Bowenoid Papulosis (Penile Intraepithelial Neoplasia, Squamous Intraepithelial Lesion, Squamous Cell Carcinoma In Situ)

Are You Confident of the Diagnosis?

What you should be alert for in the history

History of unprotected sexual relations, or sexual relations with a person with known infection of human papilloma virus (HPV).

Characteristic findings on physical examination

Presents as well circumscribed, solitary or multiple, small, pigmented papules with a flat-to-verrucous surface (Figure 1). Papules may coalesce into larger plaques. Lesions can occur anywhere but are commonly found on the shaft of the penis, external genitalia of females, or in the perianal region.

Expected results of diagnostic studies

Most lesions are removed by physical destruction, and so the diagnosis is often a clinical one. However, diagnosis may be confimed by biopsy. Routine hematoxylin and eosin (H&E) staining will show pleomorphic, hyperchromatic keratinocytes with multiple nuclei and occasional abnormal mitotic figures (Figure 2). Epidermal atypia can vary from scattered (“windblown” or “buckshot”) to full-thickness atypia (Figure 3).

H&E: note the pleomorphic, hyperchromatic keratinocytes with multiple nuclei and scattered abnormal mitotic figures.

Higher power view of full thickness epidermal atypia.

True koilocytes are uncommon but partially vacuolated koilocyte-like cells are often present. Epidermal psoriasiform hyperplasia, hyperkeratosis, and focal parakeratosis are also common features. The basement membrane is usually intact, with a preserved dermal-epidermal junction.

Immunoperoxidase staining may reveal the presence of papillomavirus antigen in the nuclei of superficial epidermal cells. Electron microscopy demonstrates a decreased number of intact desmosomes and tonofilament aggregation causing dyskeratosis. White vinegar (5% acetic acid) application may make subclinical lesions visible.

HPV subtyping is not routinely performed in bowenoid papulosis, but can be performed if necessary via Southern blot hybridization, dot blot hybridization, reverse blot hybridization, or polymerase chain reaction.

Diagnosis confirmation

Differential diagnosis Includes the following:

– Bowen’s disease: loss of S-100 protein-positive dendritic (Langerhans) cells is seen in both Bowenoid papulosis (BP) and penile Bowen disease. Communication between the clinician and the pathologist is essential to avoid misdiagnosis.

– Erythroplasia of Queyrat: squamous cell carcinoma-in situ (SCC-IS) of the glans penis. Good communication between the pathologist and clinician are necessary to avoid misdiagnosis.

– Lichen planus: A thorough history and clinical examination will help to differentiate these two entities.

– Molluscum contagiosum: Area of lesions may overlap, but BP often is without the central umbilication seen in mulloscum.

– Squamous cell carcinoma (SCC): A lesion that appears clinically as a wart but is reported as SCC-IS when biopsied most likely represents BP.

– Genital warts: Lesions of BP often resemble genital warts but are more likely to be smooth, sessile, and hyperpigmented.

– Seborrheic keratosis (SK): Usual clinical presentation differentiates BP from SK. However, smoother SKs can be mistaken for BP and may require a good history and biopsy to confirm diagnosis.

– Warty dyskeratoma: Clinically, often have umbilication with central keratotic plug.

– Nevi or atypical mole: Differentiation may require biopsy.

Who is at Risk for Developing this Disease?

Bowenoid papulosis occurs primarily in young, sexually active adults, with a mean prevalence in the fourth decade of life. Lesions are contagious and are likely transmitted via sexual contact or vertical transmission in the peripartum period. There is no racial predeliction for this disease. The male-to-female ratio is equal.

What is the Cause of the Disease?

Bowenois papulosis, originally described by Kopf and Bart in 1977 as papules on the penis, is a focal epidermal hyperplasia and dysplasia induced by HPV infection. The most common strain of HPV responsible is HPV 16, but 18,31,32,34,35,39,42,48,51-54, and 67 have also been identified.

Systemic Implications and Complications

Cervical bowenoid papulosis lesions are associated with an increased incidence of abnormal cervical smears. Yearly serial examinations (including pap smears) are recommended because of the real, albeit low rate of developing invasive SCC and the possibility of recurrence. Neoplastic transformation of bowenoid papulosis may occur in 2.6% of cases. Risk of malignant transformation increases in immunodeficient patients.

Treatment Options

PHYSICAL DESTRUCTION, LOCAL

Surgical: Simple local excision

Physical: Electrodessication, cryosurgery, laser surgery

PHYSICAL DESTRUCTION, FIELD

Topical

Imiquimod 5% applied every other day for 8 weeks or imiquimod 3.75% applied daily for 8 weeks. Topical 5-fluorouracil overnight weekly for up to 10 weeks

Photodynamic Therapy

– Retinoids: Topical tazarotene gel 0.05% daily for 1 to 2 weeks, to be repeated if lesions not cleared.–Trichloracetic acid (Tri-Chlor): apply 25% to 50% topical liquid to lesion. Repeat every 1 to 2 weeks. Wash off in 1 to 2 hours–Keratolytic agents: Podophylin (Pod-Ben, Podocon-25, Podofin): apply 10% to 25% concentration sparingly onto lesions weekly until area is covered. Wash treatment area 1 to 2 hours after first application; patient can wait 4 to 6 hours before washing off agent.

Interferon

Systemic : Retinoids

Optimal Therapeutic Approach for this Disease

The most effective treatment for BP is simple, local destruction of the lesions. Recurrences are common with all modalities. Large, randomized controlled trials are needed to elucidate a first-line therapy for this disease.

Patient Management

–A broad practice approach with the dermatologist, gynecologist and/or urologist/proctologist working together may provide the best follow-up for patients with this disease.

–Condom use should be encouraged to reduce transmission of disease between partners.

–Women who are infected should continue to get yearly Papanicolaou smears. Men should consider periodic anogenital examination. Anal pap smears may also be considered in men who have sex with men.

–If lesions do not resolve, follow-up treatment is warranted every 3 to 6 months given the potential for malignant change.

–If lesions do not resolve, testing for immunodeficiency should be considered.

–As BP is associated with HPV, a sexually transmitted disease in some cases, should a minor be diagnosed with BP, sexual abuse should be considered in the differential and appropriate reporting should occur.

Unusual Clinical Scenarios to Consider in Patient Management

Younger patients tend to have a self-limiting course of a few months. Patients who are older or who are immunocompromised can have a protracted course lasting years.

What is the Evidence?

Dubina , M, Goldenberg , G. “Viral-associated nonmelanoma skin cancers: a review”. Am J Dermatopathol.. vol. 31. 2009. pp. 561-73. (Several types of nonmelanoma skin cancers [NMSCs] and precancerous lesions have an associated viral pathogenesis, including epidermodysplasia verruciformis, verrucous carcinoma, bowenoid papulosis, Kaposi sarcoma, SCC, and Merkel cell carcinoma. This is a literature review focusing on the histologic aspects of viral-associated skin malignancies, as well as the epidemiology, etiology, and clinical aspects of the diagnoses.)

Goorney , BP, Polori , R. “A case of Bowenoid papulosis of the penis successfully treated with topical imiquimod cream 5%”. Int J STD AIDS.. vol. 15. 2004. pp. 833-5. (BP is a premalignant condition of the ano-genital area often associated with HPV. Risk of progression to invasive disease is low. Treatment of BP usually entails locally destructive or ablative therapies. This case report demonstrates successful treatment of BP in a 25-year-old male with topical imiquimod 5% every other day for 2 months.)

Lucker , GP, Speel , EJ, Creytens , DH, van Geest , AJ, Peeters , JH, Claessen , SM. “Differences in imiquimod treatment outcome in two patients with bowenoid papulosis containing either episomal or integrated human papillomavirus”. J Invest Dermatol. vol. 127. 2007. pp. 727-9. (In one case, treatment of BP with imiquimod 5% cream 3-times weekly for 4 months resulted in clinical resolution of BP as well as disappearance of lesion by PCR and FISH analysis. The virus in this case was in the episomal form. In the second case, treatment of BP with imiquimod cream 3-times weekly for 4 months resulted in good, albeit partial clearance. In this case, the virus had fully integrated into the host DNA.)

Ricart , JM, Cordoba , J, Hernandez , M, Esplugues , I. “Extensive genital bowenoid papulosis responding to imiquimod”. J Eur Acad Dermatol Venereol. vol. 21. 2007. pp. 113-5. (Immunocompetent patient with extensive BP treated with imiquimod 5% cream every other day for greater than 4 months with moderate resolution of lesions. The authors noted that although some previous reports showed good results with this therapy, it may not work very well for large or for extensive lesions. Response to the treatment may depend on immune status of patient, viral load, and severity of disease.)

Shastry , V, Betkerur , J, Kushalappa. “Bowenoid papulosis of the genitalia successfully treated with topical tazarotene: a report of two cases”. Indian J Dermatol. vol. 54. 2009. pp. 283-6. (Case reports of BP of the genitalia successfully treated with topical tazarotene. Mild burning sensation and erythema at the site of application were the only adverse effects observed in this case series, with rapid clinical clearing of disease. Absence of recurrence in the first case and successful retreatment in the second case also support the effectiveness of topical tazarotene in BP.)

Matuszewski , M, Michajlowski , I, Michajlowski , J, SokoÅowska-WojdyÅo , M, WÅodarczyk, A, Krajka , K. “Topical treatment of bowenoid papulosis of the penis with imiquimod”. J Eur Acad Dermatol Venereol.. vol. 23. 2009. pp. 978-9. (Topical treatment of BP of the penis with imiquimod 5% cream every other day for 8 weeks resulted in no recurrences 3 months after cessation of treatment.)

Nakanishi , G, Yamasaki , O, Nagao , Y, Tanaka , T. “Detection of human papillomavirus type 67 from bowenoid papulosis”. Eur J Dermatol. vol. 20. 2010. pp. 819-20. (High-risk oncogenic HPV types include 16, 18, 31, 35, 39, 42, 48 and 51 through 54. This is the first published case report documenting an HPV type 67-positive bowenoid papulosis in an immunocompetent individual.)

Elston, Dirk , M. “Photo Quiz”. Cutis. vol. 86. 2010. pp. 278(Brief discussion of clinical diagnosis, pathogenesis and treatment of BP.)

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