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PURPOSE OF REVIEW Extramammary Paget's Disease (EMPD) is an uncommon intra-epithelial malignancy, affecting primarily apocrine gland-bearing skin. EMPD is often considered an orphan diagnosis given its rarity. This review provides a contemporary overview of EMPD management. RECENT FINDINGS The mainstay of EMPD treatment centers around a high index of suspicion to allow for an early and accurate diagnosis, wide local or Mohs micrographic surgical excision with care paid toward the margin status, and thoughtful consideration for lymphadenectomy in patients with clinically positive regional disease. There is currently no consensus regarding adjuvant therapies or systemic therapies although with ongoing improvements in tumor biology and genomics, including molecular pathways and alterations specific to EMPD, targeted or combinatorial therapies may be on the horizon. SUMMARY Clinicians caring for patients with EMPD should seek consultation from or if feasible, consider referral to high-volume, experienced centers with patients counseled and provided with frequent and close follow-up for disease recurrence or progression. Collaboration with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient groups will be vital to designing trials and collaborative databases.

Objectives The aim of this study was to evaluate the expression of GCDFP15 and GATA‐binding protein 3 (GATA‐3) in extramammary Paget's disease (EMPD) skin and serum samples and to assess their availability as tumor markers for the diagnosis and assessment of disease severity in primary EMPD. Methods Skin samples and serum samples were obtained from 16 patients with primary EMPD (10 cases from male, six cases from female; stage IA six cases, stage IB seven cases, stage III one case, stage IV two cases). By immunohistochemistry, the expression of GCDFP15 and GATA3 was examined in skin specimens. The serum levels of GCDFP15 and GATA3 were quantified by ELISA. Results In our study, eight out of 16 patients showed positive staining for GCDFP15. In contrast, all 16 patients showed positive staining for GATA‐3. Immunohistochemical staining of EMPD skin samples showed that GATA‐3 had a higher positivity rate than GCDFP15. However, there was no correlation between serum levels of GCDFP15 or GATA‐3 and the disease stage. Conclusion Our results indicate that GCDFP15 and GATA‐3 are useful for the diagnosis of primary EMPD, but not for monitoring disease progression, and suggest that GATA‐3 is a more reliable marker than GCDFP15 for the diagnosis of primary EMPD.

We present a case of extramammary Paget’s disease with bilateral inguinal lymph node metastasis treated by monthly docetaxel chemotherapy. He has also well-controlled psoriasis vulgaris for 20 years. One day after completing monthly chemotherapy, cellulitis by Group G Streptococcus occurred on both legs, resulting in septic shock and disseminated intravascular coagulation. During the infection, the tumor nodule volume and the exudate from the tumor decreased, and tumor markers carcinoembryonic antigen and cancer antigen 19-9 showed low values. Simultaneously, the psoriatic eruption reoccurred. We proposed that cytokine storm including tumor necrosis factor-alpha (TNF-α) during sepsis might have suppressed tumor lesions, and also TNF-α-dependent psoriatic rash appeared temporarily on his body.

BACKGROUND Extramammary Paget's disease (EMPD) is a rare neoplasm that commonly affects post-menopausal women. It usually presents in the anogenital area where apocrine sweat glands are abundant, most commonly in the vulva. The disease is characterised by slow growth and high local recurrence rates. Clinically, EMPD presents as well-demarcated erythematous lesions or plaques that may be ulcerated. Microscopically, it shows a group of atypical cells with abundant clear cytoplasm and nuclear pleomorphism. METHODS We present the case of a 58-year-old female with a history of poorly differentiated squamous cell carcinoma of the cervix, status post-radical-hysterectomy with bilateral salpingo-oophorectomy, and chemoradiation in 2016. The patient also had a long-standing history of vulvar pain, skin changes on her left labia, and itching. RESULTS Punch biopsies of the vulva revealed acanthosis and acantholysis of the epidermis with an intraepidermal scattering of single, or clusters of, large cells with round/oval nuclei and abundant clear cytoplasm. The cells were positive for p16, CK19, CK7, and PAX8, supporting the diagnosis of EMPD without evidence of dysplasia. The concurrent Papanicolaou smear showed a hypercellular specimen composed of hyperchromatic tissue fragments with high nuclear-to-cytoplasmic ratios and apoptotic bodies. The presence of intracytoplasmic mucin and the tridimensionality of the fragments supported the diagnosis of adenocarcinoma. CONCLUSIONS This study compares the histological and cytomorphological features of EMPD with high-grade squamous intraepithelial lesions, since the pathogenesis, precursor lesions, etiological associations, staging, clinical treatment, and prognosis differ substantially and may have a significant clinical impact on the patient's treatment.

Pulmonary tumor thrombotic microangiopathy is a fatal disease secondary to some malignant tumors, such as gastric cancer, esophageal cancer, and pancreatic cancer. A 61-year-old man presented to our clinic with a red plaque with erosion on his scrotum and was diagnosed with extramammary Paget’s disease. Seven years after the initial diagnosis, multiple bone metastases were discovered, and he was started on oral administration of tegafur/gimeracil/oteracil. Two years after beginning the oral drug administration, the patient complained of dyspnea. A chest CT scan showed ground-glass opacity. Pulmonary artery blood cytology revealed carcinoma cells. He was diagnosed with pulmonary tumor thrombotic microangiopathy. At 9 days after the diagnosis, he died of circulatory and respiratory failure. The autopsy revealed microscopic metastatic tumor emboli in multiple pulmonary vessels with fibrin thrombus, which confirmed the earlier cytologic diagnosis. Observations in our case were consistent with the typical pattern of this pathology in the lung with multiple metastases. Pulmonary tumor thrombotic microangiopathy with a primary disease of cutaneous malignancy is extremely rare. Here, we report a rare case of pulmonary tumor thrombotic microangiopathy secondary to extramammary Paget’s disease with a literature review.

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.

Extramammary Paget’s disease (EMPD) is a rarely described skin neoplasm primarily affecting the anogenital region. The diagnosis of EMPD is often delayed due to misdiagnosis which results in delayed treatment. Surgical excision is the mainstay of treatment in patients diagnosed with EMPD. However, cancerous remains are relatively often found due to difficulties with defining the tumor margins during surgery. This results in multiple re-excisions and potential dissemination. We here present two cases of primary EMPD in males and challenges associated with EMPD treatment. Mapping biopsies can provide valuable knowledge and prohibit multiple unsuccessful re-excisions, in patients where the tumor border is difficult to define. A mapping strategy can also contribute to a reduced skin excision, which is crucial in the genital region. Furthermore, we find that PET-CT is an important tool in the disease staging and, hence, selection of adequate treatment strategies. Level of evidence: Level V, therapeutic study.

Extramammary Paget’s disease (EMPD) is a rare, locally aggressive cutaneous adenocarcinoma which typically involves the anogenital region. The prognosis heavily depends on early diagnosis with definitive surgical treatment. To reduce local recurrence, wide radical resection with margin control and Moh’s micrographic surgery are conventionally recommended. We describe a case of a 65-year-old female with extensive perineal EMPD involving the vulva, vagina, ectocervix, urethra, and anal canal, extending to the sacral region. She required pelvic exenteration and skin resection with 5-cm margins. A rectus abdominis myocutaneous flap (OFRAM) was designed with a fleur-de-lis skin paddle, with the vertical limb extended in an oblique fashion. We name this the OFRAM design and it allows maximal recruitment of abdominal tissue for the reconstruction of massive pelvic defects. The oblique limb obliterated the pelvic floor defect after the pelvic exenteration, while the horizontal limbs were used to resurface the perineal defect. One week later, after formal histology confirmed oncologic clearance, a gluteal keystone flap was used to resurface the remnant posterior defect. We discuss the disease pathology and reconstructive options in such cases. Level of Evidence: Level V, therapeutic study.

Lay abstract Invasive extramammary Paget’s disease (iEMPD) is a rare type of cutaneous malignancy with a heterogeneous prognosis. The prognostic factors remain poorly described, resulting in unclear risk stratification of the patients with iEMPD. The purpose of this study is to identify the prognostic factors associated with cancer-specific and overall survival rates in iEMPD and to develop accurate risk stratification models to guide the design of individualized treatment regimens. Clinicopathological data of 1955 patients pathologically diagnosed with iEMPD were retrospectively collected from the Surveillance, Epidemiology, and End Results database, and were utilized for analysis and construction of models for predicting the long-term survival in patients with iEMPD. Eventually, five (age, surgery, tumor location, stage and concurrent malignancy) and eight (gender, age, race, marital status, surgery, tumor location, stage and lymph node metastasis) factors were chosen to develop models for predicting cancer-specific and overall survival, respectively. The prediction accuracy and clinical utility of the established models were confirmed in subsequent evaluation. Because iEMPD is an extremely rare disease that a lot of clinical practitioners might not be familiar with, the availability of these quantifiable predictive models will provide convenience in daily practice.

Surgical borders of extramammary Paget's disease (EMPD) are difficult to be identified via its clinical appearance. In this study, we propose a new diagnostic technique which combines nonlinear harmonic generation microscopy (HGM) with the deep learning method to instantaneously determine whether the imaged 3D stack is malignant EMPD or surrounding normal skin digitally. To demonstrate our proposal, in this study different locations of fresh EMPD surgical samples were 3D imaged starting from the surface up to a depth of 180 μm using stain-free HGM. With the followed histopathological examination of the same sample, we mapped the gold-standard results to 3D HGM image stacks with labels for the training of the deep learning model. With only 2095 3D image stacks as training and validation data, the results of EMPD and normal skin tissue classification achieve 98.06% sensitivity, 93.18% specificity and 95.81% accuracy. This study supports our proposed 3D convolutional-neural-network-based technique with a high potential to assist physicians to quickly map the EMPD margins by providing noninvasive instant information regarding the imaged sub-millimeter site as malignant or surrounding normal with a high accuracy.

Extramammary Paget's disease is a rare neoplasm that may affect the vulva. It usually presents as a pruritic red eczematous lesion with islands of hyperkeratosis that is often mistaken for other benign conditions. There are no specific guidelines for the management of this disease. Surgical excision is the standard treatment but recurrences are common in spite of extensive surgery with negative margins. We report here a series of 7 cases of Paget's disease vulva treated by primary surgery. The series highlights some of the challenges in the diagnosis and management of Paget's disease vulva.

Background Extramammary Paget’s disease (EMPD) is a common subtype of Paget’s disease. Still, there are lacking reports concerning its clinical features, treatment options, and prognosis. Methods The Surveillance, Epidemiology, and End Results (SEER) database was queried for the patients diagnosed with mammary Paget’s disease (MPD) or EMPD from 1975 to 2016. Subsequent analysis was conducted to explore incidence rate, tumor characteristics, clinical features, and survival. Results A total of 1,848 patients with EMPD and 7,106 patients with MPD were retrieved from the SEER database and included in this study. The demographics of EMPD and MPD were significantly different. Compared with MPD, EMPD had better cancer-specific survival (CSS) but worse overall survival (OS). For EMPD, age (P

Background This study aimed to investigate the survival analysis of extramammary Paget’s disease (EMPD) in a Taiwanese population and to provide data for comparison with other studies in various locations and racial populations. Methods We retrospectively analyzed the medical records of 63 patients with EMPD who were surgically treated from 2002 to 2019 at a single institution. The primary endpoint was the 5-year overall survival rate of EMPD, and the secondary endpoint was recurrence-free 5-year survival. Independent variables included patients’ demographic data, concurrent malignancy (i.e., non-EMPD-related cancers), tumor size, distant metastasis, and surgery and/or radiation. Results Of all the 63 patients, 8 cases were excluded. A total of 43 patients (78.18%) were male, and 12 were female, with a mean age of 72.67 years (range 44–89 years). The most common affected anatomic site was the penoscrotal region (22 patients, 40.00%), followed by the perianal and perineal regions (17 patients, 30.91%). Among the 55 patients, 41 patients (74.55%) were diagnosed with at least one underlying disease, whereas the most common underlying disease was cardiovascular disease (30 patients, 54.55%). The overall survival rate was 80.00% at 36 months and 65.45% at the end of follow-up. EMPD with deep dermal invasion was a significant poor prognostic factor of overall survival in cause-specific hazard model (sub-hazard ratio (HR) 5.167, p = 0.0015, 95% confidence interval (CI) 1.876–14.230). Patients with regional metastasis or distant metastasis had poorer prognosis of 5-year survival (sub-HR 4.513, p = 0.0028, CI 1.683–12.103). The limitations of this study include its retrospective nature and sample size. Conclusions In our series, EMPD with metastasis and deep dermal invasion was the significant harmful factors in both overall 5-year survival and 5-year recurrence-free survival. The surgical excision is not associated with a low risk of local recurrence or overall survival, and long-term follow-up is still needed.

Extramammary Paget’s disease (EMPD) is a rare intraepithelial neoplasm that occurs in apocrine-bearing areas of skin. Most EMPD patients initially present with chronic pruritic eczematous lesions involving genitalia, perineum and perianal area. Familial form of EMPD is extremely rare. Several genetic mutations have been proposed but specific modes of inheritance are still unknown. This article reports two cases of familial extramammary Paget’s disease in female siblings.

Extramammary Paget’s disease is a rare skin malignancy, and its diagnosis requires invasive biopsy and histopathological examination. Surgery is the standard treatment for extramammary Paget’s disease patients; however, as incision boundaries and the depth of tumor cell infiltration are often unclear, the postoperative recurrence rate is high. We present a case in which we used photodynamic diagnosis in combination with reflectance confocal microscopy before surgery to detect an extramammary Paget’s disease lesion that was located 3 cm away from the classical lesion. This secondary lesion exhibited a subclinical presentation, and it was eventually confirmed as an extramammary Paget’s disease lesion by pathological examination. During detection using our technique, we delineated the boundaries of the extramammary Paget’s disease lesion as a guide for surgical excision. The findings of our case demonstrate that photodynamic diagnosis combined with reflectance confocal microscopy can be used for the noninvasive diagnosis of subclinical extramammary Paget’s disease and may be used to guide strategies for planning treatment and preventing relapse.

Background: Extramammary Paget's disease (EMPD) is a rare skin cancer and sometimes has fatal prognosis. For progressive cases, therapeutic options are limited. In recent years, treatment with an anti-programmed death-1 (PD-1) antibody has improved the prognosis of various malignancies. In addition, correlations between PD-ligand 1 (PD-L1) expression in tumor cells and favorable responses to anti-PD-1 therapy have been reported for several cancers. There have been a few case series of analysis of PD-L1 expression in patients with EMPD. Aims: The purpose of this study was to investigate the relationship between the EMPD and PD-L1/PD-1 expression in Japanese EMPD patients. Materials and Methods: We investigated 39 patients with EMPD by immunohistochemical staining of PD-L1 and PD-1. We counted the number of tumor cells that were positive for PD-L1 and the number of tumor-infiltrating mononuclear cells (TIMCs) that were positive for PD-L1 and PD-1. We also analyzed correlations between the expression of PD-L1 and PD-1 in EMPD and patients' characteristics. Results: We found that none of the Paget's cells expressed PD-L1. All of the specimens contained TIMCs, and some of the TIMCs expressed PD-L1 and PD-1. However, there was no correlation between the expression of PD-L1/PD-1 in TIMCs and patients' characteristics. Conclusion: Although tumor cells did not express PD-L1 and the expression of PD-L1/PD-1 in TIMCs did not correlate with patients' characteristics, future clinical studies should be carried out to explore another immune escape pathway in EMPD.

Background Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8+ tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis. Materials and methods We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections. Results PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8+ TIL count was significantly lower than that of the corresponding group with a high CD8+ TIL count and of the PD-L1- and PD-L2-negative group (p=0.026). Conclusion The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.

Pigmented extramammary Paget’s disease (EMPD) is a rare variant which is often confused clinically and histologically with melanoma or other pigmented lesions. Herein, we describe a rare case of pigmented EMPD involving the axilla of a 40-year-old female thought initially to represent malignant melanoma clinically. Immunohistochemically, the neoplastic cells are positive for Estrogen Receptor (ER), Progesterone Receptor (PR), and weakly positive for Human Epidermal Growth Factor Receptor 2 (Her2). A review of the literature reveals that the pigmented variant of EMPD could be easily misdiagnosed as melanoma initially and additional confirmatory studies are almost always needed to confirm the diagnosis. The expression of ER and PR in pigmented EMPD is rarely mentioned previously. We believe it should be further investigated for the understanding of pathogenesis in pigmented EMPD and the potential role of adjuvant hormonal therapy. Keywords: Extramammary Paget’s Disease; Axilla; Estrogen Receptor; Progesterone Receptor

This study aimed to evaluate the risk factors of recurrence and invasive disease in patients with extramammary Paget’s disease of the vulva (EPDV). We performed a retrospective analysis of patients who were initially diagnosed with EPDV in Fudan University Shanghai Cancer Center between May 2006 and March 2019. Thirty-eight patients were initially diagnosed with EPDV in our institution. Among them, 29 had intraepithelial EPDV, 8 had intraepithelial EPDV with stromal invasion, and 1 had an underlying vulvar adenocarcinoma. In total, 8 (21%) patients had 12 recurrences. Of these eight patients, four had one recurrence, while other four had two recurrences. Intraepidermal EPDV recurred nine times, while intraepidermal EPDV with invasive disease recurred thrice. The first and second recurrence intervals were 62.1 (9–146) months and 22 (15–28) months, respectively. The rate of invasive disease was 23.7% (9/38) for primary EPDV and 25% (3/12) for recurrent ones. We determined that the presence of invasive disease was associated with a history of more than 10 years (p = 0.02) and inversely correlated with positive margins (p = 0.037), However, invasive disease had no statistical relations with age (p = 0.438), recurrence (p = 0.642), and lesion diameter (p = 0.08). EPDV with a history of more than 10 years was associated with invasive disease. Close and long-term follow-up are recommended to identify those who require further treatment.

Although the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.

Summary Background Penoscrotal extramammary Paget's disease is a rarely found intraepithelial adenocarcinoma in older male patients. The challenge for surgeons to perform high-quality post-surgery reconstruction is mostly case-dependent. Here, we present a review of post-surgical reconstruction practice in 21 cases using various scrotal skin flaps. Methods During the 10-year study period (from 2008 to 2018), all 21 male patients diagnosed with penoscrotal extramammary Paget's diseases at Sun Yat-sen memorial hospital were enrolled in this study. All patients underwent expanding resections guided by frozen sections and penoscrotal reconstructions using various scrotal skin flaps alone or combined with pubic skin flaps and partial thickness skin graft depending on individual defects. The patient's clinical data, specifically the diagnosis, surgical outcome, and follow-up evaluation were retrospectively analyzed. Results The size of skin lesions ranged from 4 × 5 cm to 16 × 18 cm approximately. Out of 21 total cases, 13 patients received combined scrotal and pubic flaps, three patients received single scrotal flaps, and five patients received scrotal flaps and partial thickness skin grafts. Limited flap tip necrosis (two cases) and wound dehiscence (one case) were observed, and secondary resections were performed in four cases with positive post-operative pathological results. All patients experienced complete wound healing and had well-maintained penile morphology and function. Conclusion Various scrotal skin flaps alone or combined with pubic skin flaps designed for individual lesion conditions in patients with penoscrotal extramammary Paget's disease are efficient for scrotal reconstruction. A good match of the local skin texture helps to maintain the morphology and function of the penis and scrotum.

Hypercalcemia of malignancy occurs in up to one third of patients at some point during the course of their advanced stage. The majority of them is caused by humoral hypercalcemia of malignancy due to systemic secretion of parathyroid hormone–related protein (PTHrP) by tumor cells. Extramammary Paget’s disease is a slow-growing cutaneous malignancy commonly limited to the epidermis of the anogenital region, but rarely becomes invasive and metastatic to distant sites. Herein, we report a 70-year-old male patient with metastatic extramammary Paget’s disease. He consulted our hospital with altered consciousness and tumor in his genital area. Physical examination revealed erythematous plaque with a tumor on the scrotum and perineum. It was diagnosed as extramammary Paget’s disease (multiple liver metastases and multiple lymph node metastases by skin biopsy and image examination). Increases in serum-corrected calcium and PTHrP-intact levels (15.3 mg/dL and 66.1 pg/L, respectively) were confirmed. PTHrP immunohistochemistry showed positive staining in the tumor cells. We diagnosed humoral hypercalcemia of malignancy. We treated hypercalcemia with saline, furosemide, zoledronic acid, and elcatonin. Regarding the local control of the tumor, 30 Gy/10 Fr electron beam therapy was performed. However, treatment with zoledronic acid was only temporally effective to correct hypercalcemia, and an increased serum calcium level developed again. Concurrently, the liver metastases were rapidly enlarged, and his general condition gradually deteriorated. The patient died on day 55. When patients with extramammary Paget’s disease show unconsciousness, serum calcium level should be measured and PTHrP-producing tumor distinguished.

Primary extramammary Paget’s disease (EMPD) is a rare intraepithelial adenocarcinoma. Lymph node metastasis from noninvasive EMPD originating in the anorectal region is extremely rare, and the recurrence of noninvasive EMPD is commonly associated with local recurrence mainly due to an insufficient resection margin. We herein report a case of inguinal and para-aortic lymph node recurrence without local recurrence after complete margin-free surgical resection of noninvasive perianal EMPD. The patient was a man in his 40s who presented with an erythematous plaque of 7 × 5 cm in the perianal region, which had been present for 1 year. Biopsy from the perianal skin suggested EMPD; it was positive for cytokeratin (CK)7 and negative for CK20. Underlying malignancy was ruled out based on whole-body enhanced computed tomography (CT) and total colonoscopy. Surgery including complete wide resection of the lesion with preservation of the rectum was performed, and VY-advancement flap reconstruction and flap-rectum anastomosis were performed. A histological examination of the whole specimen with 5-mm slices confirmed noninvasive EMPD resected with all-negative surgical margins. At 2 years and 6 months after surgery, however, enlargement of the inguinal and para-aortic lymph nodes was detected by follow-up enhanced CT, and the recurrence of EMPD was diagnosed based on left inguinal lymph node biopsy. The patient underwent chemotherapy without a remarkable response. He died of the disease 53 months after the first surgery. This is the first case report of lymph node metastasis without local recurrence after complete margin-free resection of noninvasive perianal EMPD.

Background Previous studies have suggested the efficacy of HER2 antibody (trastuzumab) in scrotal Paget's disease with HER2 amplification or overexpression. However, no report about the effectiveness of HER2 inhibitor (pyrotinib) in those patients has been provided until now. Case presentation We present a case of a Chinese patient with bone-metastatic scrotal Paget's disease harboring triple uncommon HER2 mutations (R678Q/S310Y/S310F). Due to poor conditions (severe anemia, thrombocytopenia, ECOG PS3), this patient could not tolerate traditional chemotherapy and radiotherapy. Then, the patient participated in a registered clinical trial (NCT03239015) about basket trial for intractable cancer. The patient received pyrotinib (400 mg po qd) and achieved a partial response for 4.0 months. Conclusion This is the first report describing a patient with scrotal Paget's disease harboring triple uncommon HER2 mutation who responds well to pyrotinib. This case suggested that HER2 mutation is also a potential biomarker for treatment in extramammary Paget's disease and pyrotinib may be an ideal choice for these patients.

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.

Most cases of extramammary Paget's disease are diagnosed at an early stage. For advanced cases, few effective treatments are available and the prognosis is poor. Therefore, developing sensitive biomarkers for metastatic cases is a critical challenge. Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are two potentially useful biomarkers. In the present retrospective large-scale study, we identified other potential biomarkers of lymph node metastasis. Patients with extramammary Paget's disease who visited our dermatology clinic between April 2004 and March 2019 (n = 138; mean age, 73.4 years; 85 men and 53 women) were enrolled in the study. The patients were divided into three groups according to the presence of regional lymph node metastasis and distant metastasis to evaluate the relationship between metastasis and various tumor markers: serum CEA, carbohydrate antigen (CA)19-9, CA125, CA15-3 and CYFRA. For distal metastasis, each biomarker had high sensitivity and specificity. The sensitivities and specificities for regional lymph node metastasis were as follows: CEA, 50.0% and 88.6%; CA19-9, 50% and 89.5%; CA125, 0% and 98.2%; CA15-3, 0% and 96.0%; and CYFRA, 66.7% and 95.0%, respectively. We also analyzed biomarker combinations. The sensitivity and specificity of the combination of all five biomarkers (CEA, CA19-9, CA125, CA15-3 and CYFRA) were 83.3% and 70.9%, respectively. The sensitivity of the combination of just CEA and CYFRA was also 83.3%. Screening for combinations of these biomarkers will facilitate the detection of early lymph node metastasis in patients with extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare and lethal intraepithelial malignancy that remains poorly understood. No standardized guidelines or consensus statements exist with regards to the diagnostic evaluation, therapeutic approaches and follow-up management. Complete surgical excision with negative margins has been accepted as the mainstay of treatment for EMPD to decrease the risk of local recurrence and to maximize durable cure. Non-invasive therapies, such as laser therapy, photodynamic therapy, radiotherapy and topical chemotherapy have been utilized, but are best reserved for non-surgical candidates. While the debate on the surgical approach between wide local excision (WLE) and Mohs micrographic surgery (MMS) continues, several studies have demonstrated the ability of WLE to be performed safely and effectively and to yield equally satisfactory outcomes with similar rates of recurrence to MMS. Patients undergoing surgical excision often require complex closures with skin grafting or local flaps to close genital defects. We aim to provide an up-to-date review of the current knowledge of EMPD. In addition to discussing the clinical presentation and prognostic outcomes, we focus and elaborate on the diagnostic approaches and treatment alternatives available. This information may serve as a primer for the urologist who may be called upon to treat this malignancy primarily or to provide wound coverage secondarily.

Background Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well-studied in EMPD. Objective To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. Methods The mRNA expression levels of molecules involved in glycolysis and immune-related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). Results The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired-normal tissues. IHC analyses revealed increased numbers of PD-L1+ , PD-1+ , CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL-4, IL-6, IL-10, TGF-β and CCL-2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL-6 mRNA expression correlated with the number of CD163+ , Iba-1+ and Foxp3+ cells. Conclusion The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.

Extramammary Paget’s disease (EMPD) is a rare form of neoplasm. Metastasis of EMPD to locations other than lymph nodes and intra-epithelial regions is rare; there are a limited number of case reports of metastases to the liver, lung, bone, and brain. We present a rare case of EMPD that metastasized to the brain and was treated with surgical resection. A 66-year-old man presented with a small palpable mass in the scrotum. After 5 years of observation, he was diagnosed with EMPD that metastasized to the lymph nodes and lung. Tumor resection and postoperative chemotherapy were performed. Six months after the last chemotherapy treatment, he presented with a right temporal lobe tumor and underwent surgical resection. Histopathological analysis revealed brain metastasis of EMPD. Three months after surgery, magnetic resonance imaging (MRI) showed local tumor recurrence, and intensity modulated radiation therapy (IMRT) (45 Gy/15 Fr) was performed. Although the metastatic brain tumor was well controlled, the primary tumor progressed. He was provided best supportive care and died 5 months after brain tumor resection. In this report, we present a rare case of brain metastasis of EMPD, treated with surgical resection, and histopathologically confirmed to be metastatic EMPD.

Extramammary Paget’s disease and vulvar intraepithelial neoplasia are common lesions of vulve, but synchronous occurrence is rare in a same location. Herein we describe a concurrence of primary cutaneous extra mammary Paget’s disease and squamous cell carcinoma in situ of vulva in an Iranian women. A 59 year old woman, initially presented to Kosar teaching hospital gynecology clinic April 2017 with a single, well defined, scaly, white ulcerated mass, 2 cm in diameter on right minor labia, but other examinations were normal. She had no urinary or gastrointestinal symptoms. Incisional biopsies from the mass represented concurrence extramammary Paget’s disease and VIN3. She underwent radical vulvectomy .No evidence of disease recurrence was noted after 16 months follow up. Participant consent was obtained before patient was enrolled in this study. There are lot of diseases that involve genitalia and lead to vulvar lesions. But in this rare case, we diagnosed concurrence of extramammary Paget’s disease and vulvar intraepithelial neoplasia in a same location. Additionally, the clinical presentation as a vulvar mass was found unusual. Therefore, we report the case to sensitize gynecologists and pathologists for uncommon pathologies and their manifestations in vulva.

The case of a 75-year-old female with invasive extramammary Paget’s disease of the anal margin, without involvement of the anal canal, is reported. The patient underwent wide local excision of the lesion with reconstruction with a double V-Y flap, a biopsy of the inguinal sentinel node, and a laparoscopic temporary colostomy. No guidelines exist on the treatment of this rare disease, and both wide local excision and abdominoperineal resection have been proposed. In the present case, the absence of invasion of the anal canal, also confirmed by intraoperative biopsies on the resection margins, and of local lymph node metastasis, as confirmed by the sentinel lymph node biopsy, allowed a sphincter-sparing operation with good functional and oncological results.

Metastatic extramammary Paget’s disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget’s disease, with an ERBB2S310F mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3A232V and PIK3CAG106V point mutations as well as MET and CDK6 amplification, providing a potential mechanism of acquired treatment resistance. Therefore, ERBB family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of ERBB2S310F mutated, metastatic extramammary Paget’s disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget’s disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.

Patients with invasive extramammary Paget’s disease have an increased risk of secondary malignancy, mostly occurring colorectal carcinoma. TP53 is a regulator of apoptosis, cell cycle arrest, and DNA damage response pathways, and has been reported as one of the genetic biomarkers for colorectal carcinoma. In this report, we describe a case of advanced invasive EMPD concomitant with cecal cancer with a rare variant of TP53 single nucleotide polymorphism (rs121912665). To our knowledge, there is no English report that presents EMPD concomitant with cecal carcinoma.

BACKGROUND Extramammary Paget's disease is an uncommon intraepidermal adenocarcinoma with poorly defined clinical implications. OBJECTIVE The purpose of this research was to estimate the risk of second primary neoplasms in patients with extramammary Paget's disease. DESIGN This was a retrospective analysis of the Surveillance, Epidemiology, and End Results Registry (1973-2014). SETTINGS The study included population-based cancer registries from the United States. PATIENTS Patients who were diagnosed with anogenital Paget's disease were included. MAIN OUTCOME MEASURES Risk of second primary development was measured. RESULTS We identified 108 patients with anal Paget's disease, 421 patients with male genital (scrotum or penis) Paget's, and 1677 patients with female genital (vagina or vulva) Paget's. Median follow-up time was 5.9 years. The risk of developing colorectal adenocarcinoma was 18.5% for patients with anal Paget's disease. Eighty percent of colorectal adenocarcinoma diagnoses were synchronous (within 2 mo) to anal Paget's diagnoses, whereas metachronous tumors occurred at a median time of 2.4 years. Of patients with anal Paget's disease, 8.3% developed an anal adenocarcinoma or nonsmall cell cancer. In male patients with genital Paget's, the risk of proximal genitourinary malignancy was 9.7%, scrotal or testicular adenocarcinoma was 0.4%, and penile or scrotal squamous carcinoma was 1.7%. In female patients with genital Paget's, the risk of proximal genitourinary malignancy was 3.0%, vaginal or vulvar adenocarcinoma was 1.4%, and vaginal or vulvar squamous neoplasm was 1.0%. Five-year overall survival was 59.7%, 73.5%, and 80.7% in patients with anal, male genital, and female genital Paget's (p < 0.001). LIMITATIONS The registry did not record surveillance schedule, provider specialty, or nonprocedural therapies for extramammary Paget's disease. CONCLUSIONS In the largest published cohort of patients with extramammary Paget's disease, patients with anal Paget's had a much higher risk of both proximal and local neoplasms as compared with patients with genital Paget's. Patients with anal Paget's also experienced worse survival as compared with those with purely genital Paget's. See Video Abstract at http://links.lww.com/DCR/B20. ALTO RIESGO DE NEOPLASIAS PROXIMALES Y LOCALES EN 2206 PACIENTES CON ENFERMEDAD DE PAGET EXTRAMAMARIA ANOGENITAL:: La enfermedad de Paget extramamaria es un adenocarcinoma intraepidermico poco frecuente con implicaciones clinicas poco definidas.Estimar el riesgo de segundas neoplasias primarias en pacientes con enfermedad de Paget extramamaria.Analisis retrospectivo del Registro de Vigilancia, Epidemiologia y Resultados Finales (1973-2014).Registros de base poblacional en cancer de los Estados Unidos.Pacientes que fueron diagnosticados con enfermedad de Paget anogenital.Riesgo de desarrollo un cancer primario adicional.Se identificaron 108 pacientes con Paget anal, 421 pacientes con Paget genital masculino (escroto o pene) y 1677 pacientes con Paget genital femenino (vagina o vulva). Tiempo mediano de seguimiento fue de 5,9 anos. El riesgo de desarrollar adenocarcinoma colorrectal fue del 18,5% para los pacientes con Paget anal. El ochenta por ciento de los diagnosticos de adenocarcinoma colorrectal fueron sincronicos (dentro de los 2 meses) a los diagnosticos de Paget anal, mientras que los tumores metacronicos ocurrieron en un tiempo promedio de 2,4 anos. De los pacientes con Paget anal, el 8.3% desarrollo un adenocarcinoma anal o cancer de celulas no pequenas. En los pacientes masculinos con Paget genital, el riesgo de malignidad genitourinaria proximal fue del 9,7%, el adenocarcinoma escrotal o testicular fue del 0,4% y el carcinoma escamoso del pene o escroto fue del 1,7%. En pacientes femeninas con Paget genital, el riesgo de malignidad genitourinaria proximal fue de 3.0%, el adenocarcinoma vaginal o vulvar fue de 1.4% y la neoplasia escamosa vaginal o vulvar fue de 1.0%. La supervivencia general a cinco anos fue del 59.7%, 73.5% y 80.7% en pacientes con anal, genital masculino y genital femenino, respectivamente (p

Extramammary Paget’s disease (EMPD) is an uncommon intraepithelial malignancy that is rarely found in the male. Currently, there is very little knowledge pertaining to EMPD imaging, particularly in cases that involve the scrotum. Here, a 67-year-old man with lichenification on his left scrotum confirmed to be EMPD was reviewed. Bloodwork did not return a positive result, but syphilis-specific antibodies were found. Conventional high-frequency ultrasound (US) and contrast-enhanced ultrasound (CEUS) imaging were utilized to determine the lesion size and blood perfusion. In the present case, the lesion’s size and involvement were vividly depicted by CEUS, while results obtained by conventional US were grossly underestimated. Consequently, multimodal imaging assessment is likely to provide more accurate diagnoses for uncommon diseases, such as EMPD, and to aid in clinical decision-making.

Background Male cases of accessory breast carcinoma and sweat gland carcinoma associated with extramammary Paget’s disease of the axilla are uncommon. In clinical diagnosis and treatment, it is necessary to determine the disease carefully and make a reasonable treatment strategy according to the patient’s situation. Case presentation We described two male cases of the special tumor with an axillary mass as the first clinical symptom, one of which was diagnosed as accessory breast cancer and the other as sweat gland cancer associated with extramammary Paget’s disease. We treated the two diseases individually in the hopes of providing a reference for the diagnosis and management of diseases with axillary nodules as the initial symptom. Conclusions The reports of these two cases can provide reference and corresponding thinking for clinical differentiation of axillary lymphadenopathy caused by different causes and subsequent treatment. These two cases may further enrich the database of rare cases and provide some ideas for the treatment of axillary lymphadenopathy caused by different causes.

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 18 genes, 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.

Extramammary Paget’s disease is a rare condition, affecting 6.5% of all patients with Paget’s disease. The most common extramammary site is the vulvar area. Although diagnosis in some patients is difficult to set, early diagnosis is of high importance in order to detect the irreversible progression of the lesion early and prevent distant metastasis. An 89-year-old female and a 69-year-old female presented within three months with an eczematous lesion with leukoplakia in the vulva. The incisional biopsy of the skin revealed extramammary Paget’s disease. Both patients underwent a surgical wide local excision of the lesion and the specimens were sent for histopathological examination. Extramammary Paget’s disease has a high potential for distant malignancies and local recurrence, dictating that surgical excision is the most efficient treatment. The rareness of the condition and the diagnostic difficulties underline the need for early skin biopsy, which is the most efficient diagnostic tool.

Introduction: We report an elderly gentleman with Extramammary Paget’s disease (EMPD) treated with Mohs micrographic surgery (MMS) using Toluidine blue staining intraoperatively as to detect the Paget’s cells. Case Presentation: An elderly man presented with an erythematous plaque on the left inguinal fold which showed in-situ EMPD on histopathological examination. Investigations for secondary EMPD were negative and the patient was treated with MMS. During MMS, the specimens from the patient were stained using Toluidine blue in order to detect the Paget cells and to determine the appropriate negative margin. At 4 years follow up the patient is free of recurrence. Conclusion: Toluidine blue is a fast, user-friendly dye that can be used intraoperatively during MMS as to detect Paget cells and thus to determine the appropriate negative margin.