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Extramammary Paget disease
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Extramammary Paget disease (EMPD) is a rare malignancy, first described by Crocker in 1889, who reported lesions on the scrotum and penis that were histologically similar to mammary Paget disease. EMPD most commonly occurs on apocrine rich skin of individuals between the ages of 50 and 80 years, with a peak incidence at age 65. It often presents as an erythematous plaque and is commonly misdiagnosed as an inflammatory condition resulting in treatment delays. Controversy exists over the pathogenesis of EMPD, but it is favored to arise as an intraepidermal neoplasm of glandular origin and is considered primary EMPD. More recently, it has been proposed that Toker cells, present in vulvar epidermis, are benign precursors of Paget cells. There may be a small subset called secondary EMPD, which represents intraepithelial spread of malignant adenocarcinoma cells from an underlying malignancy.
Management Strategy
Biopsy should be performed immediately upon suspicion of EMPD. Histologically, EMPD is characterized by intraepidermal proliferation of Paget cells (PCs), which have large vesicular nuclei and abundant pale cytoplasm. Extension into adnexal structures is common and may be misinterpreted as dermal invasion. In addition to hematoxylin and eosin, diagnosis is confirmed by utilizing a panel of immunoperoxidase studies including cytokeratin 7, carcinoembryonic antigen (CEA), epithelial membrane antibody, HER-2/neu, and gross cystic disease fluid protein-15. These can be used to differentiate EMPD from pagetoid variants of squamous cell carcinoma in situ and melanoma in situ. The expression of tissue-specific antigens within PCs appears to correlate with that of the underlying malignancy: prostatic antigen, uroplakins, and transcription factor CDX-2 in prostatic, urothelial, and intestinal adenocarcinomas, respectively. However, limitations to the use of tissue-specific markers necessitates careful clinicopathologic correlation.
Patients diagnosed with EMPD must be risk stratified. Ambiguity exists within the literature regarding risk for associated malignancies; an associated underlying internal cancer has been reported in 7–40% of patients with EMPD. Most reported cases of internal malignancy are in close proximity to the cutaneous EMPD. Therefore, a directed internal malignancy evaluation is appropriate. Dependent on gender, appropriate studies to consider include mammography, Papanicolaou smear, pelvic ultrasonography, cystoscopy, colonoscopy, and computed tomography of the abdomen and pelvis.
The treatment of EMPD has long been surgical excision with adjuvant therapies in select cases. Mohs micrographic surgery (MMS) has emerged as a promising therapeutic option as it offers complete evaluation of tissue margin, maximal tissue preservation, and the lowest recurrence rates. However, it is limited by ill-defined clinical margins, microscopic extension of tumor cells, multifocal disease, and sometimes lesion size given the outpatient nature of MMS.
Close clinical follow-up of patients with EMPD is recommended due to recurrence risk. Biannual evaluation for at least 3 years, then annually for at least 10 years for non-invasive EMPD, has been suggested. In invasive EMPD or cases associated with a distant, underlying tumor, follow-up should be more frequent with a low threshold to biopsy any suspicious skin lesion. In general, patients with EMPD have a good prognosis with a 5-year overall survival of 75–95%. Dermally invasive EMPD is more frequently associated with regional lymph node metastasis and poor prognosis.
Specific Investigations
Extramammary Paget’s disease: a review of the literature – Part I: history, epidemiology, pathogenesis, presentation, histopathology, and diagnostic work-up
Morris C, Hurst E. Dermatol Surg 2020; 46: 151–8.
Systematic review of the literature. Patients with EMPD must be risk stratified and evaluated for an underlying internal malignancy. Sentinel lymph node biopsy is recommended in patients with invasive EMPD. The standard of treatment is surgery with new data suggesting that MMS may have superior clinical outcomes with lower recurrence rates.
Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients
Hatta N, Yamada M, Hirano T, et al. Br J Dermatol 2008; 158: 313–318.
Retrospective review of 76 patients with EMPD. Sixty-six patients underwent curative surgical excision: five developed local recurrence. Surgical margin was not correlated with local recurrence. Thirteen patients developed systemic metastases; 10 died. Nodules in the primary tumor, clinical lymph node swelling, elevated CEA, depth of tumor invasion, and lymph node metastasis were significant prognostic factors. Depth of tumor invasion and CEA level were associated with reduced survival.
The role of sentinel lymph node biopsy in the management of invasive EMPD: multi-center, retrospective study of 151 patients
Fujisawa Y, Yoshino K, Kiyohara Y, et al. J Dermatol Sci 2015; 79: 38–42.
Retrospective review of 151 patients with invasive EMPD. The rate of lymph node (LN) metastasis was 80% in patients with lymphadenopathy compared to 15% without. Lymphadenopathy was associated with advanced primary tumor (nodule, thicker tumor, deeper invasion, presence of lymphovascular invasion). Survival was not affected by sentinel LN status even when an advanced primary tumor was present. SLNB with subsequent LN dissection may improve survival of patients with early stage lymphatic spread.
Indications for lymph node dissection in the treatment of EMPD
Tsutsumida A, Yamamoto Y, Minakawa H, et al. Dermatol Surg 2003; 29: 21–4.
Prospective study of 34 patients with genital or perineal EMPD treated with wide local excision. Patients with clinical or histologic evidence of metastatic disease underwent LN dissection. No patients with in-situ disease or microscopic papillary dermal invasion had LN metastasis and all had 100% 5-year survival. Tumor invasion into reticular dermis correlated with 33% 5-year survival. Tumor invasion into subcutaneous tissue correlated with 100% LN metastasis and 0% 5-year survival.
Possible effectiveness of lymph node dissection in patients with extramammary Paget’s disease
Matsushita S, Hatanaka M, Katsue H, et al. J Dermatol 2013; 40: 574–5.
Retrospective review of 14 patients with advanced EMPD. Metastatic sentinel node (SN) was confirmed in five patients; one had a metastatic SN on bilateral sides. Their findings suggest that the incidence of distant metastasis is lower in patients with single metastatic SN and recommend LN dissection in patients with a single metastatic SN, thin primary tumor, and slight tumor burden in the metastatic SN.
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