Patient Presentation A 58-year-old Caucasian man presented with a mild pruritic discoloration on the glans penis, which had been slowly expanding for at least 3 months. He was in a stable monogamous relationship and denied any risks for sexually transmitted diseases. On physical examination, the penis was uncircumcised and there was a dark reddish-brown patch on the glans. The patch had well-defined borders and involved the dorsal and lateral sides of the glans; it also extended back to involve the distal part of the prepuce. The patient refused biopsy. What is Your Diagnosis? Diagnosis:Zoon’s Balanitis Zoon’s balanitis (ZB), also known as plasma cell balanitis or Zoon’s erythroplasia, was originally described by Zoon in 1952.1 He described eight patients presenting with “sharply demarcated red plaques” on the glans penis or prepuce, and noted a bandlike infiltrate of plasma cells in the upper dermis. He termed the condition, “balanoposthitis chronica circumscripta benigna plasmacellularis”, distinguishing it from the pre-malignant erythroplasia of Queyrat. Today, ZB is recognized as a benign inflammatory chronic balanitis of unknown origin. The condition usually manifests in middle-aged or elderly uncircumcised men, but may occur at any age from the third decade onward.2 ZB has been shown to be the sixth most common dermatosis affecting the penis, with 100% of patients affected being uncircumcised.3PathogenesisThe cause of ZB remains unknown. It has been suggested that mechanical and irritant forces acting on barely keratinized skin are the central pathogenic mechanisms. This theory is supported by a reported association with conditions leading to chronic irritation, such as poor hygiene, rubbing, formation of “smegma stones”, phimosis, and urine retention.4-6 Nikolowski and Wiehl noted that ZB is more common on the dorsal side of the glans penis, an area more often subject to minor trauma, than the ventral side.7 Based on these findings, it may be speculated that ZB represents a non-specific response to irritant and mechanical forces in a moist environment, analogous to lichen simplex chronicus. Other theories include a possible link with bacterial and human papilloma virus (HPV) infections. However, Kiene et al found no evidence of HPV by polymerase chain reaction (PCR) studies. Similarly, Yoganathan et al failed to isolate Mycobacterium smegmatis, two of the main candidate etiological microbes.8,9 Furthermore, the putative role of a preputial factor is complicated by the existence of an identical condition occurring on mucosa at other sites as well as the existence of a female equivalent.10 Clinical FeaturesZB presents as a smooth, sharply demarcated, orange-red to red-brown, shiny patch. This patch may be noted on the glans penis, coronal sulcus, or inner surface of the prepuce. The duration of the lesion prior to presentation ranges from months to decades. Solitary lesions are more common, but multiple areas of involvement do occur. The lesion may be slightly moist and on close inspection have red specks — so-called “cayenne pepper” surface spotting. “Kissing” lesions may be present with involvement of adjacent areas, such as around the urethral meatus. Shallow erosions can also be present.2 Patients may be asymptomatic or may complain of pruritus or dysuria. Equivalent lesions have been described on the female genitalia,8,11,12 oral mucosa13 and lips.14 ZB tends to be chronic and may persist for months to years. It is considered a benign condition with little malignant potential. Of note, cases have been reported in which squamous cell carcinomas (SCC) have been detected in patients with a previous diagnosis of ZB.15,16 However, it remains to be determined if these represent true neoplastic changes or mere incidental findings. HistologyThe histopathologic features of ZB remain controversial and vary depending on the source. In a recent study of 45 cases by Weyers et al, the earliest changes were a slight thickening of the epidermis and parakeratosis, a patchy lichenoid infiltrate of lymphocytes and some plasma cells. More advanced cases showed an atrophy of the epidermis, superficial erosions, a scattering of neutrophils in the upper epidermis, scant spongiosis, extravasation of erythrocytes, and a much denser infiltrate with many plasma cells. Later stages were distinguished by sub-epidermal clefts, marked fibrosis of the superficial dermis and many siderophages. The authors found these changes consistent with irritation or mild trauma in a moist environment.17 Immunohistochemical studies have demonstrated that the plasma cells are polyclonal with predominating IgG, IgA- and IgD-positive plasma cells. 18Differential DiagnosisA complete list of conditions to consider in the differential diagnosis is summarized in Table 1. Selected diagnoses are further discussed below. Erythroplasia of Queyrat is a manifestation of carcinoma in situ of the glans penis. This condition usually presents as a sharply demarcated, slightly raised and shiny erythematous plaque on the glans penis or the inner side of the foreskin. The surface may be smooth, scaly, warty or ulcerated. Associated symptoms include pruritus, pain, bleeding or retractile difficulties. Indurated or keratotic lesions are suggestive of the development of frank SCC. Transformation of erythroplasia into SCC has been reported to occur in 10% to 33% of cases.19,20Lichen planus may cause pruritus and tenderness. An array of associated clinical signs may be noted, and include typical purpuric papules with a white, reticulate surface, annular, erythematous plaques, multiple, small papules, and erosive changes of the glans and foreskin. Lichen planus can be present exclusively on the penis, but it is always pertinent to examine for extra-genital disease. Lichen sclerosus et atrophicus typically presents with pain, irritation and disturbance of sexual function or urinary symptoms, with the appearance of white plaques on the glans and/or prepuce, which become thickened and non-retractile. Candidal balanitis usually causes burning and pruritus with generalized erythema of the glans and/or prepuce with eroded white papules, small pustules and erosions and a white discharge. Psoriasis is the most common inflammatory reaction that affects the male genitalia, usually as part of a generalized cutaneous disorder. It may present solely on the penis as well-defined plaques. Fixed drug eruptions have a predilection for the glans penis, usually appearing as well demarcated, round-to-oval, dusky, erythematous areas, which may be bullous or ulcerated. Finally, irritant or allergic balanitis has a wide spectrum of clinical manifestations, varying from classical balanitis to edema of the whole penis, extending to the groin. Patch testing and avoidance of the precipitant is required. TreatmentA biopsy is mandatory to distinguish ZB from conditions such as erythroplasia of Queyrat due to its prognostic and therapeutic implications. Promotion of good hygiene is an easy and potentially beneficial measure. Patients should be instructed to retract the foreskin regularly and perform gentle cleansing of the entire glans, preputial sac and foreskin. 21Several topical agents have been employed to treat ZB. Of note, topical antimicrobial preparations have largely proven ineffective. Tang et al treated 10 patients with a high-potency corticosteroid cream until complete resolution was observed in a period ranging from 3 to 12 weeks. On follow-up, four patients had recurrences, but responded to a second course of treatment.10 Other topical and intralesional corticosteroids have been used with varying reports of success.8 Three articles to date have reported success using topical tacrolimus (Protopic) 0.03% or 0.1% twice daily in patients with biopsy-confirmed ZB. Complete regression was noted in 1 to 2 months in most patients.22-24 Of interest, two cases of vulvitis circumscripta plasmacellularis were recently successfully treated with topical imiquimod (Aldara), presumably via its ability to induce the production of interferon-alpha.25 In another study, fusidic acid 2% cream induced suppression and a total cure in 6 months in five out of eight patients, with an unclear mechanism. 26Circumcision has proven the most consistently effective long-term cure for ZB, and is considered the gold standard of therapy.5,27-30 This was clearly established in a study by Kumar et al in which 27 patients were treated with circumcision with no recurrence at 3 years follow up.5 Similar results were obtained in a more recent study by Altmeyer et al.29Lasers have also been used to treat ZB. The first patient successfully treated with the CO2 laser was reported by Baldwin et al in 1989.31 Retamar et al subsequently treated five patients with a CO2 laser using a “silk touch” technique. This technique employs a scanner that spins rapidly in a spiral pattern so that each treated point absorbs laser energy during a shorter time than the tissue’s thermal relaxation time. Complete resolution was achieved in all patients with good patient satisfaction. Two patients relapsed after treatment at 1 and 3 years posttreatment, respectively.32 Albertini et al presented a case of successfully treated ZB in one patient using Er:YAG laser ablation, advocating its advantages over the far more thermally destructive CO2 laser. Of note, there is also one report of a patient treated for three sessions with a copper vapor laser.33Our patient was treated with a super-potent topical corticosteroid (Temovate ointment) with significant improvement on follow-up 3 weeks later; circumcision was also suggested, but was declined by the patient. He was subsequently lost to follow-up.The Need to Understand ZBZB is frequently associated with the presence of penile foreskin. With more than 30% of males in the United States still uncircumcised,34 this is an important pathology to understand and know how to manage. Although the etiology is still not known, several treatment options are under investigation, with circumcision being the gold standard. Differentiating ZB from penile carcinoma and erythroplasia of Queyrat is important as it may avoid initiating an overly aggressive therapy.  Table 1Conditions to consider in the differential diagnosis for Zoon’s balanitis• Erythroplasia of Queyrat (SCC in situ)• Squamous cell carcinoma• Fixed drug eruption• Psoriasis• Erosive lichen planus• Candidiasis• Contact dermatitis• Cicatricial pemphigoid• Lupus erythematosus• Lichen sclerosus