Extramammary Paget's Disease (EMPD) is a rare, slow-growing intraepithelial adenocarcinoma that most commonly affects areas rich in apocrine glands, such as the vulva, perianal region, scrotum, and, less frequently, the glans penis. When EMPD affects the glans, it typically presents as erythematous or eczematous lesions. EMPD is categorized into 2 forms: primary, originating from the epidermis, and secondary, resulting from the epidermotropic spread of internal malignancies. These malignancies can be synchronous or metachronous.

Given the significant impact that the presence of an underlying malignancy has on prognosis, it is crucial for clinicians to conduct a thorough examination to rule out secondary forms of EMPD. This is particularly important because the clinical presentation of EMPD can easily be mistaken for benign dermatological conditions, leading to potential delays in diagnosis and treatment. The rarity of EMPD in the glans poses additional diagnostic and therapeutic challenges, underscoring the need for a high index of suspicion and comprehensive diagnostic methods, including histopathological and immunohistochemical evaluations.

This letter discusses a case of secondary EMPD of the glans in a patient with a history of high-grade urothelial carcinoma, focusing on clinical, dermoscopic, and histopathological presentations to enhance diagnostic accuracy.

In July 2019, a 79-year-old man underwent radical cystectomy and bilateral uretero-cutaneo-stomy owing to poorly differentiated, multifocal urothelial carcinoma of the bladder (T2-G3). By July 2022, persistent erythema of the glans (Fig. 1), unresponsive to a year of antibacterial and antifungal treatments, prompted a biopsy. Histological picture showed a single-cell intraepidermal proliferation with pagetoid spread (Fig. 2A) that was positive for CK7, CK20, CK8/18 (Fig. 2B), EMA, p63, and HER/neu, partially positive for androgen receptor and GATA-3 (Fig. 2C), and negative for CEA. These findings confirmed the diagnosis of EMPD secondary to urothelial carcinoma. A subsequent CT scan showed no evidence of cancer recurrence.

Multiple reports describe EMPD of the glans associated with urothelioma as presenting with erythematous lesions around the external urethral meatus.1–5 This presentation could result from the dissemination of tumor cells from the primary site, likely due to the dedifferentiation of high-grade tumor cells and the subsequent loss of adhesion proteins. If further validated by comprehensive studies, our observation could significantly affect the clinical diagnosis of this condition.

Differentiating EMPD of the glans from similar dermatological conditions, such as eczema, superficial infections, Zoon's balanitis, erythroplasia of Queyrat, psoriasis, malignant melanoma, and Bowen's disease, necessitates a comprehensive patient history and clinical examination. Polymorphous vessels, including milky-red areas, small red dots, and tortuous vessels with comma-like curvatures, along with porcelain-white patches on dermoscopy, should raise suspicion of EMPD, prompting further investigation and aiding in treatment monitoring.6 However, given the overlapping clinical presentations of these conditions, histopathological examination becomes essential for accurate diagnosis. Pathology not only confirms the diagnosis but also plays a crucial role in distinguishing EMPD from other conditions and in determining the primary tumor site, which is vital for appropriate management. Lesions that persist, increase in size, or fail to respond to topical therapies should be biopsied promptly to ensure accurate and timely diagnosis.

Secondary EMPD of the glans associated with urothelial carcinoma typically exhibits immunohistochemical positivity for CK7, CK20, and P63 markers.1 Interestingly, studies demonstrate that GATA3 expression varies depending on tumor progression and location. It is highly expressed in noninvasive urothelial carcinoma at 96.5% (95% CI: 93.8%–98.0%).7 However, this expression decreases to 75.3% (95% CI: 64.5%–83.6%) when tumor progression extends beyond the muscularis and drops further to 61.4% (95% CI: 42.6%–77.4%) in urothelial cancers that occur outside the bladder.7 These variations in GATA3 expression levels could explain the partial weak positivity of the GATA3 marker in our patient.

Considering that the urothelial carcinoma in our patient had invaded beyond the muscularis layer, it is plausible that the weakness of GATA3 could be due to the dissemination of bladder cancer cells, where the original tumor had already partially lost GATA3 expression. This pattern of expression of GATA3 in more advanced stages of urothelial carcinoma and in nonvesical locations, such as the glans, aligns with observations in the literature, suggesting a link between reduced GATA3 expression and tumor aggressiveness or advanced progression.

Furthermore, surgical interventions, particularly those involving incisions or resections in the urethral or bladder area, could potentially contribute to the mechanical spread of urothelial carcinoma cells. These cells might implant in nonurothelial sites, such as the glans, particularly if the surgery disrupts epithelial barriers, facilitating the direct seeding of tumor cells. In addition, it is unclear whether catheters used during cystectomy might affect the spread of these cells to distant sites like the glans, as this potential mechanism has yet to be thoroughly investigated. This mechanism might explain the development of secondary EMPD in patients with previous urothelial carcinoma surgeries or catheterization, where the anatomical continuity between the bladder and urethra could facilitate such dissemination.

In the broader context of EMPD, different forms of this disease and other pagetoid intraepithelial lesions can be distinguished by their immunohistochemical marker profiles. Primary EMPD typically shows positivity for markers such as CK7, GCDFP-15, and HER2, indicating its origin from apocrine glands or glandular cells of the epidermis. By contrast, secondary EMPD varies depending on its site of origin; urothelial tumors express CK7, CK20, and GATA3, while colorectal and prostatic origins have their own distinctive profiles. Specifically, colorectal-origin lesions are positive for CK20 and CDX2 but negative for CK7 and GCDFP-15, whereas prostatic-origin lesions show positivity for PSA, AR, and NKX3.1 while being negative for CK7, CK20, and GCDFP-15.

These immunohistochemical differences are crucial for accurately diagnosing the nature and origin of pagetoid lesions. In addition, other conditions, such as melanoma in situ and pagetoid squamous cell carcinoma in situ (Pagetoid SCC in situ), present with distinct marker profiles that aid in differential diagnosis. Melanoma in situ is characterized by the presence of markers such as HMB45, MART-1, and SOX10, while it is negative for CK7, CK20, and GCDFP15. On the other hand, pagetoid SCC in situ typically shows positivity for CK5/6 and p63 and is negative for CK7, CK20, and GCDFP15. Recognizing these immunohistochemical patterns is essential for distinguishing between these various entities and ensuring accurate diagnosis and treatment planning.

Management of secondary EMPD of the glans includes various treatments such as Mohs micrographic surgery, penectomy, and nonsurgical options such as Imiquimod, photodynamic therapy (PDT), and 5-fluorouracil (5-FU), tailored to individual patient needs. Given the uncommon nature of EMPD, evidence-based studies often fall short in providing conclusive guidance on the most effective treatment strategies. Nonetheless, Mohs micrographic surgery, where available, shows considerable promise as a therapeutic option.8

This case of EMPD of the glans, arising from advanced urothelial carcinoma, underscores the critical role of immune-histological evaluation in diagnosing this rare condition and investigating the possible origin of the primary tumor. The pattern of expression of GATA-3 observed in our patient likely reflects the tumor's advanced stage, highlighting the complexities of diagnosing EMPD in the context of underlying malignancies. These findings stress the importance of maintaining a high index of suspicion for secondary EMPD in patients with a history of urothelial carcinoma, particularly when atypical lesions are present. Further research is needed to clarify the mechanisms of cancer cell dissemination and to develop more effective therapeutic strategies tailored to the unique challenges of this rare disease. Continued investigation will be essential for improving patient outcomes and deepening our understanding of EMPD and its association with internal malignancies.

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