ONCOGENIC BALANITIS. G. Tchernev 1, J. Ananiev 2, J. C. Cardoso 3, S. Philipov 4 and U. Wollina 5

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1 ONCOGENIC BALANITIS G. Tchernev 1, J. Ananiev 2, J. C. Cardoso 3, S. Philipov 4 and U. Wollina 5 1 Polyclinic for Dermatology and Venerology, University Hospital Lozenetz, Saint Kliment Ohridski University, So a, Bulgaria 2 Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria 3 Dermatology Department, University Hospital of Coimbra, Coimbra, Portugal 4 Department of General and Clinical Pathology, Medical Faculty, Saint Kliment Ohridski University, So a, Bulgaria 5 Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany Summary. The so-called oncogenic balanitis is a not so rare nosological entity, whose pathogenesis is related in most cases to infection with oncogenic strains of the human papilloma viruses (HPVs). In the early stages of the disease the clinical presentation of the infection with some oncogenic or high risk human HPVs is often non-speci c, contributing to its persistance for a long time, often misdiagnosed as a candidous or bacterial balanitis. Clinically the lesions may also be confused with lichen planus or lichen sclerosus, as well as penile eczema or psoriasis. Local and/or systemic therapy with corticosteroids can lead to unmasking of the symptoms and rapid progression of the disease, with potential risk of malignant transformation. Additionally, some patients decline a biopsy, further hampering the con rmation of the diagnosis. In all these problematic cases a diagnostic PCR examination of material taken from lesional skin could be of help for the diagnosis of Bowen s disease, erythroplasia Queyrat, consequently preventing its progression to invasive squamous cell carcinoma. We present a rare case of erosive and partially verrucous balanitis, in which HPV 56 strains were identifed by PCR in repeated samples from lesional skin. Additionaly, HPV 16 was also identi ed in the second sample. The clinical ndings were entirely consistent with erythroplasia of Queyrat but histopathological examination was not possible. A local therapy with imiquimod was started. After complete clinical recovery a vaccination with Gardasil was additionaly planned with the hope that the patient would be protected from possible recurrence due to the generation of cross-immunity against HPV 56. Due 18

2 to the risk of malignant transformation into squamous cell carcinoma of the penis, HPV-associated oncogenic balanitis is a disease portending a potentially unfavorable prognosis. In patients with longstanding genital lesions unresponsive to topical treatments usually used for balanitis, the possibility of HPV-induced oncogenic balanitis should be a strong consideration. PCR testing from lesional skin is probably one of the most sensitive, accurate, and reliable methods that help the clinician identify oncogenic and nononcogenic HPV-strains in problematic patients who refuse invasive and semi-invasive diagnostic options such as biopsy and cytological examination. Subsequent therapy should be complemented by regular clinical follow-up due to the possibility of relapse. Key words: oncogenic balanitis, HPV infection, erythroplasia of Queyrat, penile intraepithelial neoplasia INTRODUCTION Erythroplasia of Queyrat (EQ) represents a form of carcinoma in situ of the glans penis, prepuce and peri-ori cial region of the urethra. EQ, Bowen s disease and bowenoid papulosis are entities in the spectrum of penile intraepithelial neoplasia (PIN). EQ was rst described in 1891 by Tarnovsky, and twenty years later studied in detail and de ned as a separate entity by Queyrat [1]. Many factors contribute to the development of this genital disease, the risk being higher for immunocompromised patients, and in association with HPV infection, although the latter remains debatable [2, 3]. A major concern in these lesions is determining the most appropriate treatment approach. Radical penectomy and partial resections are now obsolete and not recommended because of the late psychological and functional sequelae. Current therapeutic options include conservative medical treatment, photodynamic therapy, plastic penile surgery, etc. We present a patient with clinically suspected EQ, proven by positive PCR for HPV 56 and HPV 16. CASE REPORT A 52-year-old patient presented to the clinic with an 8-month history of persistent erosion on the glans penis (Figs 1a, 1b). Long-term treatment with topical corticosteroids, antibiotics and antifungals had resulted in only partial and temporary improvement of the clinical picture (Figs 1c, 1d). Clinical examination revealed a sharply demarcated, raised, erythematous, velvety plaque on the glans penis (Figs 1a-d). All laboratory investigations were within the limits of the normal range. Microbiological cultures for bacteria and fungi, HIV and syphilis serology were all negative. Acta Medica Bulgarica, Vol. XL, 2013, 2 19

3 Fig. 1 (a, b, c, d) PCR genotyping for HPV, high and medium risk types, revealed HPV 56 positivity in two repeated samples from the lesion. The patient declined biopsy and cytology for diagnostic con rmation. The clinical picture was consistent with the suspicion of EQ. Treatment with imiquimod was started. A vaccination with Gardasil after complete remission of the clinical symptoms was planned. DISCUSSION Anogenital premalignancies and malignancies are frequently encountered in clinical practice [2]. Human papillomavirus (HPV) infection plays a critical role in a signi cant proportion of these cases. However, there is a variable degree of association of HPV infection with the development of anogenital malignancies [2]. In this context, the high level of clinically unapparent HPV infection should be considered. Therefore, we may question if the association with HPV is always causative [2]. Common anogenital premalignancies comprise Bowen s disease (BD), bowenoid papulosis (BP) and erythroplasia of Queyrat (EQ) [2]. From a clinical point of view, these are clearly different entities, but essentially indistinguishable from a histopathological point of view [2]. They all represent forms of squamous intraepithelial neoplasia [2]. As a typical precancerous process, EQ could remain con ned to the epidermis only, or progress to an invasive squamous cell carcinoma (SCC). Characteristic for EQ and other similar conditions, such as Bowen s disease, is the association with HPV infection, usually with high-risk viral types. Many authors now consider HPV-associated balanoposthitis according to the type of the isolated papilloma virus and modify their approach to the lesion according to whether the HPV is a high risk strain (types 16, 18, 31 and 33) or a low risk one (types 6 and 11) [4]. By PCR 20

4 analysis, Wieland et al. found out that other HPV types, namely 8, 42, 51, also have a role in EQ development. Statistically signi cant was the association of EQ with infection with HPV 16 and a co-infection with HPV 39 and HPV 51 [5]. In our patient, a single HPV type (HPV 56) was present in the rst smear and in the second evaluation the smear was also positive for HPV 16. Data about such association in the literature are scarce and no other cases of HPV 56-associated EQ have been reported so far. Histological examination is the main diagnostic method for EQ. As our patient declined a biopsy, we sought an alternative investigation that could be equally diagnostic but less invasive. Exfoliative cytological examination is rarely used in the dermatological practice, but several authors emphasize its advantages as an easyto-perform and fairly informative procedure [6]. It has been applied in the diagnosis of various genodermatoses, infections, tumours, etc. Unfortunately, the patient did not agree with cytological investigation of lesional tissue either. Treatment is controversial and depends on the location, size and depth of the lesion, as well as on the personal experience of the treating specialist. The two main kinds of treatment approaches include physical destruction of the lesions (either by surgical or non-surgical modalities) or modulation of the immune system. Del Losada et al. reported good results with CO2 laser vaporization in a young patient with involvement of the urethra [7]. In addition to surgical clearance of the lesion, the cosmetical and functional integrity was preserved. Function and structure preservation and good prognosis were also reported for another treatment modality excision and reconstruction, as described by Angerer-Shpilenya et al. [8]. Medical treatments for EQ are also of interest. Imiquimod 5% cream is usually the rst choice for young patents. It is a modi ed immunomodulator with anti-viral and anti-cancerous effect resulting from its activating function on cytokines, such as IL-6, 12, IFN and TNF, which play a main role in anti-cancer immunity [9, 10]. In a study of 123 patients with different forms of SCC, basal cell carcinoma, Bowen s disease and EQ, Alessi et al. found evidence of the strong therapeutic effect of imiquimod 5% cream and proved its particular suitability for patients who are not ideal candidates for surgical treatment [11]. Another effective therapeutic option is 5- uorouracil 5% [12]. Regardless of the chosen treatment option, medical or surgical, close follow-up in order to detect possible relapses is warranted. REFERENCES 1. G o e t t e, D. K. Review of erythroplasia of Queyrat and its treatment. Urology. Oct., 8, 1976, 4, Henquet, C. J. Anogenital malignancies and pre-malignancies. J. Eur. Acad. Dermatol. Venereol., 25, 2011, 8, N a s c a, M. R. et al. Absence of PCR-detectable human papilloma virus in erythroplasia of Queyrat using a comparative control group. Sex Transm. Infect., 86, 2010, 3, Acta Medica Bulgarica, Vol. XL, 2013, 2 21

5 4. W i k s t r ö m, A. et al. The acetic acid test in evaluation of subclinical genital papillomavirus infection: a comparative study on penoscopy, histopathology, virology and scanning electron microscopy ndings. Genitourin Med., 68, 1992, 2, Wieland, U. et al. Erythroplasia of Queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ. J. Invest. Dermatol., 115, 2000, 3, R u o c c o, E. et al. The practical use of cytology for diagnosis in dermatology. J. Eur. Acad. Dermatol. Venereol., 25, 2011, 2, Del Losada, J. P. et al. Erythroplasia of Queyrat with urethral involvement: treatment with carbon dioxide laser vaporization. Dermatol. Surg., 31, 2005, (11 Pt 1), Angerer-Shpilenya, M., N. T. Gaisa et G. Jakse. [Excision of carcinoma in situ of the glans penis with reconstructive plastic surgery]. Urologe. A., 49, 2010, 3, Micali, G., M. R. Nasca et R. De Pasquale. Erythroplasia of Queyrat treated with imiquimod 5% cream. J. Am. Acad. Dermatol., 55, 2006, 5, Choi, J. W., M. Choi et K. H. Cho. A case of erythroplasia of queyrat treated with imiquimod 5% cream and excision. Ann. Dermatol., 21, 2009, 4, A l e s s i, S. S. et al. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clin. (Sao Paulo), 64, 2009, 10, S t a r r i t t, E. et S. Lee. Erythroplasia of Queyrat of the glans penis on a background of Zoon s plasma cell balanitis. Australas J. Dermatol., 49, 2008, 2, Address for correspondence: ssoc. Professor Dr. Georgi Tchernev Saint Kliment Ohridski University Medical Faculty University Hospital Lozenetz Polyclinic for Dermatology and Venerology 1 Koziak St So a, Bulgaria

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