RARE DISEASE
Extramammary Paget disease
Extramammary Paget disease
Extramammary Paget disease
Drug discovery
0
drugs
With orphan designations
Overview
Extramammary Paget Disease (EMPD) is a rare intraepithelial adenocarcinoma primarily affecting apocrine gland-rich areas (genital, perianal, axillary). It presents as erythematous, pruritic plaques mimicking eczema, often with delayed diagnosis due to nonspecific appearance. Primary EMPD originates in the epidermis, while secondary forms link to underlying malignancies (e.g., colorectal, urothelial). Surgical excision (Mohs or wide local) is first-line, but recurrence rates reach 30–60%. Prognosis is favorable for localized disease but declines with dermal invasion or metastases [1][2][5][8][12].
Therapies
Surgical: Mohs micrographic surgery (lower recurrence) or wide local excision [1][4][11].
Nonsurgical: Topical imiquimod, radiotherapy, photodynamic therapy, and CO2 laser for non-resectable cases [3][14][15].
Systemic: Chemotherapy, anti-HER2 agents (e.g., trastuzumab), or immune checkpoint inhibitors for metastatic disease [7][15][19].
Categories: rare gynecological and obstetric diseases, rare neoplastic diseases, rare skin diseases
Research Papers
676 drug discovery papers about Extramammary Paget disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
676 drug discovery papers about Extramammary Paget disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-24 | Concurrent chemoradiotherapy for metastatic vulvar extramammary Paget's disease involving supraclavicular nodes: a case report.
Extramammary Paget's disease (EMPD) is a rare adenocarcinoma with a poor prognosis when invasive. Here, we report an exceptionally rare case of invasive vulvar EMPD in a 70-year-old woman who presented with extensive lymphadenopathy involving the inguinal, pelvic, para-aortic, and left supraclavicular regions. Histopathology confirmed dermal and lymphovascular invasion. Given the systemic nodal spread, the patient underwent definitive concurrent chemoradiotherapy (CCRT) with weekly cisplatin. Radiotherapy was delivered to the inguinal-to-paraaortic nodes at 57.6 Gy in 32 fractions and to the supraclavicular nodes at 51.0 Gy in 17 fractions. Follow-up imaging 6 months after treatment demonstrated a complete response per Response Evaluation Criteria in Solid Tumor criteria. This case is notable because supraclavicular involvement in EMPD is extremely rare and usually reflects advanced systemic dissemination. Our findings suggest that intensive CCRT may achieve excellent locoregional and systemic disease control, supporting its potential role as an effective primary treatment option for patients with advanced metastatic EMPD.
2026-08-09 | Aminolevulinic acid photodynamic therapy for extensive genital extramammary Paget disease in older patients: A retrospective clinical case series.
Extramammary Paget disease (EMPD) involving the genital and anogenital region is difficult to manage when lesions are extensive, chronic, or located across functionally sensitive sites. In older patients with diabetes, cardiovascular disease, or advanced local involvement, wide excision may lead to considerable perioperative burden, delayed healing, and anatomical impairment. To describe the short-term clinical outcomes and symptom relief associated with aminolevulinic acid photodynamic therapy (ALA-PDT) in older patients with extensive EMPD who were unsuitable for disfiguring surgery or declined surgical treatment. We retrospectively reviewed three histologically confirmed EMPD cases affecting the mons pubis, penile root or foreskin, scrotum, inguinal region, and adjacent proximal thigh. All patients received lesion preparation by debridement followed by topical 10% ALA-PDT using a standardized illumination regimen. At the 3-month evaluation, erosive and exudative areas had re-epithelialized, and nodular lesions showed marked reduction or flattening. Pruritus and local pain improved rapidly and had resolved within 2 weeks after treatment initiation. Mild transient erythema was the only treatment-related reaction. No clinically apparent regrowth or progression was observed during the 12-month clinical and dermoscopic follow-up. In this small retrospective series, ALA-PDT was associated with short-term clinical control and palliative benefit in older patients with extensive genital EMPD, while preserving genital anatomy without creating large surgical defects. These preliminary findings support further evaluation of optimized PDT-based conservative strategies for difficult-to-treat EMPD.
2026-08-03 | Treatment outcomes and influencing factors of photodynamic therapy in extramammary Paget's disease: a retrospective analysis of 31 cases.
Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma for which surgical excision often causes functional/cosmetic impairment. Photodynamic therapy (PDT) offers a noninvasive alternative, but data on its efficacy and influencing factors remain limited. To evaluate efficacy of 5‑aminolevulinic acid (ALA)‑PDT monotherapy for localized EMPD over one year, and identify baseline predictors of response. This retrospective study included 31 patients with histologically confirmed localized EMPD treated with ALA‑PDT alone. Responses were assessed at 3, 6, and 12 months. Objective response rate (ORR), disease control rate (DCR), and associated response factors were analyzed by Fisher's exact test. At 3 months, ORR was 90.3% (28/31) and DCR 100% (31/31), with no complete responses (CR). At 6 months, CR was 19.4% (6/31), ORR 67.7% (21/31), DCR 83.9% (26/31). At 12 months (n = 30), CR remained 19.4% (6/30), ORR declined to 36.7% (11/30), and DCR to 56.7% (17/30). Lesion diameter ≤5 cm and absence of exudation predicted better 6‑month response (p = 0.020 and p = 0.006); diameter ≤5 cm remained significant at 12 months (p = 0.002). ALA-PDT monotherapy achieves high short‑term responses in localized EMPD, but efficacy declines substantially by 12 months. Lesion diameter ≤5 cm and non-exudative morphology predict better responses.
2026-08-01 | Proteomic and metabolomic profiling reveals dysregulation of immune states, mucin-type glycosylation and steroid metabolism in extramammary Paget's disease.
Extramammary Paget's disease is a rare cutaneous adenocarcinoma characterized by mucin-rich Paget cells and chronic inflammation, yet its molecular basis remains unclear. To systematically characterize the proteomic and metabolomic landscape of EMPD, uncover immune heterogeneity, and identify molecular pathways underlying tumor progression and microenvironment remodeling. We performed integrated proteomic and metabolomic analyses on 92 male tumor patients and 30 healthy controls, identifying 10,217 proteins and 1466 metabolites. Extramammary Paget's disease lesions exhibited broad activation of inflammatory pathways. Immune profiling further uncovered substantial inflammatory heterogeneity, delineating immune-cold and immune-hot subtypes, with the latter associated with stronger invasive potential. Aberrant mucin-type glycosylation was also prominent, featuring Tn-modified MUC1 and MUC5AC accompanied by elevated GALNT7, GALNT6, GALNT4, and ST6GAL1, which correlated with inflammatory intensity. Metabolomic data demonstrated elevated levels of testosterone, dehydroepiandrosterone, and related intermediates in tumor tissues, indicating an androgen-enriched metabolic profile in extramammary Paget's disease. These findings reveal immune, glycoproteomic, and metabolomic pathways in extramammary Paget's disease pathogenesis and provide novel insights for molecular classification and therapeutic targeting.
2026-07-15 | Intralesional ALA-PDT for residual extramammary Paget's disease: a case report.
Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy often associated with positive surgical margins and high local recurrence rates. While wide local excision remains the standard treatment, re-excision may be impractical in anatomically sensitive areas. Topical photodynamic therapy (PDT) is frequently used for superficial lesions but its efficacy is limited by poor photosensitizer penetration, particularly when tumor cells invade deep into the dermis or adnexal structures. An elderly male with scrotal EMPD underwent surgical excision, but postoperative pathology revealed positive margins with tumor infiltration into the subcutaneous fat. Further wide excision was deemed unfeasible due to functional and anatomical constraints. Pre-treatment high-frequency ultrasound demonstrated a lesion thickness of approximately 2.7 mm, exceeding the effective penetration depth of topical PDT. To overcome this barrier, intralesional 5-aminolevulinic acid photodynamic therapy (ALA-PDT) was administered monthly. A 10% ALA solution was injected directly into the residual plaque, followed by a 2-hour incubation and irradiation with 630 nm red light at a fluence of 120 J/cm2. After three sessions, the indurated erythematous plaque showed marked thinning and fading; complete clinical regression was achieved after six sessions. The treatment was well-tolerated, with only mild pain and transient erythema. No recurrence was observed during the 6-month follow-up period. Intralesional ALA-PDT is a highly effective, minimally invasive, and tissue-preserving treatment for residual EMPD with deep dermal invasion. By ensuring adequate photosensitizer delivery throughout the entire lesion, it overcomes the penetration limitations of topical PDT and represents a valuable option when surgery is not feasible.
cell therapies
2026-07-28 | Wide Excision and Flap Reconstruction in Perineal Extramammary Paget's Disease Patients.
Background and Objectives: Extramammary Paget's Disease (EMPD) of the perineal region is a rare intraepidermal adenocarcinoma requiring wide excision, resulting in extensive defects that are challenging to reconstruct while preserving contour and function. This descriptive case series evaluated a reconstructive selection strategy using pedicled superficial circumflex iliac artery perforator (SCIP) flaps and pedicled anterolateral thigh (ALT) flaps for perineal defects following wide excision of EMPD. Materials and Methods: This retrospective case series reviewed patients with perineal EMPD who underwent wide excision followed by reconstruction using pedicled SCIP flaps or pedicled ALT flaps. Patient demographic and lesion characteristics, operative and flap characteristics, post-reconstruction complications, oncologic outcomes, and satisfaction were analyzed. Results: 15 patients (mean age 63 years, SD 7.3) were included in this case series. Ten patients underwent reconstruction using pedicled SCIP flaps (mean 106 cm2, SD 23.3), and five patients with pedicled ALT flaps (mean 245.2 cm2, SD 41.2). All flaps survived, but one patient developed limited partial necrosis managed with secondary healing. During a mean follow-up of 17.7 months (SD 1.3), one patient (6.7%) developed recurrence and eventually distant metastasis resulting in death. Among the 14 surviving patients, 13 (92.9%) reported overall satisfaction with cosmetic and functional outcomes assessed using a non-validated ordinal scale. Conclusions: Pedicled SCIP and ALT flap reconstruction provides reliable, well-vascularized tissue coverage for perineal EMPD defects and achieves generally favorable short-term outcomes. The choice between flap types should be tailored to the defect size, location, and patient characteristics.
2025-11-01 | 679 Combined radiation and adoptive CTL therapy in advanced extramammary paget disease with pulmonary and nodal metastases: a case report and rationale for case series expansion
Background Extramammary Paget’s disease (EMPD) is a rare cutaneous adenocarcinoma, typically arising in apocrine gland-rich areas such as the vulva, perineum, and scrotum. The disease is usually confined to the epidermis but may become invasive and metastasize, with poor prognoses in advanced stages. While surgery remains the mainstay of treatment for localized disease, the management of metastatic EMPD lacks consensus. Immunotherapy and cellular therapies are emerging as promising modalities in solid tumors, yet limited data exist in the EMPD context. Adoptive CTL therapy, which involves the ex vivo expansion and activation of autologous T lymphocytes, has shown potential in melanoma, EBV-related cancers, and select solid tumors. 1 2 high-dose radiotherapy (HD-RT) with low-dose RT (LD-RT)safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.3 Here, we present a case demonstrating the successful application of combined HD-RT plus LD-RT radiotherapy and CTL therapy.Methods A 65-year-old male underwent VMAT-based radiotherapy to the cervical lesion (60 Gy in 8 fractions) and IMRT to the pulmonary and mediastinal sites (Left lung lesion: 50 Gy/5F, Mediastinal nodes (Station 5: 45 Gy/15F; Station 4L: 25 Gy/5F (HD-RT) + sequential boost 2 Gy/4 (LD-RT) respectively). Concurrently, PBMCs were isolated, activated using CD3/CD28/CD2 stimulants, expanded with IL-2 (1000 IU/mL), and re-infused following a 13-day GMP-compliant expansion protocol.CTLs were infused concurrently with the LD-RT phase duing lung and mediastinal radiation therapy.Results Follow-up PET/CT (3 days post-RT completion) showed: Left neck lesion decreased in size (from 5.2 to 4.0 cm) and SUVmax (16.6 → 13.6); Mediastinal lymph nodes reduced in size and activity (SUVmax 9.7 → 6.0); Left lung lesion decreased (SUVmax 12.1 → 7.3) Right lung nodule stable (SUVmax 2.4 unchanged) ( figure 1). Treatment resulted in partial metabolic response (PMR/PR). The patient experienced no major adverse effects and remained clinically stable.Conclusions This case highlights the potential benefit of combining radiotherapy with adoptive CTL therapy in metastatic EMPD. The rationale includes immune modulation by radiotherapy, enhancing T cell trafficking and tumor antigen release. While single-agent immune checkpoint inhibitors have demonstrated limited activity in EMPD, cell therapy may bypass tumor-induced immunosuppression. Further evaluation in a structured case series or early-phase clinical trial is justified.References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62-68.Chapuis AG, Ragnarsson GB, Nguyen HN, et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci USA. 2012;109(12):4592-4597.Patel RR, He K, Barsoumian HB, Chang JY, Tang C, Verma V, Comeaux N, Chun SG, Gandhi S, Truong MT, Erasmus JJ, Hong DS, Lee PP, Ning MS, Nguyen QN, Heymach JV, Altan M, Blumenschein G, Fossella FV, Sezen D, Chen D, Carter BW, Davies MA, Glitza IC, Diab A, Ferrarotto R, Cabanillas ME, Yuan Y, Shah SJ, Parra ER, Sun B, Cortez MA, Welsh JW. High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial. Radiother Oncol. 2021 Sep;162:60-67. doi: 10.1016/j.radonc.2021.06.037. Epub 2021 Jul 5.Abstract 679 Figure 1PET/CT pre treatment and 3 days post treatment
2025-08-11 | Surgical management of perianal Paget's disease - Case reports.
Perianal paget's disease is an uncommon malignant diagnosis for which surgical treatment is primarily opted for. This study presents two case reports of perianal paget's disease treated with surgery in a tertiary care oncologic center in India. Case 1: A 72 year old man presented with an itchy white patch in the perianal region, with a biopsy done in 2015 revealing extra-mammary paget's disease. The patient reported to us in November 2018, following which he was reevaluated and subsequently underwent wide local excision, diversion loop colostomy, and bilateral medial thigh perforator fasciocutaneous flaps reconstruction. Final histopathological examination confirmed diagnosis of Paget's disease. Case 2: A 69 year old man presented with recurrent perianal paget's disease after surgical excision and radiotherapy in 2016. The patient underwent wide local excision, diversion colostomy, bilateral sentinel lymph node biopsy, left ilioinguinal block dissection, and reconstruction with multiple medial thigh fasciocutaneous flaps in December 2019. Discussions: Perianal paget's disease is a rare cutaneous malignancy. Although studies regarding effective treatments are lacking, surgical excision is considered the best modality. Wide local excision with or without reconstruction remains the treatment proven to be successful, regardless of which long term follow up is crucial to identify recurrence. Larger case series are required to further comprehend the histopathology of the disease to prevent misdiagnoses and identify effective methods of treatment.
2019-01-25 | Accumulation of exhausted CD8+ T cells in extramammary Paget’s disease
Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03–24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.
2018-04-19 | 397 Contribution of the PD-1 and IDO pathway to T cell exhaustion in extramammary Paget disease
Cancer immunotherapy has highlighted the mechanism of tumor immune evasion in various cancer types. However, little is known about the role of the immune system against extramammary Paget disease (EMPD). We aimed to reveal the clinical relevance of tumor immunity of EMPD. We retrospectively analyzed 54 EMPD patients by immunohistochemistry (IHC) to examine immunological predictors of prognosis. We found that a high number of CD8+ cells and PD-1+ cells in the cancer stroma was associated with poor overall survival and poor disease-free survival in multivariable Cox-proportional hazard regression analysis, respectively. We also investigated tumor-derived immuno-modulating factors by IHC. EMPD tumor cells showed positive IHC staining for immunosuppressive factors, including indoleamine 2,3-dyoxygenae (IDO) and chemokines that attract CD8+ T cells, such as CXCL9, CXCL10, and CXCL11. In addition, the cytotoxicity and the effector functions of CD8+ T cells in paired samples of peripheral blood and tumors from additional 10 EMPD patients were prospectively investigated with flow cytometry. Flow cytometric analysis demonstrated that the expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in the CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in the CD8+ T cells of peripheral blood. Our findings suggest that CD8+ T cells attracted to the tumor sites by tumor-derived chemokines display an exhausted phenotype with PD-1 upregulation on CD8+ TILs and IDO expression on tumor cells. Taken together, we concluded the presence of a high number of CD8+ cells and PD-1+ cells in the cancer stroma was an indicator of poor prognosis. Restoring the effector functions of CD8+ TILs might be a new strategy of treatment for EMPD.
antibodies
2026-09-28 | Trophoblast glycoprotein is a novel therapeutic target for extramammary Paget disease
Abstract Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in the anogenital area of older people. It remains challenging to treat advanced EMPD due to the lack of effective treatments. The development of novel therapeutic approaches is thus strongly desired, but EMPD’s rarity and the lack of an appropriate in vitro model have impeded investigation of this disease. The aim of this work is to evaluate trophoblast glycoprotein (TPBG) as a promising therapeutic target for EMPD. To achieve this, TPBG expression was first analyzed in 124 (116 primary and 8 metastatic) samples from 116 EMPD patients. Using a recently established patient-derived EMPD cell line, KS-EMPD-1, the function of TPBG was assessed in vitro. TPBG was expressed in patients’ EMPD lesions with various staining intensities. It was also expressed in KS-EMPD-1 cells, while the inhibition of TPBG by siRNA in these cells significantly inhibited their proliferation accompanied by the decreased expression of cyclin D1. TPBG knockdown in KS-EMPD-1 cells also inhibited cell invasion. KS-EMPD-1 cells were also sensitive to cytotoxic agents commonly used as components of antibody-drug conjugate, a novel kind of targeted drug. These results suggest that TPBG will possibly serve as a therapeutic target for advanced EMPD.
2026-09-24 | Efficacy and safety of trastuzumab emtansine in patients with advanced human epidermal growth factor receptor 2-positive extramammary Paget's disease: an investigator-initiated, open-label, single-arm, multicentre, prospective, phase II clinical trial (TEMENOS-2).
Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with no established standard systemic therapy owing to limited clinical evidence. Approximately 40% of metastatic EMPD cases overexpress human epidermal growth factor receptor 2 (HER2), suggesting a potential therapeutic target. However, prospective evidence for HER2-directed antibody-drug conjugates (ADCs) in advanced EMPD is lacking. This study aimed to assess the efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced EMPD. This investigator-initiated, open-label, single-arm, multicentre, prospective phase II trial enrolled Japanese patients with HER2-positive metastatic EMPD who had not received prior HER2-targeted therapy. Patients received intravenous T-DM1 at 3.6 mg/kg every 3 weeks for up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Fourteen patients were enrolled and received study treatment between December 2021 and July 2024. The median age was 65 (range: 42-80) years. Thirteen patients had an Eastern Cooperative Oncology Group performance status of 0, and 12 had distant metastases at baseline. The ORR assessed by central review was 92.9% [95% confidence interval (CI) 66.1%-99.8%], with best responses of complete response (n = 2), partial response (n = 11), and progressive disease (n = 1). Median OS was not reached, whereas median PFS was 16.95 months (95% CI 5.75 months-not applicable). Grade 3 adverse events occurred in 6 (42.9%) patients. No grade ≥4 adverse events were observed, and one patient discontinued treatment due to grade 1 interstitial lung disease. This study provides the first prospective clinical evidence supporting the efficacy and safety of a HER2-directed ADC in HER2-positive advanced EMPD. T-DM1 demonstrated robust antitumour activity with a tolerable safety profile in this predominantly older adult population.
2026-09-16 | Trastuzumab deruxtecan treatment for HER2-low metastatic scrotal extramammary Paget's disease with bone marrow involvement: a case report.
Scrotal Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma commonly confined to the intraepidermal region, with potential for dermal invasion and metastasis. This report describes a rare case of metastatic scrotal EMPD with bone-marrow involvement. The patient presented with localized pruritic scrotal lesions accompanied by systemic symptoms resulting from distant metastases to the lymph nodes and multiple bones, as well as compromised hematopoiesis caused by tumor cell infiltration of bone marrow. The diagnosis was confirmed by histopathological examination of biopsy specimens from the scrotal lesion, local lymph nodes, and bone marrow. Immunohistochemistry (IHC) revealed HER2 status as 2+ with a negative fluorescence in situ hybridization result. Although the patient presented with a heavy tumor burden involving the bone marrow, he appeared to derive benefit from trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, and observed disease stability during the treatment period. This case suggests the potentially aggressive biological behavior of EMPD and demonstrates that targeted therapeutics, such as T-DXd, may achieve disease control in cases with low HER2 expression. These findings emphasize the need for further research to establish optimal treatment strategies for metastatic EMPD.
2026-08-11 | Treatment Strategies for Extramammary Paget Disease: A Narrative Review of Current Status and Future Directions
Background: Extramammary Paget disease (EMPD) is a rare epithelial malignancy that arises in the apocrine gland-bearing skin. Although localized intraepidermal EMPD generally follows an indolent clinical course, invasive EMPD is associated with lymph node metastasis, distant dissemination, and poor survival. Owing to its rarity, high-level evidence is limited and treatment strategies remain incompletely standardized, particularly for advanced disease. Recent advances in molecular profiling have revealed actionable therapeutic targets and created new opportunities for precision medicine. Methods: A narrative review was conducted using the PubMed database through May 2026. Relevant literature regarding the epidemiology, prognostic factors, surgical and non-surgical management, lymph node management, radiotherapy, systemic therapies, molecularly targeted therapies, and future therapeutic directions for EMPD is reviewed and summarized. Results: Surgical excision remains the standard treatment for resectable localized EMPD. Margin-controlled approaches, including Mohs micrographic surgery, complete circumferential peripheral and deep margin assessments, and mapping biopsy-guided excision, have contributed to improved local disease control. Radiotherapy, topical imiquimod, and photodynamic therapy provide alternative treatment options for patients who are unsuitable candidates for surgery; however, recurrence remains a major challenge. The management of regional lymph node metastases includes sentinel lymph node biopsy, lymph node dissection, and adjuvant radiotherapy in selected patients. For metastatic disease, conventional chemotherapy based on taxanes and fluoropyrimidine/platinum combinations has demonstrated moderate antitumor activity but limited durability. Molecular characterization of EMPD has identified several promising therapeutic targets. HER2 overexpression or amplification, observed in approximately 30–40% of cases, has emerged as the most clinically validated biomarker, with trastuzumab-based therapies demonstrating substantial efficacy. Immune checkpoint inhibitors have shown activity in selected patients, particularly those with a high tumor mutational burden, although predictive biomarkers remain inadequately defined. Additional emerging targets include androgen receptor signaling, TROP2, NECTIN4, FOXM1, and PIK3CA-associated pathways. Conclusions: In addition to conventional surgery- and chemotherapy-based approaches, biomarker-driven precision oncology is gaining attention as a treatment strategy for EMPD. HER2-targeted therapies, antibody–drug conjugates, and rationally selected immunotherapeutic strategies are expected to play increasingly important roles in the treatment of advanced disease. Continued translational research, international collaboration, and prospective clinical trials are essential to establish evidence-based treatment algorithms and improve outcomes in patients with this rare but potentially aggressive malignancy.
2026-07-21 | Overexpression of Brefeldin A-inhibited Guanine Nucleotide-exchange Protein 3 in Patients with Extramammary Paget's Disease.
Overexpression of brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been reported in estrogen receptor α-positive breast cancer (BC) tissues, with high BIG3 expression strongly associated with poor prognosis in patients with BC. This study investigated the expression pattern of BIG3 in patients with extramammary Paget's disease (EMPD) and evaluated its clinical significance. Sixty-one tissue and 30 serum samples were collected from patients with EMPD. Immunohistochemistry showed that most EMPD tissues were positive for BIG3 (57/61, 93.4%), and strong BIG3 intensity correlated with the degree of invasiveness, lymph node/distant metastasis, and overall survival. Serum BIG3 levels in EMPD patients with invasive lesions were significantly higher than those in patients with in situ lesions and correlated with the serum concentration of cytokeratin 19 fragment. Therefore, BIG3 expression may serve as a prognostic marker in patients with EMPD.
proteins
2026-04-28 | Pediatric-Adapted Low-Dose Immunotherapy for Rare Juvenile Cases
Extramammary Paget disease rarely occurs in pediatric populations, but when it does, standard adult treatments may be inappropriate due to toxicity concerns and long-term effects on development. Low-dose immunomodulatory therapy with agents like low-dose interferon or imiquimod could stimulate immune responses against abnormal cells while minimizing systemic toxicity in developing patients.
2008-09-01 | Mucin immunohistochemistry in the diagnosis and mapping of extramammary Paget's disease
Abstract Extramammary Paget's disease (EMPD) is a rare skin cancer of the genital region in which cancer cells with enlarged nuclei and pale cytoplasm are scattered singly in the affected epidermis. These cancer cells, called Paget cells, contain mucin, which is never found in normal epidermis. The oligosaccharide side chains of Paget cell mucin end with sialic acid. Sialic acid is easily detected by zirconyl haematoxylin or alcian blue. The other sugars in the oligosaccharide chains can be detected by the periodic acid‐Shiff reaction. Rarely, the diagnosis of EMPD is complicated by the absence of mucin from the Paget cells. We have examined such an atypical case. The oligosaccharide side chains, including the sialic acids, are absent. In both this case and a typical case, the Paget cells contain epithelial membrane antigen mucin (MUC1) core protein and usually contain gastric surface‐type mucin (MUC5AC) core protein, which can be stained by antibodies. Since neither core protein is found in normal epidermis, epithelial membrane antigen core protein may be the most reliable diagnostic marker for extramammary Paget's disease. In both the atypical case and the typical case of Paget's diseas, some cells that look like keratinocytes contain mucin core proteins. These may be incipient Paget cells. We suggest that using th epithelial membrane antigen core protein as a marker for the true extent of extramammary Paget's disease could facilitate complete excision and reduce the rate of recurrence.
small molecules
2026-08-24 | Concurrent chemoradiotherapy for metastatic vulvar extramammary Paget's disease involving supraclavicular nodes: a case report.
Extramammary Paget's disease (EMPD) is a rare adenocarcinoma with a poor prognosis when invasive. Here, we report an exceptionally rare case of invasive vulvar EMPD in a 70-year-old woman who presented with extensive lymphadenopathy involving the inguinal, pelvic, para-aortic, and left supraclavicular regions. Histopathology confirmed dermal and lymphovascular invasion. Given the systemic nodal spread, the patient underwent definitive concurrent chemoradiotherapy (CCRT) with weekly cisplatin. Radiotherapy was delivered to the inguinal-to-paraaortic nodes at 57.6 Gy in 32 fractions and to the supraclavicular nodes at 51.0 Gy in 17 fractions. Follow-up imaging 6 months after treatment demonstrated a complete response per Response Evaluation Criteria in Solid Tumor criteria. This case is notable because supraclavicular involvement in EMPD is extremely rare and usually reflects advanced systemic dissemination. Our findings suggest that intensive CCRT may achieve excellent locoregional and systemic disease control, supporting its potential role as an effective primary treatment option for patients with advanced metastatic EMPD.
2026-08-09 | Aminolevulinic acid photodynamic therapy for extensive genital extramammary Paget disease in older patients: A retrospective clinical case series.
Extramammary Paget disease (EMPD) involving the genital and anogenital region is difficult to manage when lesions are extensive, chronic, or located across functionally sensitive sites. In older patients with diabetes, cardiovascular disease, or advanced local involvement, wide excision may lead to considerable perioperative burden, delayed healing, and anatomical impairment. To describe the short-term clinical outcomes and symptom relief associated with aminolevulinic acid photodynamic therapy (ALA-PDT) in older patients with extensive EMPD who were unsuitable for disfiguring surgery or declined surgical treatment. We retrospectively reviewed three histologically confirmed EMPD cases affecting the mons pubis, penile root or foreskin, scrotum, inguinal region, and adjacent proximal thigh. All patients received lesion preparation by debridement followed by topical 10% ALA-PDT using a standardized illumination regimen. At the 3-month evaluation, erosive and exudative areas had re-epithelialized, and nodular lesions showed marked reduction or flattening. Pruritus and local pain improved rapidly and had resolved within 2 weeks after treatment initiation. Mild transient erythema was the only treatment-related reaction. No clinically apparent regrowth or progression was observed during the 12-month clinical and dermoscopic follow-up. In this small retrospective series, ALA-PDT was associated with short-term clinical control and palliative benefit in older patients with extensive genital EMPD, while preserving genital anatomy without creating large surgical defects. These preliminary findings support further evaluation of optimized PDT-based conservative strategies for difficult-to-treat EMPD.
2026-08-03 | Treatment outcomes and influencing factors of photodynamic therapy in extramammary Paget's disease: a retrospective analysis of 31 cases.
Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma for which surgical excision often causes functional/cosmetic impairment. Photodynamic therapy (PDT) offers a noninvasive alternative, but data on its efficacy and influencing factors remain limited. To evaluate efficacy of 5‑aminolevulinic acid (ALA)‑PDT monotherapy for localized EMPD over one year, and identify baseline predictors of response. This retrospective study included 31 patients with histologically confirmed localized EMPD treated with ALA‑PDT alone. Responses were assessed at 3, 6, and 12 months. Objective response rate (ORR), disease control rate (DCR), and associated response factors were analyzed by Fisher's exact test. At 3 months, ORR was 90.3% (28/31) and DCR 100% (31/31), with no complete responses (CR). At 6 months, CR was 19.4% (6/31), ORR 67.7% (21/31), DCR 83.9% (26/31). At 12 months (n = 30), CR remained 19.4% (6/30), ORR declined to 36.7% (11/30), and DCR to 56.7% (17/30). Lesion diameter ≤5 cm and absence of exudation predicted better 6‑month response (p = 0.020 and p = 0.006); diameter ≤5 cm remained significant at 12 months (p = 0.002). ALA-PDT monotherapy achieves high short‑term responses in localized EMPD, but efficacy declines substantially by 12 months. Lesion diameter ≤5 cm and non-exudative morphology predict better responses.
2026-08-01 | Proteomic and metabolomic profiling reveals dysregulation of immune states, mucin-type glycosylation and steroid metabolism in extramammary Paget's disease.
Extramammary Paget's disease is a rare cutaneous adenocarcinoma characterized by mucin-rich Paget cells and chronic inflammation, yet its molecular basis remains unclear. To systematically characterize the proteomic and metabolomic landscape of EMPD, uncover immune heterogeneity, and identify molecular pathways underlying tumor progression and microenvironment remodeling. We performed integrated proteomic and metabolomic analyses on 92 male tumor patients and 30 healthy controls, identifying 10,217 proteins and 1466 metabolites. Extramammary Paget's disease lesions exhibited broad activation of inflammatory pathways. Immune profiling further uncovered substantial inflammatory heterogeneity, delineating immune-cold and immune-hot subtypes, with the latter associated with stronger invasive potential. Aberrant mucin-type glycosylation was also prominent, featuring Tn-modified MUC1 and MUC5AC accompanied by elevated GALNT7, GALNT6, GALNT4, and ST6GAL1, which correlated with inflammatory intensity. Metabolomic data demonstrated elevated levels of testosterone, dehydroepiandrosterone, and related intermediates in tumor tissues, indicating an androgen-enriched metabolic profile in extramammary Paget's disease. These findings reveal immune, glycoproteomic, and metabolomic pathways in extramammary Paget's disease pathogenesis and provide novel insights for molecular classification and therapeutic targeting.
2026-07-15 | Intralesional ALA-PDT for residual extramammary Paget's disease: a case report.
Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy often associated with positive surgical margins and high local recurrence rates. While wide local excision remains the standard treatment, re-excision may be impractical in anatomically sensitive areas. Topical photodynamic therapy (PDT) is frequently used for superficial lesions but its efficacy is limited by poor photosensitizer penetration, particularly when tumor cells invade deep into the dermis or adnexal structures. An elderly male with scrotal EMPD underwent surgical excision, but postoperative pathology revealed positive margins with tumor infiltration into the subcutaneous fat. Further wide excision was deemed unfeasible due to functional and anatomical constraints. Pre-treatment high-frequency ultrasound demonstrated a lesion thickness of approximately 2.7 mm, exceeding the effective penetration depth of topical PDT. To overcome this barrier, intralesional 5-aminolevulinic acid photodynamic therapy (ALA-PDT) was administered monthly. A 10% ALA solution was injected directly into the residual plaque, followed by a 2-hour incubation and irradiation with 630 nm red light at a fluence of 120 J/cm2. After three sessions, the indurated erythematous plaque showed marked thinning and fading; complete clinical regression was achieved after six sessions. The treatment was well-tolerated, with only mild pain and transient erythema. No recurrence was observed during the 6-month follow-up period. Intralesional ALA-PDT is a highly effective, minimally invasive, and tissue-preserving treatment for residual EMPD with deep dermal invasion. By ensuring adequate photosensitizer delivery throughout the entire lesion, it overcomes the penetration limitations of topical PDT and represents a valuable option when surgery is not feasible.
cell therapies
2026-07-28 | Wide Excision and Flap Reconstruction in Perineal Extramammary Paget's Disease Patients.
Background and Objectives: Extramammary Paget's Disease (EMPD) of the perineal region is a rare intraepidermal adenocarcinoma requiring wide excision, resulting in extensive defects that are challenging to reconstruct while preserving contour and function. This descriptive case series evaluated a reconstructive selection strategy using pedicled superficial circumflex iliac artery perforator (SCIP) flaps and pedicled anterolateral thigh (ALT) flaps for perineal defects following wide excision of EMPD. Materials and Methods: This retrospective case series reviewed patients with perineal EMPD who underwent wide excision followed by reconstruction using pedicled SCIP flaps or pedicled ALT flaps. Patient demographic and lesion characteristics, operative and flap characteristics, post-reconstruction complications, oncologic outcomes, and satisfaction were analyzed. Results: 15 patients (mean age 63 years, SD 7.3) were included in this case series. Ten patients underwent reconstruction using pedicled SCIP flaps (mean 106 cm2, SD 23.3), and five patients with pedicled ALT flaps (mean 245.2 cm2, SD 41.2). All flaps survived, but one patient developed limited partial necrosis managed with secondary healing. During a mean follow-up of 17.7 months (SD 1.3), one patient (6.7%) developed recurrence and eventually distant metastasis resulting in death. Among the 14 surviving patients, 13 (92.9%) reported overall satisfaction with cosmetic and functional outcomes assessed using a non-validated ordinal scale. Conclusions: Pedicled SCIP and ALT flap reconstruction provides reliable, well-vascularized tissue coverage for perineal EMPD defects and achieves generally favorable short-term outcomes. The choice between flap types should be tailored to the defect size, location, and patient characteristics.
2025-11-01 | 679 Combined radiation and adoptive CTL therapy in advanced extramammary paget disease with pulmonary and nodal metastases: a case report and rationale for case series expansion
Background Extramammary Paget’s disease (EMPD) is a rare cutaneous adenocarcinoma, typically arising in apocrine gland-rich areas such as the vulva, perineum, and scrotum. The disease is usually confined to the epidermis but may become invasive and metastasize, with poor prognoses in advanced stages. While surgery remains the mainstay of treatment for localized disease, the management of metastatic EMPD lacks consensus. Immunotherapy and cellular therapies are emerging as promising modalities in solid tumors, yet limited data exist in the EMPD context. Adoptive CTL therapy, which involves the ex vivo expansion and activation of autologous T lymphocytes, has shown potential in melanoma, EBV-related cancers, and select solid tumors. 1 2 high-dose radiotherapy (HD-RT) with low-dose RT (LD-RT)safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.3 Here, we present a case demonstrating the successful application of combined HD-RT plus LD-RT radiotherapy and CTL therapy.Methods A 65-year-old male underwent VMAT-based radiotherapy to the cervical lesion (60 Gy in 8 fractions) and IMRT to the pulmonary and mediastinal sites (Left lung lesion: 50 Gy/5F, Mediastinal nodes (Station 5: 45 Gy/15F; Station 4L: 25 Gy/5F (HD-RT) + sequential boost 2 Gy/4 (LD-RT) respectively). Concurrently, PBMCs were isolated, activated using CD3/CD28/CD2 stimulants, expanded with IL-2 (1000 IU/mL), and re-infused following a 13-day GMP-compliant expansion protocol.CTLs were infused concurrently with the LD-RT phase duing lung and mediastinal radiation therapy.Results Follow-up PET/CT (3 days post-RT completion) showed: Left neck lesion decreased in size (from 5.2 to 4.0 cm) and SUVmax (16.6 → 13.6); Mediastinal lymph nodes reduced in size and activity (SUVmax 9.7 → 6.0); Left lung lesion decreased (SUVmax 12.1 → 7.3) Right lung nodule stable (SUVmax 2.4 unchanged) ( figure 1). Treatment resulted in partial metabolic response (PMR/PR). The patient experienced no major adverse effects and remained clinically stable.Conclusions This case highlights the potential benefit of combining radiotherapy with adoptive CTL therapy in metastatic EMPD. The rationale includes immune modulation by radiotherapy, enhancing T cell trafficking and tumor antigen release. While single-agent immune checkpoint inhibitors have demonstrated limited activity in EMPD, cell therapy may bypass tumor-induced immunosuppression. Further evaluation in a structured case series or early-phase clinical trial is justified.References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62-68.Chapuis AG, Ragnarsson GB, Nguyen HN, et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci USA. 2012;109(12):4592-4597.Patel RR, He K, Barsoumian HB, Chang JY, Tang C, Verma V, Comeaux N, Chun SG, Gandhi S, Truong MT, Erasmus JJ, Hong DS, Lee PP, Ning MS, Nguyen QN, Heymach JV, Altan M, Blumenschein G, Fossella FV, Sezen D, Chen D, Carter BW, Davies MA, Glitza IC, Diab A, Ferrarotto R, Cabanillas ME, Yuan Y, Shah SJ, Parra ER, Sun B, Cortez MA, Welsh JW. High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial. Radiother Oncol. 2021 Sep;162:60-67. doi: 10.1016/j.radonc.2021.06.037. Epub 2021 Jul 5.Abstract 679 Figure 1PET/CT pre treatment and 3 days post treatment
2025-08-11 | Surgical management of perianal Paget's disease - Case reports.
Perianal paget's disease is an uncommon malignant diagnosis for which surgical treatment is primarily opted for. This study presents two case reports of perianal paget's disease treated with surgery in a tertiary care oncologic center in India. Case 1: A 72 year old man presented with an itchy white patch in the perianal region, with a biopsy done in 2015 revealing extra-mammary paget's disease. The patient reported to us in November 2018, following which he was reevaluated and subsequently underwent wide local excision, diversion loop colostomy, and bilateral medial thigh perforator fasciocutaneous flaps reconstruction. Final histopathological examination confirmed diagnosis of Paget's disease. Case 2: A 69 year old man presented with recurrent perianal paget's disease after surgical excision and radiotherapy in 2016. The patient underwent wide local excision, diversion colostomy, bilateral sentinel lymph node biopsy, left ilioinguinal block dissection, and reconstruction with multiple medial thigh fasciocutaneous flaps in December 2019. Discussions: Perianal paget's disease is a rare cutaneous malignancy. Although studies regarding effective treatments are lacking, surgical excision is considered the best modality. Wide local excision with or without reconstruction remains the treatment proven to be successful, regardless of which long term follow up is crucial to identify recurrence. Larger case series are required to further comprehend the histopathology of the disease to prevent misdiagnoses and identify effective methods of treatment.
2019-01-25 | Accumulation of exhausted CD8+ T cells in extramammary Paget’s disease
Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03–24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.
2018-04-19 | 397 Contribution of the PD-1 and IDO pathway to T cell exhaustion in extramammary Paget disease
Cancer immunotherapy has highlighted the mechanism of tumor immune evasion in various cancer types. However, little is known about the role of the immune system against extramammary Paget disease (EMPD). We aimed to reveal the clinical relevance of tumor immunity of EMPD. We retrospectively analyzed 54 EMPD patients by immunohistochemistry (IHC) to examine immunological predictors of prognosis. We found that a high number of CD8+ cells and PD-1+ cells in the cancer stroma was associated with poor overall survival and poor disease-free survival in multivariable Cox-proportional hazard regression analysis, respectively. We also investigated tumor-derived immuno-modulating factors by IHC. EMPD tumor cells showed positive IHC staining for immunosuppressive factors, including indoleamine 2,3-dyoxygenae (IDO) and chemokines that attract CD8+ T cells, such as CXCL9, CXCL10, and CXCL11. In addition, the cytotoxicity and the effector functions of CD8+ T cells in paired samples of peripheral blood and tumors from additional 10 EMPD patients were prospectively investigated with flow cytometry. Flow cytometric analysis demonstrated that the expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in the CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in the CD8+ T cells of peripheral blood. Our findings suggest that CD8+ T cells attracted to the tumor sites by tumor-derived chemokines display an exhausted phenotype with PD-1 upregulation on CD8+ TILs and IDO expression on tumor cells. Taken together, we concluded the presence of a high number of CD8+ cells and PD-1+ cells in the cancer stroma was an indicator of poor prognosis. Restoring the effector functions of CD8+ TILs might be a new strategy of treatment for EMPD.
antibodies
2026-09-28 | Trophoblast glycoprotein is a novel therapeutic target for extramammary Paget disease
Abstract Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in the anogenital area of older people. It remains challenging to treat advanced EMPD due to the lack of effective treatments. The development of novel therapeutic approaches is thus strongly desired, but EMPD’s rarity and the lack of an appropriate in vitro model have impeded investigation of this disease. The aim of this work is to evaluate trophoblast glycoprotein (TPBG) as a promising therapeutic target for EMPD. To achieve this, TPBG expression was first analyzed in 124 (116 primary and 8 metastatic) samples from 116 EMPD patients. Using a recently established patient-derived EMPD cell line, KS-EMPD-1, the function of TPBG was assessed in vitro. TPBG was expressed in patients’ EMPD lesions with various staining intensities. It was also expressed in KS-EMPD-1 cells, while the inhibition of TPBG by siRNA in these cells significantly inhibited their proliferation accompanied by the decreased expression of cyclin D1. TPBG knockdown in KS-EMPD-1 cells also inhibited cell invasion. KS-EMPD-1 cells were also sensitive to cytotoxic agents commonly used as components of antibody-drug conjugate, a novel kind of targeted drug. These results suggest that TPBG will possibly serve as a therapeutic target for advanced EMPD.
2026-09-24 | Efficacy and safety of trastuzumab emtansine in patients with advanced human epidermal growth factor receptor 2-positive extramammary Paget's disease: an investigator-initiated, open-label, single-arm, multicentre, prospective, phase II clinical trial (TEMENOS-2).
Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with no established standard systemic therapy owing to limited clinical evidence. Approximately 40% of metastatic EMPD cases overexpress human epidermal growth factor receptor 2 (HER2), suggesting a potential therapeutic target. However, prospective evidence for HER2-directed antibody-drug conjugates (ADCs) in advanced EMPD is lacking. This study aimed to assess the efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced EMPD. This investigator-initiated, open-label, single-arm, multicentre, prospective phase II trial enrolled Japanese patients with HER2-positive metastatic EMPD who had not received prior HER2-targeted therapy. Patients received intravenous T-DM1 at 3.6 mg/kg every 3 weeks for up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Fourteen patients were enrolled and received study treatment between December 2021 and July 2024. The median age was 65 (range: 42-80) years. Thirteen patients had an Eastern Cooperative Oncology Group performance status of 0, and 12 had distant metastases at baseline. The ORR assessed by central review was 92.9% [95% confidence interval (CI) 66.1%-99.8%], with best responses of complete response (n = 2), partial response (n = 11), and progressive disease (n = 1). Median OS was not reached, whereas median PFS was 16.95 months (95% CI 5.75 months-not applicable). Grade 3 adverse events occurred in 6 (42.9%) patients. No grade ≥4 adverse events were observed, and one patient discontinued treatment due to grade 1 interstitial lung disease. This study provides the first prospective clinical evidence supporting the efficacy and safety of a HER2-directed ADC in HER2-positive advanced EMPD. T-DM1 demonstrated robust antitumour activity with a tolerable safety profile in this predominantly older adult population.
2026-09-16 | Trastuzumab deruxtecan treatment for HER2-low metastatic scrotal extramammary Paget's disease with bone marrow involvement: a case report.
Scrotal Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma commonly confined to the intraepidermal region, with potential for dermal invasion and metastasis. This report describes a rare case of metastatic scrotal EMPD with bone-marrow involvement. The patient presented with localized pruritic scrotal lesions accompanied by systemic symptoms resulting from distant metastases to the lymph nodes and multiple bones, as well as compromised hematopoiesis caused by tumor cell infiltration of bone marrow. The diagnosis was confirmed by histopathological examination of biopsy specimens from the scrotal lesion, local lymph nodes, and bone marrow. Immunohistochemistry (IHC) revealed HER2 status as 2+ with a negative fluorescence in situ hybridization result. Although the patient presented with a heavy tumor burden involving the bone marrow, he appeared to derive benefit from trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, and observed disease stability during the treatment period. This case suggests the potentially aggressive biological behavior of EMPD and demonstrates that targeted therapeutics, such as T-DXd, may achieve disease control in cases with low HER2 expression. These findings emphasize the need for further research to establish optimal treatment strategies for metastatic EMPD.
2026-08-11 | Treatment Strategies for Extramammary Paget Disease: A Narrative Review of Current Status and Future Directions
Background: Extramammary Paget disease (EMPD) is a rare epithelial malignancy that arises in the apocrine gland-bearing skin. Although localized intraepidermal EMPD generally follows an indolent clinical course, invasive EMPD is associated with lymph node metastasis, distant dissemination, and poor survival. Owing to its rarity, high-level evidence is limited and treatment strategies remain incompletely standardized, particularly for advanced disease. Recent advances in molecular profiling have revealed actionable therapeutic targets and created new opportunities for precision medicine. Methods: A narrative review was conducted using the PubMed database through May 2026. Relevant literature regarding the epidemiology, prognostic factors, surgical and non-surgical management, lymph node management, radiotherapy, systemic therapies, molecularly targeted therapies, and future therapeutic directions for EMPD is reviewed and summarized. Results: Surgical excision remains the standard treatment for resectable localized EMPD. Margin-controlled approaches, including Mohs micrographic surgery, complete circumferential peripheral and deep margin assessments, and mapping biopsy-guided excision, have contributed to improved local disease control. Radiotherapy, topical imiquimod, and photodynamic therapy provide alternative treatment options for patients who are unsuitable candidates for surgery; however, recurrence remains a major challenge. The management of regional lymph node metastases includes sentinel lymph node biopsy, lymph node dissection, and adjuvant radiotherapy in selected patients. For metastatic disease, conventional chemotherapy based on taxanes and fluoropyrimidine/platinum combinations has demonstrated moderate antitumor activity but limited durability. Molecular characterization of EMPD has identified several promising therapeutic targets. HER2 overexpression or amplification, observed in approximately 30–40% of cases, has emerged as the most clinically validated biomarker, with trastuzumab-based therapies demonstrating substantial efficacy. Immune checkpoint inhibitors have shown activity in selected patients, particularly those with a high tumor mutational burden, although predictive biomarkers remain inadequately defined. Additional emerging targets include androgen receptor signaling, TROP2, NECTIN4, FOXM1, and PIK3CA-associated pathways. Conclusions: In addition to conventional surgery- and chemotherapy-based approaches, biomarker-driven precision oncology is gaining attention as a treatment strategy for EMPD. HER2-targeted therapies, antibody–drug conjugates, and rationally selected immunotherapeutic strategies are expected to play increasingly important roles in the treatment of advanced disease. Continued translational research, international collaboration, and prospective clinical trials are essential to establish evidence-based treatment algorithms and improve outcomes in patients with this rare but potentially aggressive malignancy.
2026-07-21 | Overexpression of Brefeldin A-inhibited Guanine Nucleotide-exchange Protein 3 in Patients with Extramammary Paget's Disease.
Overexpression of brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been reported in estrogen receptor α-positive breast cancer (BC) tissues, with high BIG3 expression strongly associated with poor prognosis in patients with BC. This study investigated the expression pattern of BIG3 in patients with extramammary Paget's disease (EMPD) and evaluated its clinical significance. Sixty-one tissue and 30 serum samples were collected from patients with EMPD. Immunohistochemistry showed that most EMPD tissues were positive for BIG3 (57/61, 93.4%), and strong BIG3 intensity correlated with the degree of invasiveness, lymph node/distant metastasis, and overall survival. Serum BIG3 levels in EMPD patients with invasive lesions were significantly higher than those in patients with in situ lesions and correlated with the serum concentration of cytokeratin 19 fragment. Therefore, BIG3 expression may serve as a prognostic marker in patients with EMPD.
proteins
2026-04-28 | Pediatric-Adapted Low-Dose Immunotherapy for Rare Juvenile Cases
Extramammary Paget disease rarely occurs in pediatric populations, but when it does, standard adult treatments may be inappropriate due to toxicity concerns and long-term effects on development. Low-dose immunomodulatory therapy with agents like low-dose interferon or imiquimod could stimulate immune responses against abnormal cells while minimizing systemic toxicity in developing patients.
2008-09-01 | Mucin immunohistochemistry in the diagnosis and mapping of extramammary Paget's disease
Abstract Extramammary Paget's disease (EMPD) is a rare skin cancer of the genital region in which cancer cells with enlarged nuclei and pale cytoplasm are scattered singly in the affected epidermis. These cancer cells, called Paget cells, contain mucin, which is never found in normal epidermis. The oligosaccharide side chains of Paget cell mucin end with sialic acid. Sialic acid is easily detected by zirconyl haematoxylin or alcian blue. The other sugars in the oligosaccharide chains can be detected by the periodic acid‐Shiff reaction. Rarely, the diagnosis of EMPD is complicated by the absence of mucin from the Paget cells. We have examined such an atypical case. The oligosaccharide side chains, including the sialic acids, are absent. In both this case and a typical case, the Paget cells contain epithelial membrane antigen mucin (MUC1) core protein and usually contain gastric surface‐type mucin (MUC5AC) core protein, which can be stained by antibodies. Since neither core protein is found in normal epidermis, epithelial membrane antigen core protein may be the most reliable diagnostic marker for extramammary Paget's disease. In both the atypical case and the typical case of Paget's diseas, some cells that look like keratinocytes contain mucin core proteins. These may be incipient Paget cells. We suggest that using th epithelial membrane antigen core protein as a marker for the true extent of extramammary Paget's disease could facilitate complete excision and reduce the rate of recurrence.
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