Distinguishing Bowenoid Papulosis from Bowen Disease in the Mouth: a Case Report

Received: 3 July 2019 Revised: 11 September 2019 Accepted: 13 September 2019 DOI: 10.1111/cup.13579

CASE REPORT

Distinguishing bowenoid papulosis from Bowen disease in the mouth: A case report

Jean C. B. Ferreira1 | Henrique M. de Paula2 | Gustavo N. Caixeta3 | Elismauro F. Mendonça1

1Department of Oral Medicine (Oral Pathology), Dental School, Federal University Abstract of Goiás, Goiânia, Brazil Bowenoid papulosis (BPap) is an uncommon skindisorderlinkedtohumanpapillomavirus 2 Division of Anatomic Pathology, Medical (HPV) infection and characterized clinically bythepresenceofscatteredpapulesorsmall School, Federal University of Goiás, Goiânia, Brazil plaques, multiple and pigmented, that involve the stratified squamous epithelium. Bowen 3Division of Anatomic Pathology, Araújo Jorge disease (BD) is recognized as the main differential diagnosis of BPap. An 80-year old Hospital, Association of Cancer Combat of Goiás, Goiânia, Brazil white woman was referred for the evaluationofmultiple,brownverrucous papules measuring 3 to 4 mm in diameter on the right maxillary gingiva. Histopathological analysis Correspondence Dr. Elismauro F. Mendonça, Faculdade de revealed disturbed epithelial maturation withpapillarystratifiedsquamousepithelium, Odontologia, Universidade Federal de Goiás, koilocytic dysplasia, parakeratosis, acanthosis, basal double-layer, loss of cellular polarity, Av. 1 Avenida, S/n, Setor Leste Universitário, Goiânia-Goiás, CEP:74605-020, Brazil. nuclear hyperchromatism and pleomorphism, scattered mitosoid bodies, and a high Email: [email protected] degree of cytologic atypia. An immunohistochemical investigation for p53 and Ki67

Funding information showed staining of the basal and suprabasal layer, while p16 was strongly expressed in Fundaç~ao de Amparo à Pesquisa do Estado de the nuclei of epithelial cells and Bcl-2 was positive only in mitosoid bodies and the lym- Goiás; Coordenaç~ao de Aperfeiçoamento de Pessoal de Nível Superior phocytic inflammatory infiltrate. In situ DNA hybridization was negative for HPV. Oral BPap is an uncommon lesion in which the diagnostic process includes clinical, histopathological, and molecular correlations due to the similarity to aggressive behavior lesions such as BD.

KEYWORDS Bowen disease, bowenoid papulosis, HPV infection

1 | INTRODUCTION erythematous macule usually affecting of the skin or glans penis (erythroplasia of Queyrat) histopathologically characterized by carcinoma Bowenoid papulosis (BPap) is an uncommon skin disorder linked to in situ.AlthoughBPapandBDlesionsdonotresembleeachotherclini- 5 human papillomavirus (HPV) infection and characterized clinically by cally, the microscopic diagnosis can be difficult. the presence of scattered papules or small plaques, usually multiple The aim of this report is to present oral BPap in an elderly female and pigmented, that involve the stratified squamous epithelium.1 The patient and contribute to broadening our knowledge regarding this genital region in sexually active adults is the most common site of uncommon lesion in the oral region. involvement; however, extragenital lesions have been reported, including a few cases in the oral cavity.2-10 2 | CASE REPORT Bowen disease (BD), condyloma acuminatum and dysplastic oral wart associated with human immunodeficiency virus (HIV)d have been An 80-year-old white woman was referred for evaluation of asymp- described in the differential diagnosis.5,11 BD is an irregular tomatic pigmented lesions on the gingiva with approximately 2 months

J Cutan Pathol. 2020;47:257–262. wileyonlinelibrary.com/journal/cup 257 258 FERREIRA ET AL. of evolution. The medical history was positive for episodes of pneu- koilocytic dysplasia, parakeratosis, acanthosis, basal double-layer, loss monia and continuous positive airway pressure (CPAP) use for of cellular polarity nuclear hyperchromatism, and pleomorphism, obstructive sleep apnea. An intra-oral examination revealed multiple, scattered mitosoid bodies and a high degree of cytologic atypia brown verrucous papules measuring 3 to 4 mm in diameter on the (Figure 2A,B). An immunohistochemical investigation was carried for right maxillary gingiva (Figure 1). An incisional biopsy of the lesion p53, p16, Ki67 and Bcl-2 (Table 1). p53 and Ki67 showed expression in was performed and histopathological analysis revealed disturbed epi- the basal and suprabasal layers (Figure 3A,B). p16 was strongly expressed thelial maturation with a papillary stratified squamous epithelium, in the nuclei of epithelial cells, while Bcl-2 stained only mitosoid bodies and lymphocytic infiltrate (Figure 3C,D). Since p16 was positive, in situ DNA hybridization was performed and the results were negative for low (6/11) and high-risk HPV (16/18/31/33/35/39/45/51/82). Based on the histopathological findings, HPV infection associated with carcinoma in situ was excluded, and no lesions were detected elsewhere on the body, including the genital area. A surgical procedure was recommended; however, interestingly, after 2 months of post-biopsy follow-up, the lesions disappeared spontaneously without any treatment. On the second follow-up date, 4 months later, a recurrence in the same area was detected and another biopsy was performed, confirming the diagnosis of BPap.

3 | DISCUSSION

BPap is an uncommon disease in which diagnosis remains a challenge. To FIGURE 1 Clinical examination revealed multiple brown the best of our knowledge, only 13 oral cases have been reported in the verrucous papules on the right maxillary gingiva medical literature (Table 2). Wade et al12 considered the histopathological

FIGURE 2 Photomicrographs showed disturbed epithelial maturation with papillary stratified squamous epithelium, koilocytic dysplasia, parakeratosis, acanthosis, basal double-layer, loss of cellular polarity, nuclear hyperchromatism and pleomorphism, scattered mitosoid bodies (yellow arrow), and a greater degree of cytologic atypia. (Hematoxylin and eosin [H&E] stained section. Original magnification: A and B 200×) FERREIRA ET AL. 259

TABLE 1 Immunohistochemical Specificity Clone Source Dilution Positive control Results staining details p53 DO7 Dakoa 1:200 Buc Positive diffuse p16 F-12 Dako 1:100 Buc Positive diffuse Ki-67 MM1 Novocastrab 1:100 Buc Positive diffuse Bcl-2 154 Dako 1:100 Tonsil Positive focal

Abbreviation: Buc, breast or uterine cancer. aDako, Carpinteria, California. bNovocastra, Newcastle, UK.

FIGURE 3 A, Antibody against p53(A) showed positive expression predominantly in the basal and suprabasal layers. B, Antibody against Ki-67(B) showed positive expression in the basal and suprabasal layers. C, Antibody against p16 (C) stained strongly the nuclei of epithelial cells. D, Antibody against Bcl-2 (D) stained only mitosoid bodies and the lymphocytic infiltrate. (Immunohistochemistry stained section. Original magnification: A, B, C, and D 400×) findings of BPap and BD to be identical, and held that distinction histopathological difference between BPap and BD was the degree of between these two entities is made by clinicopathological correlation. cytologic atypia, as well as the absence or small number of plasma cells Conversely, Gimeno et al.13 evaluated eight genital BPap cases and in BPap. Ulbright et al15 evaluated 24 bowenoid lesions of the vulva showed that the dilated and tortuous dermal capillaries present in BPap and showed cellular uniformity and a lack of anaplasia in BPap. These were absent in BD, and the degree of atypia and dyskeratosis was less histopathological findings are in agreement with the current case. In in BPap. Additionally, Patterson et al14 showed that the most significant addition, the spontaneous resolution of our patient's lesions helped us 260

TABLE 2 Cases of oral bowenoid papulosis

Genital Authors Age/sex Site Immunosupression status involvment HPV type Outcome Background (treatment) Lookingbill et al2 33 (M) Hard palate, buccal mucosa Prednisone therapy for SLE Yes 16 SCC of tongue Surgical excision Kratochvil et al3 21 (M) Buccal mucosa, labial commissure Chemotherapy for Hodgkin Yes 16 Lost to follow-up (Therapy Bichloracetic acid and liquid and palate lymphoma failure) nitrogen Feldman et al4 31 (M) Buccal mucosa None Yes Negative Therapy failure Isotretinoin, cryotherapy, electrodesiccation and intra- muscular interferon-alpha, surgical excision Daley et al5 54 (M) Lower lip None No 16,18 No recurrence NA 34 (M) Lateral border of tongue None No Negative No recurrence NA 29 (M) Lower lip None No Negative Loss to follow-up NA Degener et al6 39 (F) Lower lip HAART (HIV-infection) Yes 32 Unaccompanied NA Rinaggio et al.7 42 (M) Upper lip HAART (HIV-infection) NA 32 Lost to follow-up Interferon-alpha and imiquimod (Therapy failure) Nakano et al9 84 (F) Lip Age No 16 No recurrence Fluoropyrimidine TS-1 Kupetsky et al10 22 (M) Lip No No 16,18 Unaccompanied NA 64 (M) Lip NA No NA Unaccompanied NA 40 (F) Oral commissure NA No NA No recurrence 5 fluorouracil and imiquimod Hoverson et al11 22 (F) Lips and gingiva NA No 16,18 Lost to follow-up No treatment Current case 80 (F) Gingiva Age No Negative Spontaneous regression No treatment

Abbreviations: F, female; HAART, highly active antiretroviral treatment; HIV, human immunodeficiency; HPV, human papillomavirus; M, male; NA, not available; SLE, systemic lupus erythematosus; SCC, squamous cell carcinoma. FERREIRA TAL ET . FERREIRA ET AL. 261 to strengthen the BPap diagnosis. Table 3 summarizes the differential staining in the basal and parabasal layers of normal tissues.19 Coinci- diagnosis between BPap and BD. dentally, only the basal and parabasal layers cells were stained in oral The immunohistochemical technique has been less explored in BPap, which may suggest the benign nature of the lesion. This is the BPap diagnosis, perhaps due to the rarity of lesions. Daley et al5 sug- first immunohistochemical study of Ki67 in oral BPap. gest that tumor suppressor protein p53 positive staining in BPap is Numerous HPV subtypes have been identified by the in situ DNA indirectly related with the presence of HPV. They showed staining in hybridization technique in genital BPap; however, only subtypes the basal, parabasal, and stratum spinosum cells, similar to our case, 16, 18, and 32 have been isolated in oral BPap, which are considered which may strengthen this hypothesis. Anti-apoptotic Bcl-2 protein at high-risk for the development of premalignant and malignant was also studied by these authors, which showed positive staining in lesions.10 In the current report, we revealed absence of low-(6/11) the lymphocytic inflammatory infiltrate. According to them, the pres- and high-risk (16/18/31/33/35/39/45/51/82) HPV by this method. ence of Bcl-2 in bowenoid mitotic cells in aggressive cases may sug- Interestingly, Daley et al5 also found similar results in two samples, gest BD. Interestingly, our study also showed staining for Bcl-2 in the although these authors used only probe cocktails for types 16/18, inflammatory infiltrate and mitosoid bodies. 6/11 and 31/33. Over 200 different HPV types have been identified p16 is an important tumor suppressor that regulates cell-cycle path- to date,20 and it was not possible in our investigation to check other ways via the inhibition of cyclin-dependent kinases 2 and 4, leading to types of HPV such as HPV 32 that may be involved in this lesion. the prevention of unchecked cellular growth and proliferation. HPV can The natural history of HPV lesions is poorly understood. Immuno- disable the retinoblastoma protein (pRb), which is a cell-cycle check- suppression by corticotherapy,2 chemotherapy3 and HIV infection6,7 point, resulting in uncontrolled cell-cycle progression and cellular prolif- has been associated with oral BPap development. According to eration. Hence, p16 is a marker suggestive of high-risk HPV-induced Beachler et al,21 it is possible that a decline in immune function with lesions with deregulated viral oncogene expression.16,17 age may reduce the ability to fight infections. The medical history of According to Samama et al,18 a strong and diffuse pattern of p16 pneumonia associated with old age in our patient may reflect an staining has been reported in 98% to 100% of genital BPap lesions, impaired immune response. Hence, we believe that aging may contrib- most often in high-risk HPV lesions compared with low-risk lesions. ute to BPap development in these patients. Lesions in elderly individ- These findings are in agreement with the results on oral BPap pres- uals, as in this current case, were also reported by Nakano et al.9 ented in the present study. In contrast, Kupetsky et al10 evaluated Treatment modalities for oral BPap include surgical excision, cryo- p16 in BPap of the oral commissure and showed less intense staining therapy with liquid nitrogen, bichloracetic acid, fluoropyrimidine TS-1, compared to that reported in the current case, limited to diffuse 5-fluorouracil, intra-lesional interferon-alpha, and imiquimod.2-11 staining of the lower portion of the lesion with individually positive Spontaneous resolution was also reported by Patterson et al14 in a cells extending into the upper reaches of the epithelium. review of 108 genital BPap cases, similar to the report in this study. Ki67 is a cellular proliferation protein expressed in the nuclei of Interestingly, Rinaggio et al7 also showed oral BPap in the upper lip of dividing cells, and is correlated with the progression of carcinomas of HIV-positive patient that presented periods of exacerbation and the genital region.16 Previous reports have shown intense Ki67 remission treated unsuccessfully by interferon-alpha and imiquimod

TABLE 3 Differential diagnosis between bowenoid papulosis and Bowen disease

Lesion Epidemiology and clinical features Histopathological features Human papillomavirus infection Bowenoid Adult individuals (mean 31 years) Rarely show malignant changes 16,18,32 papulosis Scattered papules or plaques, usually Dilated and tortuous dermal capillaries multiple, pigmented or not Lower degree of atypia and dyskeratosis Lack of recurrence More vascularity Possibility of spontaneous resolution More nuclear uniformity Good response of local treatment Low malignant potential Bowen disease Older individuals Carcinoma in situ Absent, 2, 6, 16, 33,34,35, 52, 58, 59 Solitary and irregular erythematous macule Normal dermal capillaries Recurrence potential Lack of differentiation of Malignant potential (skin 5%, genitals 30%) background epithelium Epithelium with “wind-blown” appearance Lower vascularity More mitotic figures, bowenoid elements, and atypical cells

References: Daley et al,5 Gimeno et al,13 Patterson et al,14 Ulbright et al,15 Brentjens et al,22 Murao et al.23 262 FERREIRA ET AL.

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