Extramammary Paget Disease of Oral Mucosa: Case Report with Literature Review.

Extramammary Paget disease (EPMD) of the oral mucosa is an unusual and extremely rare condition, with fewer than ten cases documented. Here, we report a case of EMPD extensively involving oral mucosa and underlying salivary ducts in a 72-year-old male and review published clinical, histologic, immunophenotypic, and prognostic features of this rare entity.

Anatomic Subtype Differences in Extramammary Paget Disease: A Meta-Analysis.

Importance: Extramammary Paget disease (EMPD) is a rare, highly recurrent cutaneous malignant neoplasm of unclear origin. EMPD arises most commonly on the vulvar and penoscrotal skin. It is not presently known how anatomic subtype of EMPD affects disease presentation and management. Objective: To compare demographic and tumor characteristics and treatment approaches for different EMPD subtypes. Recommendations for diagnosis and treatment are presented. Data Sources: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Reviews CENTRAL from December 1, 1990, to October 24, 2022. Study Selection: Articles were excluded if they were not in English, reported fewer than 3 patients, did not specify information by anatomic subtype, or contained no case-level data. Metastatic cases on presentation were also excluded. Data Extraction and Synthesis: Abstracts of 1295 eligible articles were independently reviewed by 5 coauthors, and 135 articles retained. Reporting was in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis was cunducted in August 2019 and updated in November 2022. Findings: Most vulvar EMPD cases were asymptomatic, and diagnosis was relatively delayed (mean, 25.1 months). Although most vulvar EMPD cases were intraepidermal (1247/1773 [70.3%]), radical surgeries were still performed in almost one-third of cases. Despite this aggressive surgical approach, 481 of 1423 (34%) recurred, commonly confined to the skin and mucosa (177/198 [89.4%]). By contrast, 152 of 1101 penoscrotal EMPD cases (14%) recurred, but more than one-third of these recurrences were regional or associated with distant metastases (54 of 152 [35.5%]). Perianal EMPD cases recurred in one-third of cases (74/218 [33.9%]), with one-third of these recurrences being regional or associated with distant metastasis (20 of 74 [27.0%]). Perianal EMPD also had the highest rate of invasive disease (50% of cases). Conclusions and Relevance: The diagnosis and treatment of EMPD should differ based on anatomic subtypes. Considerations for updated practice may include less morbid treatments for vulvar EMPD, which is primarily epidermal, and close surveillance for local recurrence in vulvar EMPD and metastatic recurrence in perianal EMPD. Recurrences in penoscrotal subtype were less common, and selective surveillance in this subtype may be considered. Limitations of this study include the lack of replication cohorts and the exclusion of studies that did not stratify outcomes by anatomic subtype.

NECTIN4-targeted antibody-drug conjugate is a potential therapeutic option for extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Case report: A case of Paget disease outside the axillary breast.

BACKGROUND: Extramammary Paget disease is a relatively rare and less malignant intraepithelial adenocarcinoma. t is found in areas with abundant distribution of apocrine sweat glands such as the external genitalia, external genitalia, and perianal area, with fewer armpits. The disease progresses slowly and is prone to misdiagnosis in clinical practice. METHODS: We retrospectively analyzed a female patient. She had a left axillary mass for more than 2 years. Recently, the mass increased and the surface skin was ulcerated. Then she went to Jiangxi Provincial Dermatology Hospital for left axillary lesion resection, and the postoperative pathology showed Paget disease outside the breast. For further diagnosis and treatment, she came to our hospital. We diagnosed a tumor with uncertain or unknown dynamics in the left axillary breast. Under general anesthesia, left subaxillary mass resection, freezing and left breast cancer breast conserving surgery was performed. RESULTS: The postoperative pathology of the left axillary mass combined with morphological and immunohistochemical results was consistent with Paget disease. Postoperative immunohistochemistry showed estrogen receptor (+, 20%), progesterone receptor (-), human epidermal growth factor receptor-2 (3+), Ki-67 (30%), cytokine7 (+), and p63 (-). Following up for 22 months, there has been no local recurrence, no swelling of the right axillary lymph node, no distant metastasis found on follow-up, and no complications such as upper limb lymphedema, upper limb sensory abnormalities, or motor disorders have been observed. CONCLUSION: Paget disease outside the axillary breast is relatively rare, and surgical resection is the best choice. The prognosis is good, and the recurrence rate is low.

Recent treatment and prognosis in 643 patients with extramammary Paget's disease.

Information about extramammary Paget's (EMPD) treatment is limited because of the rarity of the disease. The prognosis differs between in situ EMPD and invasive EMPD; therefore, therapy should be planned according to the disease stage. We collected data on 643 EMPD cases treated between 2015 and 2019 in Japan and assessed recent trends in EMPD treatment and prognosis based on the EMPD-oriented TNM staging. Among the 643 patients, 317 had stage 0 (49.3%), 185 had stage I (28.8%), 51 had stage II (7.9%), 18 had stage IIIA (2.8%), 48 had stage IIIB (7.5%) and 24 had stage IV (3.7%) disease. Each stage showed a distinct survival curve, with the exception of stages II and IIIA. Curative surgery was most common in patients with stage 0-III disease. Chemotherapy was the first-line therapy, mainly in patients with stage IIIB and IV disease, most commonly with docetaxel (DTX), followed by DTX + tegafur gimeracil oteracil potassium (TS-1) and TS-1. Patients with local disease exhibited a 4.4% recurrence rate. Univariate analysis revealed no prognostic differences according to age, sex or primary tumour site. SLNB was not related to disease-specific survival. In multivariate analysis, female sex significantly predicted local relapse in stage 0-I (HR 3.09; 95% CI, 1.13-8.43), and initial treatment with curative surgery was significantly protective in terms of disease-specific survival in stage II-IIIA (HR, 0.17; 95% CI, 0.04-0.71) and stage IIIB-IV (HR 0.16; 95% CI, 0.05-0.51). Further clinical studies are needed to improve the prognosis of patients with stage II-IV EMPD.

Incidence and survival rates of primary cutaneous malignancies in Korea, 1999-2019: A nationwide population-based study.

Primary cutaneous malignancies are among the most commonly diagnosed types of cancer worldwide. We aimed to examine the incidence and 5-year survival rates of all types of primary cutaneous malignancies in the Korean population. Data from the Korean Nationwide Cancer Registry from 1999 to 2019 were analyzed. The crude incidence rates, age-standardized incidence rates, and 5-year relative survival rates of each type of skin cancer were calculated. A total of 89 965 patients were diagnosed with primary cutaneous malignancies, which was a 7-fold increase from 1999 to 2019. The age-standardized incidence rates increased 3.4-fold in basal cell carcinoma (3.7/100 000 person-years), 2.0-fold in squamous cell carcinoma (1.6/100 000 person-years), 12.0-fold in Bowen disease (1.2/100 000 person-years), and 1.8-fold in malignant melanoma (0.7/10 000 person-years) in 2019. Average annual percentage changes in age-standardized incidence rates were statistically significant in basal cell carcinoma (15.8%), Bowen disease (5.8%), squamous cell carcinoma (5.1%), malignant melanoma (1.2%), melanoma in situ (1.1%), dermatofibrosarcoma protuberans (1.2%), mycosis fungoides (0.5%), primary cutaneous CD30+ T-cell proliferations (0.5%), adnexal and skin appendage carcinoma (0.4%), extramammary Paget's disease (0.2%), and Merkel cell carcinoma (0.2%). The 5-year relative survival rates were the highest in basal cell carcinoma (103.3%), followed by dermatofibrosarcoma protuberans (99.7%) and mycosis fungoides (96.6%), and lowest in angiosarcoma (24.7%). The 5-year relative survival rates steadily increased in extramammary Paget's disease (23.6%), cutaneous B-cell lymphoma (21.3%), mycosis fungoides (20.2%), extranodal NK/T-cell lymphoma, nasal type (18.1%), and malignant melanoma (16.1%) from 1996-2000 to 2015-2019. Most primary cutaneous malignancies have increased in incidence and survival rates in the Korean population, but to varying extents depending on the type of skin cancer.

FOXM1: a new therapeutic target of extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older individuals predominantly in areas with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic EMPD have a poor prognosis due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (FOXM1), a potent transcription factor, in EMPD and assessed the potential of FOXM1 as a therapeutic target. Immunohistochemistry of 112 primary and 17 metastatic EMPD samples revealed that FOXM1 expression increased with tumor progression. Patients in whom FOXM1 was expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397). In in vitro studies using our newly established EMPD cell line, KS-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1 impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

The elusive extremities: a case of extramammary Paget disease.

Extramammary Paget disease is a rare dermatological condition resembling Paget disease that occurs most commonly in the anogenital area and axilla. We present the case of an elderly male who had come with complaints of an itchy, erythematous and raised lesion in the perianal region for 3 months that did not respond to antifungals. A biopsy was taken from the lesion site and the diagnosis was confirmed by histopathological examination. It is important to be aware of conditions like extramammary Paget disease when an elderly individual presents with a non-specific pruritic lesion in the perianal area that is non-responsive to treatment; the diagnosis of which can be made only by doing a biopsy from the concerned site. This highlights the importance of histopathological examination in such ambiguous cases.

Eribulin for patients with metastatic extramammary Paget disease: Study protocol for a single-arm phase II trial.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.

Recurrent Primary Paget Disease of Vulva with Paget-Like Epithelial Cells in Papillary Dermis: Displaced or Invasion?

While histological diagnosis of Paget disease of vulva is mostly straightforward, identifying and confirming invasion can be challenging. Often invasion is accompanied by epidermal hyperplasia, marked inflammatory response and desmoplastic reaction. Diagnosis of invasion in Paget disease portends a poor outcome. We report findings from a recurrent primary vulvar Paget disease where overall histomorphology of possible invasive disease is unusual and raises a possibility of displacement of Paget cells in the dermis. We compare histology of the index case with known invasive vulvar Paget disease cases retrieved from our pathology archives. Unique histomorphology in the index case suggests a possibility of previous excision related dermal displacement of Paget cells.