Primary Invasive Paget's Disease in a Clinical Practice: A Case Report.

Invasive Paget's disease (IPDN) is a rare phenomenon characterised by invasive carcinoma localised to the nipple. It is associated with Paget's disease of the nipple (PDN) whereby Paget cells locally invade the underlying epidermis. Often in PDN, histopathological confirmation is needed, due to a lack of clear symptoms on clinical presentation. An 82-year-old female with single duct ectasia presented to the breast clinic in September 2023 with a tender, inflamed right nipple with a necrotic appearance. The lesion was excised, and an ultrasound scan showed right U2, implying no underlying malignancy. Microscopy showed Paget's disease with underlying ductal carcinoma in situ and two small (0.4 and 0.3mm) foci of dermal invasion by Paget cells in keeping with IPDN. Research suggests that dermal invasion by Paget cells has little effect on clinical outcome and prognosis depends largely on the associated underlying malignancy. However, all cases of IPDN with deep invasion or penetration of Paget cells into the dermis have the potential for regional and distant lymphatic spread. In extramammary Paget's disease, depth of invasion has been associated with poorer survival. Therefore, wide variability in clinical patterns and presentations of PDN mandates that a careful clinical approach correlated with in-depth histopathological evaluation is adopted in all cases.

Mammary Paget's Disease as a Sign of Local Recurrence Two Decades Following Breast Conservation and Adjuvant Therapy for Early Stage Breast Cancer.

Reports of mammary Paget's disease (MPD) as a manifestation of breast cancer recurrence are rare. MPD presents a particular challenge when emerging more than two decades after a breast cancer treated with evidence-based therapy. There is a broad spectrum of non-malignant causes for dermatitis of the nipple during the initial presentation that may delay cancer work-up. This case highlights the MPD work-up and management in the context of a personal history of breast cancer. This unique clinical presentation emphasizes the importance of vigilant cancer surveillance for timely intervention, especially for a presumed cured cancer.

Recurrence of Quadruple Extramammary Paget's Disease after 12 Years: A Case Report and Literature Review.

Introduction: Extramammary Paget's disease (EMPD) is a rare skin cancer that tends to be multicentric, with quadruple EMPD cases being scarcely reported. Case Presentation: We report the case of an 81-year-old man with heterochronous quadruple EMPD. Twelve years after total resection of vulvar EMPD, the patient developed erythematous lesions on the resection margin in the lower abdomen, umbilical region, and both axillae. Histological examination revealed that all lesions were in situ EMPD. Discussion: We reviewed six reported cases of quadruple EMPD with respect to race, sex, site, recurrence, time to recurrence, serum carcinoembryonic antigen, and depth. All patients were elderly Japanese males. In all but one case, the lesions were located in the apocrine region, which is a common site in such as the genital and axillary areas. Our case was the only heterochronous quadruple EMPD. The lesions were limited to the epidermis; therefore, they were unlikely to cause metastasis. It has been reported that the therapeutic effects of imiquimod can be expected in in situ EMPD. Therefore, quadruple EMPD may be a good indication of treatment option. Conclusion: EMPD is a disease whose pathogenesis is not yet clear; however, it is hoped that the origin and aetiology of EMPD will be elucidated from the clinical features of multiple EMPD in the future.

Modified clock mapping biopsy sec. Della Corte-Bifulco in the preoperative assessment of excisional surgery for vulvar Paget's disease.

We have developed a biopsy technique aimed at preoperative evaluating the extent of Paget's vulvar disease in order to plan subsequent radical vulvar surgery. The aim is to find all possible lesion sites that are not visible macroscopically, to obtain a clear evaluation of the disease spread and to tailor the radical surgical procedure to remove even microscopic lesions, avoiding recurrences and excessively destructive surgery, adopting as conservative an approach as possible. We used this procedure for the first time to establish the radicality of the surgical intervention in a 68-year-old patient initially suffering from a single invasive vulvar Paget's lesion.

Independent Risk Factors for Postoperative Recurrence of Patients with Primary Extramammary Paget's Disease: A Retrospective Analysis.

Background: Extramammary Paget's disease (EMPD) is a rare skin cancer with unclear pathogenesis, insidious progression, and high recurrence rate. The purpose of this study was to investigate the clinical features and postoperative recurrence factors of primary EMPD. Methods: We retrospectively analyzed the medical records of 40 patients with primary EMPD who underwent wide local excision surgery at a single medical center between 2009 and 2019. Risk factors for recurrence of primary EMPD were analyzed using multivariate binary logistic regression. Results: The study included 40 patients with primary EMPD, comprising 31 males (77.5%) and 9 females (22.5%), with a median age of 75.52 years (range 52-99 years). The most common lesion location was the scrotum (22 cases, 55.0%), followed by the vulva, penis, scrotum, underarm and anus. Multivariable regression analysis revealed significant differences in the presence of ill-defined tumour borders, exudation and nodules in the primary lesion affecting the relapse of primary EMPD (p<0.05). Conclusion: Our findings indicate that ill-defined tumour borders, exudation and nodules in the primary site should be considered as independent risk factors for disease recurrence, which may provide useful suggestions for the diagnosis, treatment and follow-up of primary EMPD.

Case report: Disitamab vedotin combined with immunotherapy demonstrated excellent efficacy in scrotal Paget's disease with Her-2 overexpression.

Background: Extramammary Paget's disease (EMPD) is a rare epithelial malignancy, and approximately 30%-40% of EMPD patients overexpress human epidermal growth factor receptor 2 (Her-2). Currently, there are no established standard treatments for advanced EMPD while anti-Her-2 therapy is recommended for Her-2-positive cases. Case presentation: Here, we report a 51-year-old male diagnosed with advanced Her-2-positive EMPD, presenting with numerous lymph node metastases. This patient received disitamab vedotin (an antibody-drug conjugate, targeting Her-2) combined with serplulimab as first-line treatment. After seven cycles of combination therapy, the patient tolerated the treatment well and the lymph node lesions continued to shrink. However, the patient developed immunotherapy-related pneumonia following the eighth treatment. Hormone therapy was administered while all the anti-tumor therapies were halted. After the pneumonia improved, the patient underwent positron emission tomography-computed tomography, revealing a complete response to his tumor. To consolidate the effect, he received another five cycles of disitamab vedotin monotherapy as maintenance therapy, without experiencing any adverse events. To date, the patient has remained in good health without any recurrence 10 months after drug discontinuance. Conclusion: Disitamab vedotin combined with immunotherapy demonstrated a long-term clinical benefit in advanced Her-2-positive EMPD. For rare solid tumors with Her-2 overexpression, disitamab vedotin combined with immunotherapy might offer a viable therapeutic choice.

Superficial circumflex iliac artery perforator propeller flap for penoscrotal extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intra-epidermal adenocarcinoma, and reconstruction of the penoscrotal region remains a clinical challenge. The superficial circumflex iliac artery perforator (SCIP) flap has been successfully used as a free flap, while its application as a propeller flap in the reconstruction of penoscrotal EMPD defect is rarely reported. The objective was to evaluate the safety and efficacy of the SCIP propeller flap in the reconstruction of penoscrotal defects in EMPD. METHODS: Between September 2010 and August 2022, consecutive patients diagnosed with penoscrotal EMPD were enrolled. All patients underwent penoscrotal EMPD excision and reconstruction with SCIP propeller flap combined with other flaps or skin grafts on individual defects. Demographic information, surgical parameters, postoperative complications, patient satisfaction, and recurrence rates were analyzed. RESULTS: Twenty-four patients (mean age, 73 ± 8.8 years; mean BMI, 23.98 ± 3.62 kg/m2) with 33 SCIP propeller flaps (mean size 120.1 cm2; range, 24-208 cm2) were included, and the mean defect size was 67.4 cm2 (range, 12-255 cm2). The mean operative duration was 385.4 ± 146.8 min. Fifteen patients received autologous full-thickness skin grafts, and four received other flaps simultaneously. All flaps survived without total or partial loss, and all donor sites achieved primary closure, though local hematoma (one case) and limited skin graft necrosis (two cases) were observed. All patients experienced complete wound healing and maintained penoscrotal morphology and function without recurrent lesions over a mean follow-up of 59 months. CONCLUSIONS: The SCIP propeller flap seems a safe and effective reconstructive method for penoscrotal EMPD. LEVEL OF EVIDENCE: IV.

Headache and Status Epilepticus Reveal Paget's Disease of the Bone.

Paget's disease of the bone (PDB) is a benign osteodystrophy of the elderly characterized by excessive remodeling of bone tissue, mainly in the pelvis, femur, and skull. Its neurological manifestations are numerous and affect both the central and peripheral nervous systems. As headaches are often reported, epileptic seizures remain exceptional. We report the case of a 75-year-old female patient with a history of chronic worsening headache who was admitted to the emergency department for the first episode of a seizure. Brain imaging revealed heterogeneous bone thickening and circumscribed skull osteoporosis. Bone scintigraphy showed pagetoid lesions restricted to the skull and face. Alkaline phosphatases increased. The rest of the biological work-up and the cerebrospinal fluid study ruled out other metabolic causes or central nervous system infections. The patient was treated with bisphosphonates and anti-convulsive treatment. The evolution was satisfactory, with progressive improvement in headache and seizure control, even several months after discontinuation of anti-seizure medication. Our case report highlights the importance of exploring chronic headaches in the elderly, not only in search of lesions of the cerebral parenchyma but also of the structures containing them, in this case, the skull.

Preliminary analysis of the efficacy of Mohs micrographic surgery combined with photodynamic therapy in a case of noninvasive extramammary Paget's disease.

PURPOSE: To evaluate the efficacy of Mohs micrographic surgery (MMS) combined with photodynamic therapy (PDT) in treating non-invasive extramammary Paget's disease (EMPD). MATERIALS AND METHODS: A 77-year-old male patient with non-invasive EMPD was treated with MMS followed by PDT. Preoperative fluorescence localization using 5-aminolevulinic acid (ALA) was performed to determine the surgical scope. MMS was conducted under lumbar anesthesia with intraoperative frozen-section pathology. Postoperative PDT was administered weekly for three sessions. RESULTS: The patient achieved negative surgical margins after two rounds of intraoperative pathology. Postoperative follow-up over two years showed no recurrence, and the patient did not experience significant adverse reactions. CONCLUSION: The combination of MMS and PDT was effective in treating non-invasive EMPD, demonstrating favorable clinical outcomes and no recurrence over the two-year follow-up period.

Genetic intratumour heterogeneity and clonal evolution in extramammary Paget's disease.

All tumour cells in a patient have shared and non-shared genetic alterations, and the diversity of mutations is described as intratumoural heterogeneity (ITH). Multiregion sequencing is a genome sequencing analytical technique used for multiple, spatially-separated biopsy tissues that may further our understanding of ITH and tumour evolution. Although genetic mutations in extramammary Paget's disease (EMPD) have recently been detected by next-generation sequencing analysis, there have been no reports of ITH based on multiregion sequencing in EMPD. Thus, we clarified the landscape of ITH and tumour evolution in EMPD. We performed whole-exome sequencing on 35 tissues (30 tumour tissues and five normal skin samples as a paired control), collected from five patients with EMPD. The rate of private mutations was significantly higher than that of ubiquitous and shared mutations. Ubiquitous mutations were not present in driver genes, and most driver genes exhibited private and shared mutations. The most frequent base substitution was C>T in almost all lesions, and most mutational signatures corresponded to signature 1, 2, 3, and 8. The types of proposed aetiology in most lesions were based on age and AID/APOBEC family and BRCA1/BRCA2 mutations. Evolutionary trees were characterized by short trunks and long branches due to the extremely high ratio of private mutations. In contrast, pathogenic factors, such as base substitutions, mutational signatures, and proposed aetiology, were shared. Tumour evolution in EMPD appears to be characterized by a high level of genetic ITH with shared background factors.

A case of endoscopic submucosal dissection of esophageal acantholytic Paget's disease with discontinuously spreading and unclear neoplastic extension.

BACKGROUND: Paget's disease (PD) is a carcinoma, in which irregular atypical cells with abundant cytoplasm proliferate mainly within the epithelium and is classified into PD occurring in the breast and extramammary Paget's disease (EMPD) occurring outside the breast. Essentially, extramammary PD is reported as a tumor for which it is difficult for surgeons to properly determine the line of resection. CASE PRESENTATION: An 83-year-old male was admitted to our hospital because of roughness of the esophageal epithelium during the follow-up examination for a gastric ulcer. A preoperative biopsy revealed squamous cell carcinoma; therefore, endoscopic submucosal dissection (ESD) was performed. CONCLUSIONS: The characteristic feature in this patient was the distribution of tumor cells and, accordingly, the difficulty in identifying the neoplastic distribution. In this patient, the odd distribution and growth pattern of the tumor cells made it difficult for the operator to identify the distribution of the lesion preoperatively.

The Decline of Paget's Disease of Bone and Domestic Coal Use-A Hypothesis.

The cause of Paget's disease of bone (PDB) is unknown. It emerged as a distinct entity in Britain in the late nineteenth century when it was prevalent, and florid presentation not uncommon. Epidemiological surveys in the 1970s showed that Britain had a substantially higher prevalence of PDB than any other country. Studies in the late twentieth and early twenty-first centuries have documented an unexplained change in presentation, with a greatly reduced prevalence and less severe disease than formerly. The emergence of PDB in Britain coincided with rapid industrialization which, in turn, was driven by the use of coal for energy. In the home, bituminous coal was customarily burnt on an open hearth for heating. Using data on coal production, population size, and estimates of domestic use, the estimated exposure to domestic coal burning rose threefold in Britain during the nineteenth century and began to fall after 1900. This pattern fits well with the decline in PDB documented from death certification and prevalence surveys. Colonists moving from Britain to North America, Australia and New Zealand established coal mines and also used coal for domestic heating. PDB was found in these settler populations, but was largely absent from people indigenous to these lands. In all parts of the world PDB prevalence has fallen as the burning of coal in open hearths for domestic heating has reduced. The nature of the putative factor in coal that could initiate PDB is unknown, but possible candidates include both organic and inorganic constituents of bituminous coal.

Invasive cribriform carcinoma of the breast presenting as an erythematous papule on the nipple: A case report.

Invasive cribriform carcinoma (ICC) is a rare form of invasive breast carcinoma with good prognosis. To date, case reports considering skin manifestations of ICC are scarce. We herein report a case of pure ICC presenting as an erythematous papule on the nipple with mammary Paget's disease in the epidermis. We aim to bring awareness to skin manifestation of ICC.

Clinicopathological Correlation and Recurrence Outcome of Adnexal Involvement on Primary Extramammary Paget's Disease (EMPD).

Introduction Primary extramammary Paget's disease (EMPD) is a rare neoplasm that manifests as well-defined erythematous plaques, often misdiagnosed due to its similarity with different dermatoses. It may exhibit invasive features, involving adnexal invasions. The study aims to assess and compare the clinicopathological correlation of primary EMPD with adnexal features. Materials and methodology The monocentric observational retrospective study observed 43 confirmed primary EMPD cases in patients aged 45-95, excluding those with infectious dermatoses, pseudo-tumors, secondary lesions, or survived less than a month. Demographical, clinical and pathological observations were recorded. Expert dermatopathologists, blinded to the initial diagnosis, conducted a comprehensive histopathological evaluation yielding differential pathological diagnosis. Statistical analysis involved Pearson's Chi-square, Mann-Whitney U, and Spearman's Correlations for clinicopathological concordance and adnexal features. Recurrence was evaluated using Kaplan-Meier and log-rank tests, while multivariate recurrence analyses include Cox regression. A p-value < 0.05 was deemed significant. Results There was a significant association between adnexal involvement and the site of lesion (p < 0.05). There was a significant association (p < 0.05) between involved adnexal depth and primary EMPD subtypes. Adnexal involvement has a significant association with the concordance rates derived from clinicopathological correlations (p < 0.05). Smaller lesions and non-invasive EMPD significantly predict longer recurrence onset (p < 0.01). The primary EMPD subtype was the only independent predictor for recurrence time using the Cox regression model. Conclusion Adnexal proliferation in primary EMPD is considered vital on clinicopathological correlations and recurrence predictions, suggestive of its utility on both diagnosis and prognosis.

Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

BACKGROUND: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. METHODS: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. RESULTS: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. CONCLUSION: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

Extramammary Paget Disease. Part I. Epidemiology, Pathogenesis, Clinical Features, and Diagnosis.

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer.

Long-Term Complete Response and Survival in Metastatic Extramammary Paget's Disease Treated With Trastuzumab Plus Paclitaxel: A Case Report.

Extramammary Paget's disease is a rare skin cancer that usually arises from the secretory cells of the apocrine glands. In most cases, an extramammary Paget's tumor occurs as a single intraepithelial form not associated with another cancer, although rarely, it may be associated with other loco-regional or distant cancer. It is generally slow-growing and diagnosed in situ. Most often, surgical excision with wide margins is curative, with the local recurrence rate being lower after the Mohs micrographic surgery technique. Nonetheless, relapses are frequent. In the metastatic setting, there are no treatment guidelines or standard therapies; additionally, the experience is limited to a few individual cases, and the efficacy of conventional chemotherapies is not well-defined. Moreover, chemotherapy can also have serious side effects; therefore, there is a need to identify more effective and less toxic therapies. In this case report, we have observed a long-lasting complete response with anti-HER2 plus paclitaxel.