In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease. In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Although mammary and extramammary Paget disease are both characterized by epidermal Paget cells and share a similar clinical presentation, their uniqueness lies in anatomical location and histogenesis. EMPD presents as an erythematous plaque on apocrine gland bearing areas (i.e. vulva, perineum, perianal region, scrotum, and penis) in older men and women. It can be a focal, multifocal, or an ectopic process. Immunohistochemical staining allows for differentiation between primary and secondary EMPD in addition to the many other disease entities that clinically resemble this malignancy. When diagnosing a patient with EMPD, a full history and physical should be performed given the possibility of an underlying malignancy. Surgical excision currently is first line therapy and the prognosis is often favorable. Recent advances within the field have examined the expression of chemokine receptors within tumors, which may be applicable in determining prognosis. This review addresses the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis, diagnosis, management, and new observations with respect to extramammary Paget disease.

Differential diagnoses of pigmented lesions of the nipple include melanocytic nevus, melanosis of the nipple, seborrheic keratosis, pigmented basal cell carcinoma, melanoma and Paget disease. The histologic exam with appropriate immunohistochemistry is a fundamental tool to achieve a correct diagnosis. We present a patient with a pigmented lesion of her right nipple revealing mammary Paget disease and elucidate diagnostic obstacles and prognostic importance of early breast cancer detection.

Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Paget disease of the breast is an uncommon tumor ofthe nipple-areola complex that usually presents as anerythematous and erosive lesion. We report the caseof a 61-year-old man that presented with a three-yearhistory of an erythematous lesion of the right areola,first treated with topical corticosteroids withoutbenefit. He was then referred to our dermatologydepartment and the clinical suspicion of Paget diseasewas considered. The diagnosis was later confirmed bybiopsy. This case report highlights the importanceof clinical recognition of this entity along with otherdiseases that mimic these skin changes in order toallow earlier diagnosis and proper follow-up.

Extramammary Paget disease (EMPD) is a rare malignant neoplasm of apocrine sweat glands that is morphologically and histologically identical to Paget disease of the breast. The primary lesion is usually a solitary, well-demarcated, erythematous, scaly plaque that may contain crust, erosions, or ulcerations. The vulva is the most common site, but any area containing apocrine sweat glands may be involved. We present a case of triple extramammary Paget disease of the groin and bilateral axillae in a diabetic patient whose axillary lesions appeared consistent with acanthosis nigricans. This case demonstrates the need to consider EMPD in the evaluation of acanthosis of the axilla given its ability to mimic more common conditions.

Extramammary Paget disease (EMPD) is a rare skin cancer that affects areas with a high concentration of apocrine glands including genital, axillary, and anal skin. When it affects other locations it is called ectopic extramammary Paget disease (E-EMPD) and is uncommon. To date, there are only 45 case reports to the best of our knowledge. The clinical manifestation is typically a soft, red or bright pink patch or plaque with scattered white islands of hyperkeratosis and erosion. Diagnostic confirmation requires conventional histology with immunohistochemistry. The importance of immunohistochemical staining for the diagnosis of primary neoplasia, without underlying malignancy, is highlighted. We report the first Latin American confirmed case, to our knowledge, of primary E-EMPD in a 55-year-old man with a 1-year history of asymptomatic thoracic plaque.

Paget disease of the nipple is a rare presentation of breast cancer. It is sometimes mistaken for a benign skin condition of the nipple and surrounding areola, which can significantly delay the diagnosis and treatment. In over 90% of cases there is an underlying carcinoma, either ductal carcinoma in situ (DCIS) or invasive breast cancer. We present a rare case of Paget disease of the nipple without the typical characteristics, detected by simple nipple scraping technique. A 62-year-old woman presented with a small fissure on the left nipple with scant clear nipple discharge. There were no other changes to the nipple-areola complex. The mammography and ultrasound were unremarkable. However, nipple scraping provided the immediate cytological diagnosis of Paget disease. Breast MRI with core biopsy showed high grade ductal carcinoma in situ with suggestion of microinvasion, confirmed histologically after mastectomy. Nipple scraping is a simple and inexpensive technique, which can be used in the office without anesthesia and with minimal discomfort to the patient. It could allow for significantly earlier cancer detection and treatment at the earliest stage of breast cancer. However, if the results are negative, full thickness biopsy may be needed if clinically indicated.

A case of Paget's disease of the vulva is presented which, over a period of 6 years, was characterized by local recurrences and metastases to the bone marrow. Detailed examination of multiple sections of the primary tumor and of the bone marrow biopsy specimen failed to demonstrate an underlying adenocarcinoma in any of the sites. The routine histologic staining and immunohistochemical staining demonstrated that the metastatic cells strongly correlated with cells from the vulvar lesion. Specifically, immunohistochemical staining of the specimens from the primary and metastatic sites was positive for the gross cystic disease fluid protein-15, which has been associated with extramammary Paget's disease uncomplicated by underlying malignancies. Finally, during several years of close follow-up, no other primary site of Paget's disease declared itself clinically or was found by radiographic studies or analysis of serum tumor markers.