Multiple epidermolytic acanthomas mimicking condyloma: a retrospective study of 8 cases

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1 Report Multiple epidermolytic acanthomas mimicking condyloma: a retrospective study of 8 cases Tsung-Ju Lee 1, MD, and Yu-Hung Wu 1,2, MD 1 Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan, and 2 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan Correspondence Yu-Hung Wu, MD Department of Dermatology Mackay Memorial Hospital 92, Sec. 2, Zhongshan North Road Taipei, 10449, Taiwan dr.yhwu@gmail.com Funding: Supported by Mackay Memorial Hospital (13MMH ). Conflicts of interest: None. Abstract Background Epidermolytic acanthoma (EA) is an uncommon benign cutaneous lesion. Multiple epidermolytic acanthomas (multiple EAs) are rarely reported. Methods We retrospectively identified patients diagnosed with multiple EAs between 2005 and 2017 from our dermatopathology database and analyzed their clinical, pathological, and immunohistochemical features. We also evaluated the association of multiple EAs with human papillomavirus (HPV) infection. Results In total, eight patients (average age 51 years; 3 : 1 male predominance) with multiple EAs were found. All patients had lesions on the genitocrural area. The two most common clinical diagnoses were condyloma (5/8) and soft fibroma (3/8), which were predominantly skin-colored (5/8) or whitish (2/8). The lesions were less than 1 cm in diameter, and most (6/8) appeared to have a smooth surface. No molecular evidence suggesting HPV infection was found. Immunohistochemical staining showed low mitotic activity. The lesions were removed in one of two patients via cryotherapy, and one patient was treated with electrocauterization. The other five patients were followed without treatment. Conclusion The genital area was the most common location for multiple EAs, which was commonly misdiagnosed clinically as condyloma. Patients presenting with uniformly smallsized, skin-colored to whitish, smooth papular lesions in the genitalia should be carefully evaluated. The specific pathological features of epidermolytic hyperkeratosis are diagnostic, and the lesions can be observed without aggressive treatment after confirmed diagnosis. 28 Introduction Epidermolytic acanthoma (EA) is a rare benign tumor which usually appears as a solitary small papule. Solitary EAs were initially reported by Shapiro and Baraf in 1970, and multiple EAs were first described by Hirone and Fukushiro in ,2 Lesions are generally asymptomatic, although they can be pruritic, and appear on the trunk and extremities. The most significant pathological feature is epidermolytic hyperkeratosis (EHK). Epidermolytic hyperkeratosis is a pathological phenomenon characterized by hyperkeratosis, perinuclear vacuolization, and reticular degeneration in the granular and spinous layers. 3 Although these pathological features are key characteristics of bullous ichthyosiform erythroderma, they can also appear in other localized or/and generalized genetic and acquired diseases, including V orner s palmoplantar keratoderma, ichthyosis hystrix, epidermolytic epidermal nevi, acrosyringial epidermolytic papulosis neviformis, and EA. 3 6 Therefore, the pathological findings of EHK must be correlated with patients clinical presentation to reach the correct diagnosis. Only a few case reports of multiple EAs have been reported to date. In this retrospective case review, we demonstrate the clinical characteristics of our cases and evaluate the association with human papillomavirus (HPV) infection. Materials and methods Patient selection We retrospectively evaluated patients with a pathologic diagnosis of EA from our dermatopathology database between January 2005 and January 2017 after the approval by the Institutional Review Board of Mackay Memorial Hospital (16MMHIS121). Patients who presented with multiple lesions (3 or more) confirmed by medical records and clinical photographs were included. Histopathologically, they were well-demarcated papular lesions or keratoses showing the typical features of EHK, including hyperkeratosis, perinuclear vacuolization, and reticular degeneration in the granular and upper spinous layers, coarse basophilic keratohyaline granules, and intracytoplasmic eosinophilic inclusion bodies in the upper spinous layers (Fig. 1). The portion of EHK must be more than 50% in the International Journal of Dermatology 2018, 57, ª 2017 The International Society of Dermatology

2 Lee and Wu Multiple epidermolytic acanthomas Report 29 Figure 1 Histopathology of epidermolytic acanthoma. This is a well-demarcated papular lesion characterized by compact hyperkeratosis, perinuclear vacuolization, and reticular degeneration in the granular and upper spinous layer, coarse basophilic keratohyalin granules, and presence of intracytoplasmic eosinophilic inclusion bodies in the upper spinous layers (hematoxylin and eosin, original magnification, a 940, b 9200) was obtained using the QIAamp DNA FFPE tissue kit (QIAGEN Inc., Valencia, California, USA) following the manufacturer s instructions. PCR with the SPF1 and SPF2 primer pair was used to detect HPV DNA as previously described. The HPV DNA PCR products spanned the L1 region from nucleotides 6582 to The system can detect at least 43 different HPV genotypes, including high-risk anogenital HPV genotypes and common cutaneous HPV genotypes. 7 The monoclonal mouse anti-human Ki-67 antigen (clone MIB- 1, DakoCytomation, Glostrup, Denmark) was used to detect mitotic activity and was overexpressed in HPV infected lesions The normal epidermis has scattered nuclear staining in the basal cell layer but not in the suprabasal cells and upper epidermis. When present, this nuclear staining was graded based on the percentage of positive cells as follows: 0 (normal basal distribution), 1 (continuous basal distribution), 2 (<25% suprabasal distribution), 3 (25 50% suprabasal distribution), 4 (51 75% suprabasal distribution), and 5 (>75% suprabasal distribution). The monoclonal mouse anti-p16ink4a antibody (clone E6H4; Ventana, Tucson, Arizona, USA) was used to detect p16ink4a protein levels; p16ink4a is a cyclin-dependent kinase inhibitor that functions in the control of the G1-S phase transition. p16ink4a is expressed in the epithelium infected by high-risk HPV. 9,10 The cytoplasmic overexpression of p16ink4a was graded as follows: 0 (negative), 1 (focal, <10%), 2 (10 24%), 3 (25 50%), 4 (51 75%), and 5 (>75% positive cells). The monoclonal mouse anti-human p21 antibody (clone SX118; DakoCytomation, Glostrup, Denmark) was used to provide additional evidence of cell-cycle disruption secondary to low-risk HPV infection, 8,11 and the percentages of positive cells were graded as follows: 0 (negative), 1 (focal basal distribution), 2(<25% suprabasal distribution), 3 (25 50% suprabasal distribution), 4 (51 75% suprabasal distribution), and 5 (>75% suprabasal distribution). lesion. The pathological diagnosis was confirmed by an independent dermatopathologist (YH Wu). Clinical information Clinical information and photographs of eligible patients were collected and analyzed, including sex, age, clinical impression before the biopsy, morphology and location of the lesions, symptoms, comorbidity, treatment methods, and response. Study of association of HPV Polymerase chain reaction (PCR) was performed to detect HPV, and immunohistochemical staining including Ki-67, p16, and p21 was performed to understand the proliferative status of multiple EAs and the association with low- and high-risk HPV infection. Human papillomavirus deoxyribonucleic acid (DNA) extraction and sequencing was performed as follows. Four to five 10-lm sections were cut from each paraffin-embedded block. DNA Results A total of eight patients with multiple EAs were found in our database and included in the study. The basic demographic characteristics of the patients are summarized in Table 1. The average age was 51 years, ranging from 33 to 91. The male-tofemale ratio was 3 : 1. Distribution and location The most common location for lesions was on the genital area (7/8, 87.5%; Fig. 2), with one case on the groin (Fig. 2a). Both women included in the study had lesions on the labia majora (Fig. 2c). Color, size, symptoms, and duration Most lesions were skin-colored (5/8, 63%, Fig. 2b,d), followed by whitish (2/8, 25%, Fig. 2c) and brownish (1/8, 12%, Fig. 2a). ª 2017 The International Society of Dermatology International Journal of Dermatology 2018, 57, 28 33

3 30 Report Multiple epidermolytic acanthomas Lee and Wu Table 1 Clinical features of multiple epidermolytic acanthoma in eight patients Case Age Sex Location Color Surface Size Symptoms Impression Comobidity Duration Treatment 6 months Observation Papules Asymptomatic Soft fibroma BPH, GERD, fatty liver 1 48 M Groin Brownish Verrucous (Conical) Not given 3 months Cryotherapy Skin-colored Smooth Papules Asymptomatic Condyloma/ Bowenoid papulosis/ Seborrheic keratosis 2 33 M Scrotum and penis 1 week Observation DM, HTN, peptic ulcer, CHF, CKD, gout, hyperlipidemia, 3 91 F Labia majora Whitish Smooth Papules Pruritus Condyloma/Bowenoid papulosis 4 43 M Scrotum Skin-colored Smooth Papules Asymptomatic Epidermolytic acanthoma Not given 2 months Observation 5 51 M Scrotum Skin-colored Smooth Papules Asymptomatic Condyloma Gouty arthropathy 1 month Observation 6 43 M Scrotum Skin-colored Smooth Papules Pruritus Soft fibroma Not given 3 years Observation 7 46 F Labia majora Whitish Smooth Papules Pruritus Condyloma Not given More than Cryotherapy 1 month Electrocauterization More than 1 month Papules Asymptomatic Condyloma/Soft fibroma HTN, gout, hyperlipidemia, BPH 8 52 M Scrotum Skin-colored Verrucous (Conical) M, male; F, female; BPH, benign prostate hyperplasia; GERD, gastroesophageal reflux disease; DM, diabetes mellitus; CHF, congestive heart failure; CKD, chronic kidney disease; HTN, hypertension. Lesion sizes were uniform and ranged from 2 to 6 mm. The surface appearance was smooth (6/8, 75%, Fig. 2c,d) and verrucous, conical, or keratotic (2/8, 25%, Fig. 2a,b). Most were asymptomatic (5/8, 62%). Three patients (3/8, 37%) had pruritus. Women had a higher percentage of pruritus in the labia majora (2/2). The duration from discovery of the lesions to surgery ranged from 1 week to 3 years. Clinical diagnosis Clinical diagnoses of patients included condyloma (5/8, 62%), soft fibroma (3/8, 37%), bowenoid papulosis (2/8, 25%) and seborrheic keratosis (1/8, 12%). Three patients had more than one diagnosis. Only one case was clinically diagnosed with epidermolytic acanthoma. Association with HPV infection DNA extraction was successful in all eight patients, and no HPV was detected using PCR. The immunohistochemical staining showed only normal basal nuclear activity based on the Ki-67 stain in all eight patients (Fig. 3a). The findings indicate low mitotic activity in the tumor. All eight patients showed negative results for p16 (Fig. 3b). Two patients showed negative results for p21 (Fig. 3c); however, six patients showed weak positive results in the nuclei of parabasal keratinocytes (Fig. 3d). However, none of the keratinocytes in the upper epidermis stained positively for p21. Comorbidity None of the patients included in this study had alternative dermatological diagnoses, and there was no family history of related skin disorders. Medical comorbidities included gout or gouty arthropathy (3/8), hypertension (2/8), and hyperlipidemia (2/8). Other sporadic systemic diseases were chronic kidney disease, benign prostatic hyperplasia, diabetes mellitus, and congestive heart failure. Treatment course Most patients were only observed regularly after being diagnosed with EA (5/8, 62%) and the number of EAs did not change at 6-month follow-up. Two patients were treated with cryotherapy with a success rate of only 50% (1/2). One patient was treated using electrocauterization. Discussion This study described the clinical features of patients with multiple EAs. These often occurred in the genitocrural areas and clinically mimicked condyloma. With respect to solitary EA, only about 34.4% appeared on or around the genital area, but all multiple EAs in our study appeared in these regions. 12 None of our patients had HPV infection. There are a number of features that help clinically distinguish multiple EAs from condyloma. First, in our study, the average International Journal of Dermatology 2018, 57, ª 2017 The International Society of Dermatology

4 Lee and Wu Multiple epidermolytic acanthomas Report 31 (c) (d) Figure 2 Clinical presentation of multiple epidermolytic acanthoma. Scattered small brownish verrucous or conical papules on the inner thighs (patient 1). Skincolored conical papules on the scrotum (patient 8). (c) Discrete small whitish papule with smooth surface on the vulva (patient 3). (d) Skin-colored smooth papules on the scrotum (patient 2) Figure 3 The immunohistochemistry of multiple epidermolytic acanthomas. The Ki-67 stain in all eight patients shows low mitotic activity in the tumor. Only the normal basal nuclear activity is present. The p16 is negative in all eight patients. (c) The p21 is negative (two patients) or (d) shows weak nuclear positivity in the parabasal keratinocytes (six patients). However, none of the keratinocytes in the upper epidermis stain for p21 (original magnification, a d 940) (c) (d) age of patients with multiple EAs was 51 years, which is older than the average age for condyloma (17 to 33). 13 The other features included color, size, and distribution. Multiple EAs tended to be lighter in color (skin-colored or whitish), the size was uniformly smaller (2 6 mm), and the lesions were sporadically distributed. Condylomas in oriental people tend to be more darkish-brownish, of various sizes, more cauliflower-like in the later stage, and often grouped (Fig. 4a,b). Condyloma often occurs on the glans penis, penile shaft, penile root, pubic area, groin, and perianal area, in contrast to multiple EAs which occur on the scrotum in men and labia majora in women. A verrucous or smooth surface is not very helpful in helping to distinguish between the two lesions, since condyloma is often verrucous, and bowenoid papulosis (Fig. 4c,d) may have a smooth surface. Even though the multiple EAs were localized and scattered, there could occasionally appear as many as nearly 50 lesions. 14 Skin biopsy is always important to confirm the diagnosis when clinical diagnosis is difficult. The pathological diagnosis of EA was relatively simple because of the presence of characteristic EHK. The architecture of a well-demarcated papular lesion was also helpful to exclude the possibility of bullous congenital ichthyosiform ª 2017 The International Society of Dermatology International Journal of Dermatology 2018, 57, 28 33

5 32 Report Multiple epidermolytic acanthomas Lee and Wu (c) (d) Figure 4 The main differential diagnosis. Condyloma of a male patient and a female patient. Bowenoid papulosis of (c) a male patient and (d) a female patient. They tend to be more grouped together, rather than discrete in multiple epidermolytic acanthoma. The distribution of condyloma and bowenoid papulosis is close to the penile root and perivulvar area, rather than on the scrotum or vulva in multiple epidermolytic acanthoma erythroderma, which shows diffuse EHK and linear epidermolytic epidermal nevi demonstrating prominent papillomatosis and acanthosis. 3 5 However, diagnosis can be more complicated when a small focus of EHK is present in benign keratosis or seborrheic keratosis lesions. Therefore, the foci of EHK have to be more than 50% to meet the diagnostic criteria for EA, and a careful inspection of the entire lesion is important. 3,4 Fortunately, the clinical behavior of multiple EAs is benign and not contagious. The etiopathogenesis of EA remains unclear. Although a functional mutation of either keratin 1 or keratin 10 genes predisposes to the development of EHK in bullous congenital ichthyosiform erythroderma, whether EA has a similar association has not been shown. 4,5,15 Other potential exogenous factors include HPV or other viral infection, ultraviolet light, trauma, and an immunosuppressed state. 5 Banky and Turner reported the case of a 44-year-old man with a 5-year history of pruritus localized to the scrotum, which was repetitively scratched by the patient. This was thought to be one of the reasons for the generation of multiple scrotal EAs. 16 Sanchez et al. 17 reported a case of disseminated EA on the lower abdomen and thorax in another patient thought to be because of friction from tight clothing. 17 In our analysis, although most patients were asymptomatic, 37% did experience pruritus. Nakagawa et al. reported a patient who received psoralen and ultraviolet A radiation treatment for Sezary syndrome and subsequently developed disseminated EA during treatment, which disappeared 5 months after the end of treatment. 14 Chun et al. reported a case of disseminated EA in a renal transplant patient with a 14-year history of immunosuppressive therapy. 18 Although HPV infection has been speculated as one cause of disseminated EA, this has not been confirmed. 5 PCR and immunohistochemical staining (Ki- 67, p16 and p21) could not demonstrate an association with HPV infection in our cases. In a literature review, we found that six other patients had also been tested for HPV, but immunohistochemical and molecular studies both failed to detect viral genome. 15,16,19 22 None of the eight patients had a personal or family history of ichthyosiform disorders. No consistent systemic comorbidities were found, although our patients did suffer from cardiovascular diseases, hyperlipidemia, and renal disease, which are common presentations in old age. Multiple EAs usually required no specific treatment once the diagnosis was established. Among the eight patients in this study, five were observed without any treatment. Potential treatments for EA include surgery, curettage, cryotherapy, and ablative laser therapy. Two patients with multiple EAs (Cases 2 and 7) received cryotherapy, with a 50% success rate. One of the patients receiving cryotherapy continued to be treated because the lesions persisted without increasing numbers (Case 7). Topical medications or emollients, such as imiquimod, calcipotriol, pimecrolimus cream, tacrolimus, retinoids, lactic acid, glycolic acid, and salicylic acid, have been utilized for multiple EAs, with variable response rates. 4,15,20,23,24 Although this present study has clinical and pathological implications, we acknowledge that there were several limitations. In particular, it had a small sample size because of the rarity of multiple EAs. We also used a retrospective study design and short follow-up time. In addition, we did not assess the molecular etiology of EA, such as the functional mutation of keratin genes, in our patients. Nonetheless, these initial results provide insight into the association between clinical examination and histopathological findings when diagnosing patients with a rare condition. It is important to take EA into consideration as part of the differential diagnosis of patients with uniformly sized, skin-colored or whitish, and smooth lesions in the genitalia. A International Journal of Dermatology 2018, 57, ª 2017 The International Society of Dermatology

6 Lee and Wu Multiple epidermolytic acanthomas Report 33 second implication derived from our finding was that multiple EAs are not contagious. Conclusion Multiple EAs commonly occur on the genital area and may easily be misdiagnosed as condyloma. The clinical features, including older age, lighter color, smaller size, and sporadic distribution, and specific pathological EHK features were helpful to confirm the diagnosis. There was no association with HPV found in this case series. There was no need of aggressive treatment once the diagnosis was established. References 1 Hirone T, Fukushiro R. Disseminated epidermolytic acanthoma. Nonsystematized multiple verrucoid lesions showing granular degeneration. Acta Derm Venereol 1973; 53: Shapiro L, Baraf CS. Isolated epidermolytic acanthoma. A solitary tumor showing granular degeneration. Arch Dermatol 1970; 101: Abbas O, Wieland CN, Goldberg LJ. Solitary epidermolytic acanthoma: a clinical and histopathological study. J Eur Acad Dermatol Venereol 2011; 25: Hijazi MM, Succaria F, Ghosn S. Multiple localized epidermolytic acanthomas of the vulva associated with vulvar pruritus: a case report. Am J Dermatopathol 2014; 37: e49 e52. 5 Bogale SR, Chan CS, McIntire H, et al. Epidermolytic acanthoma of the scrotum: a rare mimicker of condyloma acuminatum. Dermatol Online J 2011; 17: 6. 6 Russell P, Valmadre S, Howard V. Localised epidermolytic hyperkeratosis of the vulva: a case of mistaken identity. Pathology 2010; 42: Kleter B, van Doorn LJ, ter Schegget J, et al. Novel shortfragment PCR assay for highly sensitive broad-spectrum detection of anogenital human papillomaviruses. Am J Pathol 1998; 153: Lyman RC, Wilson ML, Herrington CS. Cell-cycle control protein expression is disrupted in anogenital condylomata infected with low-risk human papillomavirus types. J Low Genit Tract Dis 2008; 12: Bean SM, Eltoum I, Horton DK, et al. Immunohistochemical expression of p16 and Ki-67 correlates with degree of anal intraepithelial neoplasia. Am J Surg Pathol 2007; 31: Walts AE, Lechago J, Bose S. P16 and Ki67 immunostaining is a useful adjunct in the assessment of biopsies for HPVassociated anal intraepithelial neoplasia. Am J Surg Pathol 2006; 30: Wu Y-H, Hsiao P-F, Chen C-K. Histopathologic and immunohistochemical distinction of condyloma and seborrheic keratosis in the genitofemoral area. Dermatologica Sinica 2013; 31: Kazlouskaya V, Lambe J, Elston D. Solitary epidermolytic acanthoma. J Cutan Pathol 2013; 40: Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J 2006; 12: Nakagawa T, Nishimoto M, Takaiwa T. Disseminated epidermolytic acanthoma revealed by PUVA. Dermatologica 1986; 173: Tan GF, Tan ES, Tey HL. Anogenital epidermolytic acanthomas: effective treatment of pruritus with 0.1% tacrolimus ointment. Dermatol Ther 2014; 27: Banky JP, Turner RJ, Hollowood K. Multiple scrotal epidermolytic acanthomas; secondary to trauma? Clin Exp Dermatol 2004; 29: Sanchez-Carpintero I, Espana A, Idoate MA. Disseminated epidermolytic acanthoma probably related to trauma. Br J Dermatol 1999; 141: Chun SI, Lee JS, Kim NS, et al. Disseminated epidermolytic acanthoma with disseminated superficial porokeratosis and verruca vulgaris in an immunosuppressed patient. J Dermatol 1995; 22: Kukreja T, Krunic A. Multiple epidermolytic acanthomas must not be confused with genital human papillomavirus infection. Acta Derm Venereol 2009; 89: Berryman JL, Nutt TJ, Groo SC. Painless genital papules and plaques. Dermatol Online J 2008; 14: Reguiai Z, Cribier B, Derancourt C, et al. Multiple spreading epidermolytic acanthomas of the genital and perigenital skin. Dermatology 2005; 211: High WA, Miller MD. Localized epidermolytic hyperkeratosis of the female genitalia: a case report and review of an underappreciated disorder of women. MedGenMed 2005; 7: Batalla A, Carpintero ML, De la Torre C. Disseminated epidermolytic acanthoma with partial response to calcipotriol ointment. J Dermatol 2013; 40: Jang BS, Jang HS, Park HJ, et al. Multiple scrotal epidermolytic acanthomas successfully treated with topical imiquimod. J Dermatol 2007; 34: ª 2017 The International Society of Dermatology International Journal of Dermatology 2018, 57, 28 33