Extramammary Paget's Disease Research Articles

Extramammary Paget's disease: A retrospective study in a medical center in Taiwan

Extramammary Paget's disease: A retrospective study in a medical center in Taiwan

Defining surgical margins with dermoscopy and frozen section in recurrent extramammary pagets disease

Defining surgical margins with dermoscopy and frozen section in recurrent extramammary pagets disease

Extramammary Paget Disease of Peristomal Skin Secondary to Bladder Urothelial Carcinoma

An 87-year-old man with history of invasive transitional cell urothelial carcinoma of the bladder and left distal ureter status-post radical cystoprostatectomy and left distal uretectomy with uretero-ureterostomy and ileal conduit urinary diversion 14 years prior presented to our dermatology clinic with complaint of peristomal rash for many years. The patient reported the rash had been present for at least 5 years and was getting larger. It was described as pruritic and tender.

Laparoscopic pelvic surgery after reconstructive surgery with vertical rectus abdominis muscle flap: A case report.

IntroductionPatients who have experienced vertical rectus abdominis muscle (VRAM) flap reconstruction are under risk of the abdominal incisional hernia (donor site hernia), and laparotomy increases the risk.Presentation of the caseWe present the case of a 71-year-old nulliparous woman who experienced radical vulvectomy against extramammary Paget disease and reconstructive surgery with VRAM flap 7 years ago and developed right ovarian tumor. In this case, right ovarian tumor was removed with laparoscopic surgery, instead of laparotomy, and the risk of incisional hernia was successfully minimized.DiscussionIncisional (donor site) hernia after reconstructive surgery using VRAM flap has been reported in between 2 and 10%. While VRAM flap can fill larger amount of skin and subcutaneous tissue to recipient site, the risk of postoperative incisional hernia of abdominal wall is substantial.ConclusionReconstructive surgery of with VRAM flap is required for extramammary vulvar Paget disease expanding wide range, and develops the risk of incisional hernia.Laparoscopic surgery should be applied in patients who have experienced VRAM flap reconstruction and developed pelvic tumor for avoiding the risk of incisional hernia as long as it can be allowed on oncologic aspects such as recurrence.

COL17A1 germline variant p.Ser1029Ala and mucosal malignant melanoma: An autopsy study.

Collagen type XVII α1 (COL17A1) encodes a hemidesmosomal protein at the epidermal-dermal junction and its variants are implicated in blistering skin diseases. Recent experiments in rodents revealed that Col17a1 has critical roles in stem cells of epidermal origin and in melanoma carcinogenesis. In the present study, it was investigated whether germline variants in COL17A1 are associated with skin cancer and other cancer types using indexed consecutive autopsy cases from the Japanese Geriatric Single Nucleotide Polymorphism database (n=2,343; mean age, 80 years). The database included 12 patients with skin cancer. A total of 53 COL17A1 missense variants on an exome chip were analyzed. One variant, p.Ser1029Ala (rs118166857), which had a minor allele frequency of 1.0%, exhibited a nominal positive sign of association with skin cancer [Fisher's exact P=0.002, odds ratio (OR)=16.93, 95% CI: 4.44-64.64]. This variant was detected in 2/2 patients with mucosal malignant melanoma (mMM) and 1/3 patients with extramammary Paget's disease, and in none of the patients with non-melanoma cancer, e.g., squamous cell and basal cell carcinoma. Other cancer types were searched in the database and the p.Ser1029Ala variant was indicated to be nominally associated with breast cancer (P=0.006, OR=4.17, 95% CI: 1.72-10.11). In the two mMM cases, targeted exome sequencing of 55 cancer-predisposing genes (including tumor protein 53, BRCA1/2 and mismatch repair genes) detected no apparent pathogenic variants, but revealed variants of unknown significance in axin 2, DNA directed polymerase ζ catalytic subunit and contactin 6. Since COL17A1 provides a niche for melanocyte stem cells, it was hypothesized that the p.Ser1029Ala variant in the COL17A1 ectodomain may affect the microenvironment, e.g., the cell competition. This is a working hypothesis generated from human autopsy cases and warrants further epidemiological and molecular biological validation.

Cyclin-dependent kinase 4/6 inhibitors suppress tumor growth in extramammary Paget's disease.

Extramammary Paget’s disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development of potential treatments has long been sought. Cyclin‐dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient‐derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor‐bearing NOD/Scid mice over a 3‐week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX. The Ki‐67‐positive ratio of the treated EMPD‐PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD.

Efficacy and safety of HpD-PDT for Extramammary Paget's Disease refractory to conventional therapy: A prospective, open-label and single arm pilot study

BackgroundExtramammary Paget's Disease (EMPD) is an intraepithelial cancer that is prone to recurrence and sometimes refractory to therapy. A few EMPD cases have been treated with Photodynamic therapy (PDT), which reported high complete remission (CR) rates and low recurrence with hematoporphyrin derivatives (HpD) The aim of this study was to further explore the efficacy and safety of HpD-PDT for EMPD patients. MethodsOpen-label, single arm, pilot study was designed to investigate the role of HpD-PDT in EMPD. The HpD sensitizer was given intravenously at a dose of 3 or 5 mg/kg 48 h before light irradiation with a laser 630 nm red light at a dose level of 150–200 J/cm2. Clinical parameters involving gender, age, disease course, previous treatment, tumor thickness, long diameter of lesion, TNM staging, EMPD staging, HpD dosage, Visual Analogue Scale (VAS) score, 1st month visit result, subsequent treatment, follow up period and endpoint outcomes were collected to evaluate efficacy and safety of the intervention. ResultsEleven patients with pathologic confirmed EMPD were treated with HpD-PDT. The thickness of skin lesions which were located in vulva, penis, scrotum, and perianal area is 0.8∼6.7 mm (mean thickness 2.9 mm). All patients were followed up for an average of 17.4 months (12∼27 months). Complete remission (CR) rate and partial remission (PR) rate at the 1st month were 90.1% (10/11) and 9.1% (1/11) respectively. At the end of follow-up, 72.7% of the subjects (8/11) showed CR. Pain, infection, photosensitivity and uroschesis are recorded as adverse events (AEs) in this population, and no event of hepatic impairment was reported. After treatment, all the eleven patients showed different degrees of scar in the treatment site, but none of them had any structural or functional abnormalities. ConclusionsAccording to our study, HpD-PDT in EMPD is able to offer acceptable disease outcomes including relatively high CR rate, with good cosmetic and functional outcomes, and could be considered a potential recommended therapy for patients with EMPD. Trial RegistrationChinese Clinical Trial Register (ChiCTR-1900024965).

Unusual lesion on the vulva of a postmenopausal woman

Unusual lesion on the vulva of a postmenopausal woman

Treatment-refractory extramammary Paget disease responsive to radiotherapy

A 66-year-old female with extramammary Paget disease of the mons, perineum, vulva, vagina, and lower abdomen, status postradical vulvectomy, multiple excisional procedures, laser treatments, and radical cystectomy for bladder carcinoma in situ, presented to the dermatology clinic. Examination revealed diffuse red erosions of the vulva extending into the introitus with overlying maceration and scattered pink plaques with overlying crust and scale of the mons pubis and the abdomen (Figure, A). Treatment with a mixture of 1:1 fluorouracil 5% cream with calcipotriene 0.005% cream to the right mons and the lower abdomen and imiquimod 5% cream to the left mons and the lower abdomen was begun but was discontinued secondary to irritation.

Detection of MSH2 Gene Methylation in Extramammary Paget's Disease by Methylation-Sensitive High-Resolution Melting Analysis.

Background Extramammary Paget's disease (EMPD) is a rare skin tumor. Hypermethylation in the MSH2 promoter resulting in the downregulation of its protein expression shows a high detection rate in EMPD tumor tissue, which indicates that the methylation of MSH2 may play an important role in the pathogenesis of EMPD. Objective This study aims to establish a rapid analysis strategy based on the methylation-sensitive high-resolution melting curve (MS-HRM) to detect the methylation level of the MSH2 promoter. Methods With the use of universal methylated human DNA products, we established the MS-HRM standard curve to quantitatively detect the methylation level of the MSH2 promoter. Then, all 57 EMPD tumor DNA samples were analyzed. Pyrosequencing assay was also carried out to test the accuracy and efficacy of MS-HRM. Besides, a total of 54 human normal and other cancerous tissues were included in this study to test the reliability and versatility of the MS-HRM standard curve. Results In this study, by using the established MS-HRM, we found that 96.5% (55/57) EMPD tumor samples had varying methylation levels in the MSH2 promoter ranging from 0% to 30%. Then, the methylation data were compared to the results obtained from pyrosequencing, which showed a high correlation between these two techniques by Pearson's correlation (r = 0.9425) and Bland–Altman plots (mean difference = −0.1069) indicating that the methylation levels analyzed by MS-HRM were consistent with DNA pyrosequencing. Furthermore, in 23 normal and 31 other cancerous tissue samples, there were two colorectal cancer (CRC) tissues that tested MSH2 methylation positive (1% and 5%) which confirmed that our established MS-HRM can be widely applied to various types of samples. Conclusion MS-HRM standard curve can be used for the detection of the methylation level of MSH2 in EMPD tumor samples and other cancerous tissues potentially, which presents a promising candidate as a quantitative assay to analyze MSH2 promoter methylation in routine pathological procedure.

Genomic landscape of circulating tumour DNA in metastatic extramammary Paget's disease.

Although cancer personalized profiling by deep sequencing (CAPP-Seq) of cell-free DNA (cfDNA) has gained attention, the clinical utility of circulating tumour DNA (ctDNA) in extramammary Paget's disease (EMPD) has not been investigated. In this study, genomic alterations in the cfDNA and tumour tissue DNA were investigated in seven patients with metastatic EMPD. CAPP-Seq revealed mutations in 18genes, 11 of which have not yet been reported in EMPD. The variant allele frequency of some of the mutated genes reflected the disease course in patients with EMPD. In one patient, the mutation was detected even though imaging findings revealed no metastasis. In another patient with triple EMPD (genital area and both axilla), cfDNA sequencing detected the mutation in a rib metastatic lesion, which was also detected in both axilla lesions but not the genital region. Investigations of the ctDNA may be useful towards the elucidation of clonal evolution in EMPD.

Selection of surgical strategies for vulvar Paget's disease.

Selection of surgical strategies for vulvar Paget's disease.

283 Neutrophil/lymphocyte ratio as a predictor of lymph node metastasis in extramammary Paget disease: A retrospective study

To prevent further development of extramammary Paget’s disease (EMPD), it is critical to detect lymph node metastasis at an early stage. Therefore, biomarkers that predict the risk of lymph node metastasis are required. In the present retrospective study, we evaluated the potential of neutrophil- to-lymphocyte ratio (NLR) in peripheral blood samples as a biomarker for the risk of lymph node metastasis in EMPD. This study involved 137 EMPD patients who underwent sentinel lymph node biopsy (SLNB) at our hospital from March 2003 to March 2020. The χ2 test, Mann-Whitney U test, logistic regression analysis and Kruskal-Wallis test were used to analyze the correlations between NLR and clinical features/laboratory findings and between SLNB positivity and clinical features/ laboratory findings. Receiver-operator curves were constructed using the DeLong model to define the optimal NLR cutoff value. The NLR cutoff value was defined as 3.0. The high NLR group had 30 patients whose NLRs exceeded 3 (NLR > 3), and 23% of the patients showed sentinel lymph node metastasis (SLNM). The low NLR group had 107 patients whose NLRs were no more than 3 (NLR ≤ 3), and 8% of the patients had SLNM. The rate of SLNM was significantly higher in the high NLR group than in the low NLR group (χ2 test; P = .0245). The odds ratio of SLNM for patients with NLR greater than 3 was 3.311 (95% confidence interval [CI], 1.117 to 9.804; P = .0380) compared with patients with NLR of 3 or less. Then, we classified the patients into 2 groups by SLNB results. Sixteen of the 137 patients (11.7%) showed SLNM. In the logistic regression analysis of 5 variables in 137 patients (Table II) and six variables including carcinoembryonic antigen (CEA) in 55 patients for SLNB positivity, only NLR was found to be significantly associated with SLNB positivity. Here we reported NLR might be a significant predictor for LNM in EMPD patients, providing us with a clue for determining which of them could benefit from SLNB.

Long-term Survival in a Patient with Extramammary Paget's Disease and Liver Metastasis

Long-term Survival in a Patient with Extramammary Paget's Disease and Liver Metastasis

Gastrointestinal: Extramammary Paget disease of the esophagus.

Gastrointestinal: Extramammary Paget disease of the esophagus.

The treatment of anogenital extramammary Paget's disease as part of a multidisciplinary approach: The use of Mohs surgery moat method with CK7.

Although most cases of extramammary Paget's disease (EMPD) are localized to the intraepidermal, the extensive subclinical extension can lead to high rates of marginal recurrence with wide local excisions and topically destructive treatments. Recurrence rates of EMPD treated with Mohs micrographic surgery (MMS) without immunohistochemical staining are better but variable. Here, we describe our multidisciplinary approach for treating large EMPD tumors of the anogenital region involving critical anatomy using MMS for peripheral margin clearance (moat method) and intraoperative CK7 immunostaining. Our clinical pearls for the management of anogenital EMPD are based on 53 multidisciplinary cases treated at the author's institution between 2014 and 2020.

The application of Wood's lamp combined with 5-aminolevulinic acid for defining tumor margins in patients with extramammary Paget's disease

Objective: To evaluate the value of Wood's lamp examination combined with 5-aminolevulinic acid (5-ALA) photodynamic therapy (PDT) to determine positive tumor margins in patients with extramammary Paget's disease (EMPD) before surgery. Methods: We admitted 36 patients with EMPD from January 2016 to June 2019. The experimental group was the 5-ALA-PDT group, and the control group was the wide local excision (WLE) group. In the 5-ALA-PDT group, Wood's lamp examination combined with 5-ALA-PDT was used to trace the fluorescence range, and multipoint biopsy was performed according to the pathology to determine the final excision scope. We applied the standard partial expansion excision method for the WLE group, while frozen pathology assessment was applied to confirm the excision range. We measured the overall resection area of the WLE group and 5-ALA-PDT group. We analyzed the overall duration of surgery, the number of frozen pathology sections, patient satisfaction with appearance and function, the rate of functional sequelae, and the recurrence rate for both groups. Results: The results suggested that the difference in final resection margin between the WLE group and the 5-ALA-PDT group was significant. The number of frozen pathology sections, overall surgery time, and recurrence rate were significantly lower in the experimental group than in the control group (p<0.05). The occurrence rate of functional sequelae in the experimental group was lower, and patient satisfaction with appearance and function was significantly higher than that of the control group (p<0.05). Conclusion: Wood's lamp examination combined with 5-ALA-PDT may predict tumor margins in EMPD.

Evaluation of in vivo reflectance confocal microscopy in the diagnosis of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy that most commonly affects the apocrine glands of older men and women. Because it is associated with other cancers, early diagnosis and evaluation are needed. This study is to evaluate the value of reflectance confocal microscopy (RCM) in diagnosing EMPD. A total of 73 patients with clinically suspicious diagnosis of EMPD were enrolled in this study, and the RCM device imaged their lesions. Moreover, 67 patients underwent skin biopsies to confirm the diagnosis. We retrospectively analyzed the results of RCM and histological diagnosis and then evaluated the RCM value of biopsy-confirmed lesions. Based on the RCM image analysis, 54 of 73 (74.0%) patients were diagnosed with EMPD. Of all 67 biopsied lesions, 52 (77.6%) were EMPD. Then, we analyzed the RCM characteristics of 52 cases of biopsy-confirmed EMPD, compared their RCM image characteristics of three different lesions of EMPD, and further concluded the key points of EMPD under RCM microscopy based on the 52 EMPD cases. Finally, we focused on the differential diagnosis of EMPD from other skin diseases. RCM showed great diagnostic value in diagnosing EMPD.

28581 Vulvar mammary-like adenocarcinoma with overlying extramammary Paget disease

Observations: An 88-year old Asian female with a history of thyroid cancer presented with an itchy 5 cm erythematous inflammatory plaque on the right labia majora extending to the clitoris and left labia majora. Biopsy revealed mammary-like adenocarcinoma beneath extramammary paget disease of the vulva. Breast mammograms revealed no malignancy. The invasive dermal tumor resembled invasive ductal adenocarcinoma of the breast, being positive for cytokeratin 7 and negative for cytokeratin 20. Malignant pagetoid cells were in the epidermis. Immunohistochemical reactions found PR negative, weakly ER positive, 3+ positive for HER2, and S100 negative. Abdominal and pelvic PET/CT images revealed a hypermetabolic area only in the vulvar region. Advanced age advised against chemotherapy. The patient was treated with 4500 cGy intensity-modulated radiation therapy followed by 2160 cGy boost to the vulva and pelvic lymph nodes. A month after completion, there were no complications. She died 8 months later, cause not known.

Extramammary Paget's Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments.

Extramammary Paget’s disease (EMPD) is a rare neoplasm that usually develops in apocrine gland-bearing areas, such as the vulva, scrotum, and penis. EMPD may present with a focal, multifocal, or an ectopic lesion. Clinically, EMPD lesions often exhibit infiltrative erythema, which is sometimes similar to other skin disorders such as eczema. While primary EMPD arises as intraepithelial neoplasm of the epidermis, EMPD-like lesions may occur from epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm, known as secondary EMPD. Because treatment strategies differ for primary EMPD and secondary EMPD, accurate diagnosis based on detailed histopathological evaluation is required. In the early stages, EMPD usually shows indolent growth, and most cases are diagnosed as carcinoma in situ. However, invasive lesions may result in metastases, and deep invasion is associated with high incidence of metastases. Conventional chemotherapies have been used for EMPD treatment in patients with distant metastases, but the efficacy is not satisfactory, and the prognosis for such patients remains poor. Recent studies have provided various insights into the molecular pathogenesis of the development and advancement of EMPD, which may lead to novel treatment approaches for metastatic EMPD. This review addresses the diagnosis, pathogenesis, and treatment of EMPD with focus on recent progress in understanding this disease.