Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape. METHODS: Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed. RESULTS: Notable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFß) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event. CONCLUSION: Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

Review on the Role of Paraffin-embedded Margin-controlled Mohs Micrographic Surgery to Treat Skin Tumors. / [Artículo traducido] Revisión del rol de la cirugía micrográfica con cortes en parafina en el tratamiento de tumores cutáneos.

Paraffin-embedded margin-controlled Mohs micrographic surgery (PMMS) includes various procedures such as slow Mohs or deferred Mohs technique, the Muffin and Tübingen techniques, and staged margin excision, or the spaghetti technique. PMMS is a variation of conventional Mohs micrographic surgery (MMS) that allows histopathological examination with delayed margin control. PMMS requires minimum training and may be adopted by any hospital. The setback is that PMMS can require procedures across multiple days. PMMS lowers the rate of recurrence of basal cell carcinoma vs wide local excision in high-risk basal cell carcinoma, and improves the rates of recurrence and survival in lentigo maligna. PMMS can be very useful in high-risk squamous cell carcinoma treatment. Finally, it is a promising technique to treat infrequent skin neoplasms, such as dermatofibrosarcoma protuberans, or extramammary Paget's disease, among others. In this article, we present a literature narrative review on PMMS, describing techniques and indications, and highlighting long-term outcomes.

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.

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.

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.

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.

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.

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.

Review on the Role of Paraffin-embedded Margin-controlled Mohs Micrographic Surgery to Treat Skin Tumors.

Paraffin-embedded margin-controlled Mohs micrographic surgery (PMMS) includes various procedures such as slow Mohs or deferred Mohs technique, the Muffin and Tübingen techniques, and staged margin excision, or the spaghetti technique. PMMS is a variation of conventional Mohs micrographic surgery (MMS) that allows histopathological examination with delayed margin control. PMMS requires minimum training and may be adopted by any hospital. The setback is that PMMS can require procedures across multiple days. PMMS lowers the rate of recurrence of basal cell carcinoma vs wide local excision in high-risk basal cell carcinoma, and improves the rates of recurrence and survival in lentigo maligna. PMMS can be very useful in high-risk squamous cell carcinoma treatment. Finally, it is a promising technique to treat infrequent skin neoplasms, such as dermatofibrosarcoma protuberans, or extramammary Paget's disease, among others. In this article, we present a literature narrative review on PMMS, describing techniques and indications, and highlighting long-term outcomes.

Extramammary Paget's Disease of the Scrotal and Penile: A Case Report and Review of the Literature.

INTRODUCTION: Extramammary Paget's disease of the scrotum and penis is a relatively rare cutaneous malignant tumor. At present, its pathogenesis, and clinical and pathological characteristics are not very clear. This is controversial regarding surgical margin width to decrease the high recurrence rate. This paper aimed to report the case and review the literature of extramammary Paget's disease of scrotum and penis. CASE PRESENTATION: We presented the case of a 74-year-old male patient with the patchy erythema and pruritus in the perineum who was admitted to our department. Biopsy of the large plaque revealed Paget disease. Under the condition of ensuring negative surgical margins by rapid frozen pathology, a wide local excision of the lesion, bilateral orchiectomy, and adnexectomy were performed on the patient. Pathology revealed that many scattered vacuolated Paget cells were observed in the epidermal layer, and the diagnosis was Paget's disease of the scrotum and penis. The 2 cm outside the skin lesion was used as the initial surgical margin, and free skin flap transplantation was used to repair the surgical wound. The patient recovered well and was discharged 1 week after surgery. CONCLUSION: Currently, histopathologic biopsy is the most important diagnostic method for EMPD. Once confirmed, for patients eligible for surgical intervention, wide local excision of the lesion and rapid intraoperative frozen pathological examination should be performed as soon as possible. The skin flap transplantation is the first choice for the repair of large-scale wound after surgery.

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.

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.