed in HIV-positive women. This is a strong argument for a clinical follow-up with detailed genital and anal examinations in this HIV-positive population. Skin cancers were a rare event in our series and in the published cases, which differs from patients with genetic EV, who are affected by nonmelanoma skin cancer in 50% of cases. Because the mean interval between the onset of benign EV lesions and the first skin cancer in genetic EV cases is long,4 a prolonged follow-up after the onset of skin involvement is probably required to detect a higher incidence of nonmelanoma skin cancer in this population. First, EV lesions were often concomitant to intense immunodeficiency state, confirming the role of T-cell immune responses in the control of HPV infection.4244 We focused on the presence of current or past lymphoproliferative disorder in 36% of the patients in our series, including 2 fatal cases. In 2 patients (patients 8 and 10), immunodeficiency related to lymphoproliferative syndrome may have triggered the skin eruption. These observations demonstrate that acquired EV should be considered a marker of chronic and intense immunosuppression.45

We noticed that preexistent skin lesions were not improved by immune restoration under HAART. Complete and partial responses after the initiation of HAART have been previously documented only twice.14,24 An impairment of CD4 cell function may be involved in viral persistence, suggesting that nadir CD4 T-cell counts should be considered.46 This confirms the inefficiency of HAART reported in other HPV infections.47 Cutaneous and mucosal HPV-induced lesions may reveal a specific defect in the immune response to the HPV family not corrected by immune restoration. In other cases, EV lesions are concomitant with the immune restoration by HAART. In the case reported by Mermet et al19 and in 2 patients in the present series (patients 2 and 4), the chronology of skin eruption and the immunologic and virologic data were consistent with immune reconstitution inflammatory syndrome Patient 8 seems different because his first EV lesions occurred at the start of both multicentric Castleman disease diagnosis and HAART. Like common and flat warts, which do not display the histological features of EV, EV-like eruptions are an example of skin manifestations of immune reconstitution inflammatory syndrome.28,29 The physiopathologic mechanism of such eruptions remains unclear owing to a lack of peripheral and local immunomonitoring data, but we suggest an exacerbated cutaneous inflammatory response against commensal β-HPV in a particular genetic background.

Evidence for the genetic heterogeneity of EV is provided by the lack of EVER mutations in some EV cases, including familial cases. X-linked inheritance has been suggested in some of these cases.4850 The low frequency of EV-like syndrome in HIV-positive and other immunocompromised patients are suggestive of additional genetic susceptibility. In our series, familial history of patients was not suggestive of any pattern of inheritance. An EVER2 polymorphism potentially associated with β-HPV infection was previously reported.26 Further genetic explorations are warranted in immunocompromised patients to identify risk factors associated with an EV phenotype.

In conclusion, acquired EV-like eruptions in HIV-positive patients should be considered not only as a marker of specific susceptibility to β-HPV infection and skin cancers, but also as a generalized immunodeficiency state associated with low- or high-risk mucosal HPV infection and lymphoproliferative disorders. Skin lesions often remain refractory, despite immune restoration by HAART, and may reflect a genetic susceptibility.

ARTICLE INFORMATION

Correspondence: Simon Jacobelli, MD, Department of Dermatology, Tarnier-Cochin Hospital, 89 rue d’Assas, 75006 Paris, France (simonjacobelli@gmail.com).

Accepted for Publication: October 25, 2010.

Published Online: January 17, 2011. doi:10.1001/archdermatol.2010.399

Authors Contributions: Drs Jacobelli, Avril, and Dupin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jacobelli, Avril, and Dupin. Acquisition of data: Jacobelli, Laude, Carlotti, Rozenberg, Deleuze, Morini, Franck, Gorin, Avril, and Dupin. Analysis and interpretation of data: Jacobelli, Avril, and Dupin. Drafting of the manuscript: Jacobelli and Laude. Critical revision of the manuscript for important intellectual content: Laude, Carlotti, Rozenberg, Deleuze, Morini, Franck, Gorin, Avril, and Dupin. Administrative, technical, and material support: Laude, Carlotti, and Rozenberg. Study supervision: Avril.

Financial Disclosure: None reported.

Additional Contributions: Michel Favre, PhD (Pasteur Institute, Paris, France), provided plasmids containing the whole genomes of HPV-5 and HPV-8.

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Tanigaki  TKanda  RSato  K Epidermodysplasia verruciformis (L-L, 1922) in a patient with systemic lupus erythematosus. Arch Dermatol Res 1986;278 (3) 247- 248
PubMed Link to Article
García-Río  IGarcia-F-Villalta  MJDaudén  EFraga  JGarcía-Díez  A Epidermodysplasia verruciformis-like lesions in a patient with systemic lupus erythematosus. Acta Derm Venereol 2003;83 (3) 229- 230
PubMed Link to Article
Tobin  ERohwedder  AHolland  SMPhilips  BCarlson  JA Recurrent ‘sterile’ verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia. Br J Dermatol 2003;149 (3) 627- 633
PubMed Link to Article
Stetson  CLRapini  RPTyring  SKKimbrough  RC CD4+ T lymphocytopenia with disseminated HPV. J Cutan Pathol 2002;29 (8) 502- 505
PubMed Link to Article
Piketty  CDarragh  TMHeard  I  et al.  High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis 2004;31 (2) 96- 99
PubMed Link to Article
Yutsudo  MKanda  RTanigaki  TKitano  YHakura  A Human papillomavirus type 38 isolated from patients with epidermodysplasia verruciformis. Intervirology 1986;26 (1-2) 104- 108
PubMed Link to Article
Bourgault Villada  IMoyal Barracco  MVillada  IB  et al.  Spontaneous regression of grade 3 vulvar intraepithelial neoplasia associated with human papillomavirus-16-specific CD4(+) and CD8(+) T-cell responses. Cancer Res 2004;64 (23) 8761- 8766
PubMed Link to Article
Coleman  NBirley  HDRenton  AM  et al.  Immunological events in regressing genital warts. Am J Clin Pathol 1994;102 (6) 768- 774
PubMed
Knowles  GO’Neil  BWCampo  MS Phenotypical characterization of lymphocytes infiltrating regressing papillomas. J Virol 1996;70 (12) 8451- 8458
PubMed
Bohlius  JSchmidlin  KCostagliola  D  et al. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group, Incidence and risk factors of HIV-related non-Hodgkin's lymphoma in the era of combination antiretroviral therapy: a European multicohort study. Antivir Ther 2009;14 (8) 1065- 1074
PubMed Link to Article
Rodrigues  LKBaker  TMaurer  T Cutaneous warts in HIV-positive patients undergoing highly active antiretroviral therapy. Arch Dermatol 2001;137 (8) 1103- 1104
PubMed
van der Burg  SHPalefsky  JM Human Immunodeficiency virus and human papilloma virus—why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful. J Transl Med 2009;7108
PubMed Link to Article
Androphy  EJDvoretzky  ILowy  DR X-linked inheritance of epidermodysplasia verruciformis: genetic and virologic studies of a kindred. Arch Dermatol 1985;121 (7) 864- 868
PubMed Link to Article
Akgül  BKöse  OSafali  M  et al.  A distinct variant of epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations. J Dermatol Sci 2007;46 (3) 214- 216
PubMed Link to Article
Zavattaro  EAzzimonti  BMondini  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 2008;128 (3) 732- 735
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Histologic features of epidermodysplasia verruciformis. Epidermal thickening with presence of large cells, sometimes in nests, in the spinous and granular layers presenting with an atypical nucleus and a large blue-gray cytoplasm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Clinical features of epidermodysplasia verruciformis. Clinical presentation includes lichenoid dyschromic papules (A) and disseminated flat warts and extensive pityriasis versicolor–like macules (B and C).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Epidemiologic, Clinical, Virologic, and Immunological Characteristics of Present Series

References

Orth  G Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin Immunol 2006;18 (6) 362- 374
PubMed Link to Article
Ramoz  NRueda  LABouadjar  BMontoya  LSOrth  GFavre  M Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 2002;32 (4) 579- 581
PubMed Link to Article
Lazarczyk  MPons  CMendoza  JACassonnet  PJacob  YFavre  M Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med 2008;205 (1) 35- 42
PubMed Link to Article
Lutzner  MA Epidermodysplasia verruciformis. An autosomal recessive disease characterized by viral warts and skin cancer: a model for viral oncogenesis. Bull Cancer 1978;65 (2) 169- 182
PubMed
Frisch  MBiggar  RJGoedert  JJ Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92 (18) 1500- 1510
PubMed Link to Article
Sun  XWKuhn  LEllerbrock  TVChiasson  MABush  TJWright  TC  Jr Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997;337 (19) 1343- 1349
PubMed Link to Article
Arends  MJBenton  EC McLaren  KMStark  LAHunter  JABird  CC Renal allograft recipients with high susceptibility to cutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours and a greater risk of anogenital malignancy. Br J Cancer 1997;75 (5) 722- 728
PubMed Link to Article
Paternoster  DMCester  MResente  C  et al.  Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 2008;40 (6) 1877- 1880
PubMed Link to Article
Ozsaran  AAAteş  TDikmen  Y  et al.  Evaluation of the risk of cervical intraepithelial neoplasia and human papilloma virus infection in renal transplant patients receiving immunosuppressive therapy. Eur J Gynaecol Oncol 1999;20 (2) 127- 130
PubMed
Forslund  OAntonsson  ANordin  PStenquist  BHansson  BG A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin. J Gen Virol 1999;80 (pt 9) 2437- 2443
PubMed
Prose  NSvon Knebel-Doeberitz  CMiller  SMilburn  PBHeilman  E Widespread flat warts associated with human papillomavirus type 5: a cutaneous manifestation of human immunodeficiency virus infection. J Am Acad Dermatol 1990;23 (5, pt 2) 978- 981
PubMed Link to Article
Berger  TGSawchuk  WSLeonardi  CLangenberg  ATappero  JLeboit  PE Epidermodysplasia verruciformis-associated papillomavirus infection complicating human immunodeficiency virus disease. Br J Dermatol 1991;124 (1) 79- 83
PubMed Link to Article
Barzegar  CPaul  CSaiag  P  et al.  Epidermodysplasia verruciformis-like eruption complicating human immunodeficiency virus infection. Br J Dermatol 1998;139 (1) 122- 127
PubMed Link to Article
Haas  NFuchs  PGHermes  BHenz  BM Remission of epidermodysplasia verruciformis-like skin eruption after highly active antiretroviral therapy in a human immunodeficiency virus-positive patient. Br J Dermatol 2001;145 (4) 669- 670
PubMed Link to Article
Trauner  MARuben  BSHatcher  SLLawry  MA Groin eruption in an HIV-positive man: epidermodysplasia verruciformis (EDV). Arch Dermatol 2002;138 (4) 527- 532
PubMed
Carré  DDompmartin  AVerdon  R  et al.  Epidermodysplasia verruciformis in a patient with HIV infection: no response to highly active antiretroviral therapy. Int J Dermatol 2003;42 (4) 296- 300
PubMed Link to Article
Hu  WNuovo  GWillen  MSomach  S Epidermodysplasia verruciformis in two half brothers with HIV infection. J Cutan Med Surg 2004;8 (5) 357- 360
PubMed Link to Article
Davison  SCFrancis  N McLean  KBunker  CB Epidermodysplasia verruciformis-like eruption associated with HIV infection. Clin Exp Dermatol 2004;29 (3) 311- 312
PubMed Link to Article
Mermet  IGuerrini  JSCairey-Remonnay  S  et al.  Cervical intraepithelial neoplasia associated with epidermodysplasia verruciformis HPV in an HIV-infected patient: a manifestation of immune restoration syndrome. Eur J Dermatol 2007;17 (2) 149- 152
PubMed
Bonamigo  RMaldonado  GLondero  RMCartell  A Epidermodysplasia verruciformis-like disorder in a teenager with HIV and HCV infections. Pediatr Dermatol 2007;24 (4) 456- 457
PubMed Link to Article
Hultgren  TLSrinivasan  SKDiMaio  DJ Epidermodysplasia verruciformis occurring in a patient with human immunodeficiency virus: a case report. Cutis 2007;79 (4) 307- 311
PubMed
Kroft  EBMelchers  WJBlokx  WAde Hoop  DWarris  A A generalized skin eruption in a human immunodeficiency virus-infected boy. J Eur Acad Dermatol Venereol 2008;22 (7) 896- 897
PubMed Link to Article
Chen  P  JrKamino  HWalters  RFRosenman  KPomeranz  MKSanchez  M Epidermodysplasia verruciformis in the setting of HIV infection. Dermatol Online J 2008;14 (10) 1
PubMed
Rallis  EPaparizos  VKyriakis  KKatsambas  A Treatment of epidermodysplasia verruciformis in human immunodeficiency virus-positive patients. J Eur Acad Dermatol Venereol 2009;23 (2) 195- 196
PubMed Link to Article
Berk  DRBruckner  ALLu  D Epidermodysplasia verruciform-like lesions in an HIV patient. Dermatol Online J 2009;15 (1) 1
PubMed
Hohenstein  ERady  PLHergersberg  M  et al.  Epidermodysplasia verruciformis in a HIV-positive patient homozygous for the c917A—>T polymorphism in the TMC8/EVER2 gene. Dermatology 2009;218 (2) 114- 118
PubMed Link to Article
Rogers  HDMacgregor  JLNord  KM  et al.  Acquired epidermodysplasia verruciformis. J Am Acad Dermatol 2009;60 (2) 315- 320
PubMed Link to Article
Iarikov  DDuke  WSkiest  D Extensive development of flat warts as a cutaneous manifestation of immune reconstitution syndrome. AIDS Read 2008;18 (10) 524- 527
PubMed
Kerob  DDupuy  AVignon-Pennamen  MDBournerias  IDohin  ELebbe  C A case of efflorescence of cutaneous warts as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected patient. Clin Infect Dis 2007;45 (3) 405- 406
PubMed Link to Article
Lutzner  MCroissant  ODucasse  MFKreis  HCrosnier  JOrth  G A potentially oncogenic human papillomavirus (HPV-5) found in two renal allograft recipients. J Invest Dermatol 1980;75 (4) 353- 356
PubMed Link to Article
Rüdlinger  RSmith  IWBunney  MHHunter  JA Human papillomavirus infections in a group of renal transplant recipients. Br J Dermatol 1986;115 (6) 681- 692
PubMed Link to Article
Morrison  CEliezri  YMagro  CNuovo  GJ The histologic spectrum of epidermodysplasia verruciformis in transplant and AIDS patients. J Cutan Pathol 2002;29 (8) 480- 489
PubMed Link to Article
Gross  GEllinger  KRoussaki  AFuchs  PGPeter  HHPfister  H Epidermodysplasia verruciformis in a patient with Hodgkin's disease: characterization of a new papillomavirus type and interferon treatment. J Invest Dermatol 1988;91 (1) 43- 48
PubMed Link to Article
Kawai  KEgawa  NKiyono  TKanekura  T Epidermodysplasia-verruciformis-like eruption associated with gamma-papillomavirus infection in a patient with adult T-cell leukemia. Dermatology 2009;219 (3) 274- 278
PubMed Link to Article
Kunishige  JHHymes  SRMadkan  V  et al.  Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J Am Acad Dermatol 2007;57 (5) ((suppl)) S78- S80
PubMed Link to Article
Tanigaki  TKanda  RSato  K Epidermodysplasia verruciformis (L-L, 1922) in a patient with systemic lupus erythematosus. Arch Dermatol Res 1986;278 (3) 247- 248
PubMed Link to Article
García-Río  IGarcia-F-Villalta  MJDaudén  EFraga  JGarcía-Díez  A Epidermodysplasia verruciformis-like lesions in a patient with systemic lupus erythematosus. Acta Derm Venereol 2003;83 (3) 229- 230
PubMed Link to Article
Tobin  ERohwedder  AHolland  SMPhilips  BCarlson  JA Recurrent ‘sterile’ verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia. Br J Dermatol 2003;149 (3) 627- 633
PubMed Link to Article
Stetson  CLRapini  RPTyring  SKKimbrough  RC CD4+ T lymphocytopenia with disseminated HPV. J Cutan Pathol 2002;29 (8) 502- 505
PubMed Link to Article
Piketty  CDarragh  TMHeard  I  et al.  High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis 2004;31 (2) 96- 99
PubMed Link to Article
Yutsudo  MKanda  RTanigaki  TKitano  YHakura  A Human papillomavirus type 38 isolated from patients with epidermodysplasia verruciformis. Intervirology 1986;26 (1-2) 104- 108
PubMed Link to Article
Bourgault Villada  IMoyal Barracco  MVillada  IB  et al.  Spontaneous regression of grade 3 vulvar intraepithelial neoplasia associated with human papillomavirus-16-specific CD4(+) and CD8(+) T-cell responses. Cancer Res 2004;64 (23) 8761- 8766
PubMed Link to Article
Coleman  NBirley  HDRenton  AM  et al.  Immunological events in regressing genital warts. Am J Clin Pathol 1994;102 (6) 768- 774
PubMed
Knowles  GO’Neil  BWCampo  MS Phenotypical characterization of lymphocytes infiltrating regressing papillomas. J Virol 1996;70 (12) 8451- 8458
PubMed
Bohlius  JSchmidlin  KCostagliola  D  et al. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group, Incidence and risk factors of HIV-related non-Hodgkin's lymphoma in the era of combination antiretroviral therapy: a European multicohort study. Antivir Ther 2009;14 (8) 1065- 1074
PubMed Link to Article
Rodrigues  LKBaker  TMaurer  T Cutaneous warts in HIV-positive patients undergoing highly active antiretroviral therapy. Arch Dermatol 2001;137 (8) 1103- 1104
PubMed
van der Burg  SHPalefsky  JM Human Immunodeficiency virus and human papilloma virus—why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful. J Transl Med 2009;7108
PubMed Link to Article
Androphy  EJDvoretzky  ILowy  DR X-linked inheritance of epidermodysplasia verruciformis: genetic and virologic studies of a kindred. Arch Dermatol 1985;121 (7) 864- 868
PubMed Link to Article
Akgül  BKöse  OSafali  M  et al.  A distinct variant of epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations. J Dermatol Sci 2007;46 (3) 214- 216
PubMed Link to Article
Zavattaro  EAzzimonti  BMondini  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 2008;128 (3) 732- 735
PubMed Link to Article

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HPV induced fatal anorrectal SSC in an EV-HIV-positive patient
Posted on March 16, 2011
Jesús Bastida, MD
Hospital Universitario de Gran Canaria,, Néstor Santana-Molina, Begoña San Román-Budiño, Pilar de la Rosa-del Rey, Carlos Díaz-Cascajo
Conflict of Interest: None Declared
Sir, we read with great interest the online article of Jacobelli et al. titled Epidermodysplasia verruciformis in human immunodeficiency virus-infected (EV-HIV) patients.1 The authors concluded that "acquired EV-HIV should be considered (..) as a generalized immunodeficiency state associated with low or high-risk mucosal HPV infection and lymphoproliferative disorders". We would like to highlight this conclusion reporting the first case of EV-HIV and fatal HPV-induced anorectal squamous cell carcinoma (SCC) association reported up to now.
Case report. A 43 year-old, HIV-positive homosexual man with AIDS C3 stage, CD4+ cells count of 517 cel/uL and under highly active antiretroviral therapy (HAART), was sent to us in april, 2009 for years of asymptomatic and progressive cutaneous and perianal lesions. He noted also perianal induration, serosanguineous discharge, tenesmus and pain during defecation, symptoms that started insidiously nine months before and progressed up to the time of consultation.
Exploration showed generalized skin lesions that distally were flat papular confluent skin-colored papules. On trunk, lesions were oval confluent maculae with light desquamation. Koebnerization was evident. Papular fibroma-like lesions seated on a suppurative fistulized perianal mass were also seen. A biopsy of cutaneous lesions was consistent with verrucciform epidermodysplasia and a biopsy of perianal lesions was compatible with condyloma showing high dysplasia. An intraanal biopsy of the mass showed an SCC. Image studies disclosed hepatic and peritoneal metastasis. Treatment of skin lesions with cryotherapy and immunomodulators were of no aid. SCC was treated with surgical and radiation palliative measures. Finally, He died 10 months after diagnosis from complications of metastatic disease of anorrectal SCC. We conducted PCR studies to determine the presence of HPV in paraffin embedded specimens that disclosed the presence of HPV-5 in EV lesions and HPV-59 in both high grade dysplastic condylomas and epidermoid anal carcinoma.
As EV-HIV,1 HPV induced mucosal carcinoma, notably anal carcinoma, as result of chronic HPV infection is an emerging problem in HIV populations.2 In immunocompetent patients, a lengthy period from HPV infection is necessary for development of neoplasia but in HIV patients this incubation period is shortened (2). Pre-HAART, the diagnosis of anal SCC often fairly quickly followed the diagnosis of HIV disease.3 However, introduction of HAART therapy has changed the natural evolution of HPV infection in HIV patients and now a substantial delay from the time of diagnosis of HIV disease to diagnosis of anal SCC, which averages 10 years or more, is observed.3 In spite of this, HAART does not restore the defective immune response against HPV in HIV patients including EV-HIV and high grade dysplastic condylomas.1,2 Therefore, we must be prepared for a significant increase of this type of patient in the near future and encourage, as suggested by Jacobelli et al,1 for clinical follow-ups with detailed mucosal, oral, genital and anal examinations in EV-HIV patients.
References
1. Jacobelli S, Laude H, Carlotti A, Rozemberg F, Deleuze J, Morini JP, et al. Epidermodysplasia verrucciformis in human immunodeficiency virus- infected patients. Arch Dermatol Online jan,17:2011.
2. Kreuter A, Potthoff A, Brockmeyer NH, Gambichler T, Swoboda J, St?cker M, et al. Anal carcinoma in human immunodeficiency virus-positive men: results of a prospective study from Germany.Br J Dermatol. 2010;162:1269- 77.
3. Nagle D. Anal squamous cell carcinoma in the HIV-positive patient. Clin Colon Rectal Surg 2009;22:102-6.

Conflict of Interest: None declared
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Epidermodysplasia Verruciformis in Human Immunodeficiency Virus–Infected Patients: A Marker of Human Papillomavirus–Related Disorders Not Affected by Antiretroviral Therapy
Arch Dermatol.2011;147(5):590-596.eTable

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