Human Papillomavirus Type 5 Related Epidermodysplasia Verruciformis in A Patient with Systemic Lupus Erythematosus

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1 Human Papillomavirus Type 5 Related Epidermodysplasia Verruciformis in A Patient with Systemic Lupus Erythematosus Report of Two Cases and Review of the Literature Chao-Chin Wang Hsiu-Hsin Tsai Tsung-Hsien Tsai 1 Woan-Ruoh Lee Kuo-Hsien Wang Epidermodysplasia verruciformis (EV) is a rare cutaneous human papilomavirus (HPV) infection characterized by an unusual susceptibility to a specific group of HPVs, so-called epidermodysplasia verruciformis associated human papillomaviruses (EV-HPVs). We herein report a 42-year-old women with a history of systemic lupus erythematosus (SLE) who initially showed multiple erythematous flattopped papules on the neck and medial forearms and progressively developed numerous brownish macules on her face, neck, upper chest and back in the following three years. The histopathology revealed characteristic viral cytopathic changes in an acanthotic epidermis: multifocal enlarged keratinocytes with cytoplasmic vacuolization in granular layer and upper spinous layer. The diagnosis of EV was thus made. Besides, the presence of human papillomavirus type 5 (HPV 5) DNA was detected on the lesional and peri-lesional skin. The patient was then treated with different modalities including Erbium-YAG laser, cryotherapy with liquid nitrogen, and topical 5% imiquimod. Partial clearing of the lesions were observed by all these three modalities up to a 6-month period of follow-up. In addition, we make a review of the relationship between EV, EV-HPV and development of non-melanoma skin cancers (NMSCs). (Dermatol Sinica 24: , 2006) Key Words: Epidermodysplasia verruciformis, Human papillomavirus, Systemic lupus erythematosus, Non-melanoma skin cancers From the Department of Dermatology, Taipei Medical University Hospital, and Taipei Municipal Wanfang Medical Center 1 Accepted for publication: July 27, 2006 Reprint requests: Kuo-Hsien Wang, M.D., Department of Dermatology, Taipei Medical University Hospital, No.252, Wuxing Street, Xinyi District, Taipei City 110, Taiwan. TEL: ext.1122 FAX: Dermatol Sinica, Dec 2006

2 Imiquimod ( 24: , 2006) INTRODUCTION Epidermodysplasia verruciformis (EV) is a rare cutaneous disorder characterized by an unusual susceptibility to a generalized infection by human papillomaviruses (HPVs). There are a specific group of HPVs involved in the disease process called epidermodysplasia verruciformis associated human papillomaviruses, or EV- HPVs. EV is manifested by the appearance of widespread, polymorphic skin eruptions of verruca-like lesions and pityriasis versicolor-like macules. The lesions may undergo malignant transformation to non-melanoma skin cancers in 30% to 50% of cases, with a predilection for sun-exposed sites. 1, 2 CASE REPORT A 42-year-old Taiwanese woman presented with multiple erythematous flat-topped papules on the neck and medial forearms since The initial diagnosis was verrucae planae. She therefore received topical tretinoin 0.05% once daily before sleep. In addition to the original flat wart-like lesions, numerous brownish macules progressively developed on her face, neck, upper chest and back over the subsequent three years. The newly developed pityriasis versicolor-like lesions varied in size from 3 mm to 1 cm in diameter; Koebner phenomenon was observed (Fig. 1). All the skin lesions were asymptomatic. She had no family history of similar skin lesions. The patient had been diagnosed as systemic lupus erythematosus (SLE) 12 years before the onset of the skin problem. The initial presentation of SLE was symmetrical arthritis on knees and ankle joints, malar rash and oral ulcer. Elevated titer of ANA (1:1280X+) and low levels of C3 and C4 were also noted. She had been treated elsewhere with systemic corticosteroid, plaquenil and azathioprine. During the ensuing years, she had been admitted for more than ten times because of Fig. 1 Multiple erythematous flat-topped papules and brownish macules (3 mm-1 cm in diameter) progressively developed on the face, neck, upper chest, back and arms. Koebner phenomenon was also noted. Dermatol Sinica, Dec

3 various infections. Her SLE was controlled by prednisolone 5mg every other day over the last few years. At the time of presentation, complete blood cell counts revealed pancytopenia (WBC: 1,920 cells/ l, normal: 5,200-12,400; RBC: 3.29 cells/ l, normal: / 10 6 ; platelet: 7.1 fl, normal: ) and lymphopenia (absolute peripheral lymphocyte count: 267 cells/ l, normal: 1,600-2,400). In addition, the CD4 and CD8 count was 36 and 88 cells/ l, respectively, and the CD4/CD8 ratio was Blood biochemistry studies showed elevated C- reactive protein level (3.80 mg/dl, normal: < 0.8). Liver and renal functions were within normal limits; HIV serology and a potassiumhydroxide (KOH) examination for fungal element from forearm lesions were negative. An incisional skin biopsy was performed from the left forearm. The histopathologic result revealed viral cytopathic changes in an acanthotic epidermis i.e. multifocal enlarged keratinocytes with vacuolated cytoplasm in granular layer and upper spinous layer. Moreover, some basophilic keratohyalin granules were occasionally seen in those enlarged cells (Fig. 2). In addition, the skin scrapings from the lesional and peri-lesional skin were sent for polymerase chain reaction (PCR) followed by DNA sequencing (Fig. 3). The result demonstrated the presence of human papillomavirus type 5 (HPV 5). The protocols for PCR and DNA sequencing have been described. 3 Briefly, the PCR solution (25 l) contained 0.75 M (each) FAP59 and FAP64 primers which were designed from two relatively conserved regions of the L1 open reading frame of most HPV, 4 0.2% bovine serum albumin (Sigma-Aldrich, Steinheim, Germany), 0.2 mm (each) deoxynucleoside triphosphate, U of AmpliTaqGold DNA polymerase, GeneAmp PCR buffer II, 3.5 mm MgCl2 (Applied Biosystems, Foster City, CA, U.S.A.), and 5 l of the sample. Forty cycles of amplification were performed after denaturation for 10 min at 94 ; each cycle consisted of 94 for 90 s, 50 for 90 s, and 72 for 90 s. Subsequently, the clones were sequenced (ABI 310 automatic sequencer, Advanced Biotechnologies, Foster City, CA, U.S.A.) with both forward and reverse primers. The DNA sequences obtained were compared with all sequences in Gen Bank through the BLAST server (National Center for Biotechnology Information; The patient was then treated with different modalities including Erbium-YAG laser, cryotherapy with liquid nitrogen, and topical 5% imiquimod (Aldara cream, 3M). Partial clearing of the lesions were observed by all Fig. 2 Enlarged keratinocytes are found in granular layer and upper spinous layer of epidermis, with occasional presentation of basophilic keratohyalin granules. (H&E, x400) Fig. 3 Human papillomavirus type 5 is detected on the lesional and peri-lesional skin, confirmed by DNA sequencing. 280 Dermatol Sinica, Dec 2006

4 these three modalities up to a 6-month period of follow-up. DISCUSSION Lewandowsky and Lutz first described EV in It can be hereditary or sporadic, and no sexual, racial or geographic preference is noted. 5 Autosomal recessive transmission of the disease has been postulated as a main mode of inheritance, although autosomal dominant and sex-linked inheritance has also been described. 5-7 However, the sporadic form of EV remains to be the most commonly reported form of the disease. 7 The pathogenesis of EV is largely unknown. There has been accumulating evidence which suggests that dysfunction in cellmediated immunity may play a role. While the activity of non-specific nature killer cells and antigen presentation by Langerhans cells seem to be normal, 8-10 reduced natural cell-mediated cytotoxicity against EV-HPV harboring keratinocytes has been demonstrated. 11 All these findings indicate that there may be defects in cell-mediated immunity which result in the immunotolerance to these viruses. 12 There are two subsets of cutaneous lesions in EV; one is malignant form and the other benign. The benign form presents as monomorphous lesions that are plane wart-like and is associated with HPV types 3 and 10. The malignant subset is characterized by polymorphic skin manifestations, e.g. pityriasis versicolorlike lesions, flat wart-like papules, red macules, pre-malignancies such as actinic keratosis, and non-melanoma skin cancers. This form of EV is strongly associated with HPV types 5, 8, 9, 12, 14, 15, 17, 19-25, 36-38, 47, 49, 50, 75, 76 and 80; among them, only a few (predominantly type 5, 8 and occasionally type 14, 17, 20 and 47) have been demonstrated to have an association with carcinoma. 2, 6, 7, 13, 14 Noteworthily, the onset of initial cutaneous changes is often in the childhood 15 while malignant transformations, if any, usually occur in the third to fourth decades with preferential localization at the sun-exposed areas, especially the forehead. 1, 16 All these imply that both prolonged infection with EV-HPVs and ultraviolet irradiation may contribute to the development of skin cancers in EV patients. HPVs are small double-stranded DNA viruses that are strictly epitheliotropic and induce wide diversity of highly proliferating epithelial lesions. 17, 18 HPV infection is known to be linked to around 10% of the tumor burden worldwide and has been regarded as an important carcinogen in various epithelial tumors, such as the cancers of the cervix, squamous cell carcinoma (SCC), and verruca vulgaris. Their linkage to the development of non-melanoma skin cancers (NMSCs), namely SCCs, basal cell carcinomas (BCCs), comes first from some observational studies in transplant patients. 19 Studies on the detection of HPV DNA in NMSCs gave confusing results before early 1990s because of the technical difficulties in detecting the diversities of genomes which belong to the numerously different types of HPVs. It was not until the introduction of a highly sensitive degenerate PCR method by Shamanin et al. that the technique of HPV-DNA detection made a breakthrough. 20 With the subsequent combination of degenerate, nested and type-specific PCR followed by direct sequencing, hybridization or cloning, the prevalence of HPV DNA in transplant SCCs ranges from 69% to 88%, of which the EV-HPV types usually predominate and mixed infection with two or more HPV types are common. 21 EV-HPV DNA is also detected in SCCs from other immunosuppressed subjects, including those treated 22, 23 with psoralen-ultraviolet A (PUVA). The prevalence of HPV-DNA in transplant premalignant lesions (actinic keratoses, SCC in situ, keratoacanthomas) are as high as in their invasive counterparts. 24 In contrast, most studies reported a lower prevalence of HPV in transplant BCCs than in SCCs. 22, 25, 26 There are only two previous case reports regarding the association between EV and 27, 28 SLE, while EV / EV-like eruptions have been described in organ transplantation, Hodgkin's disease, leukemia, thymoma, lepro- Dermatol Sinica, Dec

5 matous leprosy and HIV infection These sporadic cases all demonstrated derangement of immune status, either due to immunosuppressive agents, hematologic neoplasms, or HIV infection. They showed characteristic clinicopahologic features and viral evidences of EV as were seen in classical (familial) EV, except in some patients (i.e. Hodgkin s disease), the EVlike lesions were almost exclusively present on irradiated and UV-exposed skin. 28, 29 One of the two SLE-related cases was a 32-year-old female with EV who had been diagnosed with of SLE for 13 years and had been treated with 33 pulses of intravenous cyclophosphamide, 3 pulses with methylprednisolone, oral prednisone (15-30 mg daily) and oral azathioprine ( mg daily). Consequently, she had experienced multiple complications such as Aspergillus pulmonary infection, Hemophilus influenza pneumonia, and Salmonella diarrhea during the course of the disease. In this sporadic case, HPV 17 DNA was found on the cutaneous lesion while HPV 20 DNA was identified in both lesional and adjacent normal skin. 28 The authors thus presumed that the long-standing use of immunosuppressive agents could result in the wide distribution of latent HPV that in turn contribute to 28, 29 the formation of EV. In addition to the prolonged immunosuppressive treatment, the role of autoimmunity itself in the genesis of EV-HPV is interesting. Anti-HPV 5 antibodies were detected (20%) in some autoimmune disorders with cutaneous involvement, such as SLE and systemic scleroderma; whereas HPV DNA sequences were detected in a much higher percentage (90%) of the patients in this group. 32 Another study demonstrated that damaged hair follicles in both of the diseases harbor EV-HPV DNA 33, 34 sequences, which could partly account for the high detection rate of HPV DNA. Given the low yield rate of HPV 5 antibodies identified from the sera of neurological autoimmune diseases without skin lesions of epidermal proliferation (multiple sclerosis: 4.6%; myasthenia gravis: 8.0%) 32 used for control, autoimmunity by itself appeared not to be sufficient for generation of anti-hpv 5 antibodies, if not associated with keratinocyte proliferation. The possible relationship between the development of EV and the immune status in SLE deserves further investigation. It has been demonstrated that SLE is caused by polyclonal activation of B lymphocytes, with subsequent generation of autoantibodies against a variety of self-antigens, including antibodies to nuclear, cytoplasmic, and extracellular components In our case, the prolonged use of prednisolone and azathioprine may not only reduce the production of B-cell antibody but also inhibit the actual function of T-cell mediated immunity, 38 thus increases the risk of various infection, including that of the HPV. Additionally, local immune responses play important roles during HPV infection in which CD4-positive T lymphocytes and macrophages predominate. A number of studies concerning interferon-resistant anogenital warts demonstrated reversed 39, 40 CD4/CD8 ratio (range, 0.38 to 0.97). Depleted infiltration of CD4 and, to a lesser extent, CD8 lymphocytes in this group of warts was found in comparison with interferonresponding ones. 41 In EV patients, it has been reported that the levels of CD3+ and CD4+ T lymphocytes were decreased with maintenance of CD8+ levels, and thus inversion of the CD4/CD8 ratio, however, the ratio may be variable according to duration and severity of disease. Furthermore, impairment of cell-medi- 8, 42 ated immunity was manifested by the cutaneous anergy to a variety of common skin antigens and, by the reduction of the lymphocyte transformation to phytohemagglutinin. 42 To sum up, we assumed that depleted CD4 lymphocytes, resulting in reversed CD4/CD8 ratio, may attribute to impaired local immune response and are associated with prolonged HPV infection. Given the rarity of cases of EV associated with SLE to date; it is likely that the larger reservoir of EV-HPV in autoimmune disease, the immunocompromised state secondary to drug treatments, and lastly, the genetic predisposition may all play certain roles in such a rare occurrence. With the disclosure of two suscepti- 282 Dermatol Sinica, Dec 2006

6 ble loci mapped to chromosome 2p21-p24 and 17q25 by linkage analysis, 43 it sheds light on advancing our knowledge to the innermost of EV. Unfortunately, we are unable to verify the genetic status in this patient because she loses her mother earlier in her life and there was no other affected member in her family. CONCLUSION EV is a rare cutaneous disorder characterized by persistent infection of EV-HPVs. This case is the third reported case of EV in a SLE patient. Although the pathogenesis of EV in this particular scenario remains to be elucidated, the finding of polymorphic skin lesions and presence of HPV type 5 in our patient warrants possible evolution to malignant cutaneous tumors and thus mandates strict sun protection and careful surveillance for pre-malignant and malignant lesions. ACKNOWLEDGEMENT We appreciate the technical aids for PCR and DNA sequencing from Taiwan Molecular Diagnostic Laboratories Ltd. REFERENCES 1. Majewski S, Jablonska S: Immunology of HPV infection and HPV associated tumors. J Invest Dematol 37: 81-95, de Oliveira WRP, Festa Neto C, Rady PL, et al.: Clinical aspects of epidermodysplasia verruciformis. J Eur Acad Dermatol 17: , Antonsson A, Hansson BG: Healthy skin of many animal species harbors papillomaviruses which are closely related to their human counterparts. J Virol 76: , Forslund OA, Antonsson P, Nordin B, et al.: 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 80: , Lutzner MA: Epidermodysplasia verruciformis: An autosomal recessive disease characterized by viral warts and skin cancer. Bull Cancer 65: , Harris AJ, Purdie K, Leigh IM, et al.: A novel human papillomavirus identified in epidermodysplasia verruciformis. Br J Dermatol 136: , Androphy EJ, Dvoretzky I, Lowy DR: X-Linked inheritance of epidermodysplasia verruciformis. Arch Dermatol 121: , Majewski S, Skopinska-Rozewska E, Jablonska S, et al.: Partial defects of cell-mediated immunity in patients with epidermodysplasia verruciformis. J Am Acad Dermatol 15: , Cooper KD, Androphy EJ, Lowy DR, et al.: Antigen presentation and T-cell activation in epidermodysplasia verruciformis. J Invest Dermatol 94: , Haftek M, Jablonska S, Szmanczyk J, et al.: Langerhans cells in epidermodysplasia verruciformis. Dermatologica 174: , Majewski S, Malejczyk J, Jablonska S: Natural cell-mediated cytotoxicity against various target cells in patients with epidermodysplasia verruciformis. J Am Acad Dermatol 22: , Lane JE, Bowman PH, Cohen DJ: Epidermodysplasia verruciformis. South Med J 96: , de Villiers EM: Human pathogenic papillomavirus types: an update. Curr Top Microbiol Immunol 186: 1-12, Motegi S, Tamura A, Endo A, et al.: Malignant proliferating trichilemmal tumour associated with human papillomavirus type 21 in epidermodysplasia verruciformis. Br J Dermatol 148: , Jablonska S, Majewski S: Epidermodysplasia verruciformis: Immunological and clinical aspects. Curr Top Microbiol Immunol 186: , Jablonska S, Majewski S: Epidermodysplasia verruciformis: what's new? J Eur Acad Dermatol 17: , Zur Hausen H: Papillomavirus infections: a major cause of human cancers. Biochim Biophys Acta 1288: F55-F78, Severson J, Evans TY, Lee P, et al.: Human papillomavirus infections: epidemiology, pathogenesis, and therapy. J Cutan Med Surg 5: 43-60, Boyle J, McKie R, Briggs J, et al.: Cancer, warts and sunshine in renal transplant recipients: a case control study. Lancet i: , Shamanin V, Glover M, Rausch C, et al.: Specific types of human papillomavirus found in benign proliferations and carcinomas of the skin in immunosuppressed patients. Cancer Res 54: , Shamanin V, zur Hausen H, Lavergne D, et al.: HPV infections in nonmelanoma skin cancers from renal transplant recipients and non-immunosuppressed patients. J Natl Cancer Inst 88: , Meyer T, Arndt R, Christophers E, et al.: Dermatol Sinica, Dec

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