EMPD Report

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Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

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Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

Primary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known.

Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers).

Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable.

Extramammary Paget’s disease: what do we know and how do we treat?

Extramammary Paget’s disease: what do we know and how do we treat?

The complexity of Extramammary Paget’s Disease (EMPD) has been apparent for decades with minimal improvements in diagnostic and therapeutic options. This rare carcinoma generally afflicts individuals greater than 60 years old and more often Caucasians than any other ethnicity.1 There are a multitude of case series, case reports, and retrospective studies, offering various treatment protocols; however, there is insufficient evidence for clear management guidelines. The heterogeneity of this disease in its presentation, location, depth of invasion and its typical multidisciplinary approach to management make it difficult to treat. The association with other malignancies is a well-described phenomenon and should inform treatment and long term management.2 Use of biomarkers shows promise in diagnosis and treatment monitoring. As immunotherapy (IO) is becoming a mainstay for many cancers, there is growing support for the use of these agents in advanced EMPD patients.

A Case of Chronic and Relapsing Paget Disease of the Vulva

A Case of Chronic and Relapsing Paget Disease of the Vulva

Extramammary Paget disease is a rare neoplastic condition that more commonly affects postmenopausal Caucasian women. Although the vulvar area is the most frequently affected location, it corresponds solely to 1 to 2% of all vulvar malignancies. A 72-year-old female patient was observed in our outpatient clinic with a 2-year history of an erythematous and pruritic plaque on the vulva. Histopathology and immunohistochemistry studies were compatible with extramammary Paget disease of the vulva. Associated neoplastic conditions were excluded. Due to multiple relapses, the patient was submitted to three surgical interventions, including a total vulvectomy, and to external radiotherapy. The present case illustrates the chronic and recurrent nature of extramammary Paget disease despite aggressive procedures as well as the challenge in obtaining tumor-free resection margins.

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Expression of PD-1 and PD-L1 in Extramammary Paget Disease: Implications for Immune-Targeted Therapy

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Expression of PD-1 and PD-L1 in Extramammary Paget Disease: Implications for Immune-Targeted Therapy

Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21; 14%) and the tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543–2115;) than in those who died (median, 611 cells/mm2; range, 481–908; p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

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Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

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Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

Extramammary Paget disease (EMPD), a rare intraepithelial adenocarcinoma, poses a therapeutic challenge with high postoperative recurrence rates and a limited number of effective local treatment options. This retrospective case series of 3 women with recurrent, refractory EMPD was conducted at Beth Israel Deaconess Medical Center, Boston, Massachusetts and Washington University School of Medicine, St Louis, Missouri. All patients were treated with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream or ointment.

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Extramammary Paget disease

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Extramammary Paget disease

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease. In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Although mammary and extramammary Paget disease are both characterized by epidermal Paget cells and share a similar clinical presentation, their uniqueness lies in anatomical location and histogenesis. EMPD presents as an erythematous plaque on apocrine gland bearing areas (i.e. vulva, perineum, perianal region, scrotum, and penis) in older men and women. It can be a focal, multifocal, or an ectopic process. Immunohistochemical staining allows for differentiation between primary and secondary EMPD in addition to the many other disease entities that clinically resemble this malignancy. When diagnosing a patient with EMPD, a full history and physical should be performed given the possibility of an underlying malignancy. Surgical excision currently is first line therapy and the prognosis is often favorable. Recent advances within the field have examined the expression of chemokine receptors within tumors, which may be applicable in determining prognosis. This review addresses the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis, diagnosis, management, and new observations with respect to extramammary Paget disease.

【少見癌症】Extramammary Paget's Disease（EMPD)

【少見癌症】Extramammary Paget's Disease（EMPD)

顧名思義，既然叫做「Extramammary」，表示這個診斷原本最常發生在乳房。乳腺是全身上下最大的 apocrine gland ，如果 Paget's disease 發生在乳房，通常在乳房內都能找到 infiltrating ductal carcinoma 或者 DCIS。

但是，發生 EMPD 時，並不一定能找到相對應的侵襲性癌症或原位癌。若 EMPD 位於生殖器官，能找到其他癌症的機率為 4-7%；若 EMPD 位於肛門周邊，能找到其他癌症的機率則是 25-35%。

EMPD 在組織學上的特徵就是 adenocarcinoma 的癌細胞（在此又特稱 Paget's Cell）侵犯到表皮（epidermis）。可以分為：

  • Primary EMPD ：沒有合併其他癌症存在，單獨出現。

  • Secondary EMPD ：合併有其他 adenocarinoma 存在。

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Accumulation of exhausted CD8+ T cells in extramammary Paget’s disease

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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 exam- ined 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 dis- ease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppres- sive 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.

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

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An advanced case of extramammary Paget disease: Safe and effective treatment in an inoperable elderly patient using extensive en face electron irradiation

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma characterized by epithelial infiltration of large atypical cells with prominent nuclei.1 The disease process is hypothesized to originate in the apocrine sweat glands in the anogenital region. It is often diagnosed in postmenopausal women and most commonly affects the vulva, perianal skin, and axilla but can sometimes be associated with invasive visceral or adnexal adenocarcinoma.2

Standard therapy for EMPD is wide local excision. However, many of the elderly patients affected by EMPD may be medically unfit for aggressive surgery. Radiotherapy is rarely used, and there is a paucity of reports detailing the efficacy of electron beam radiotherapy for exceptionally large EMPD lesions.

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Paget Disease, Extramammary

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Paget Disease, Extramammary

Introduction

Extramammary Paget disease (EMPD) is a rare dermatologic condition that frequently presents in areas where apocrine sweat glands are abundant, most commonly the vulva, although perineal, scrotal, perianal, and penile skin may also be affected. Lesions clinically present as erythematous, well-demarcated plaques that may become erosive, ulcerated, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life. Professionals disagree about many aspects of EMPD, for example, the prevalence of concurrent vulvar adenocarcinoma or invasive EMPD, association with regional and distant cancers, and recurrence rates following surgical excision. Early recognition is imperative because the diagnosis is frequently delayed and there is a high incidence of associated invasive disease.

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Rare perianal extramammary Paget disease successfully treated using topical Imiquimod therapy

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Rare perianal extramammary Paget disease successfully treated using topical Imiquimod therapy

Background: Perianal Paget’s disease (PPD) is a rare intraepithelial adenocarcinoma of the anal margin. Primary PPD likely represents intra-epithelial neoplasm from an apocrine source, whereas secondary disease may represent“pagetoid” spread from an anorectal malignancy.

Case presentation: Histologic CDX-2 and CK20 are hallmark markers for colorectal-derived Paget’s cells. Interestingly, our primary PPD patient presented both positive and no internal malignancy was identified. In addition, a negative CK7 marker was observed in our case in contrast with previously reported. Surgical excision is the standard treatment; however, previous studies have demonstrated good response with Imiquimod 5% cream in patients with vulval extramammary Paget disease (EMPD). The efficiency of Imiquimod treatment for PPD has not been well described. Our PPD patient was successfully treated using Imiquimod 5% cream.

Conclusions: This study describes a primary cutaneous PPD patient CDX-2+/CK20+/CK7- without invasion of the dermis and no associated colorectal carcinoma effectively treated using topical Imiquimod therapy, suggesting that Imiquimod might potentially be considered as a first-line treatment for PPD.

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Survival analysis of patients with invasive extramammary Paget disease -- Implications of anatomic sites

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Survival analysis of patients with invasive extramammary Paget disease -- Implications of anatomic sites

Extramammary Paget disease (EMPD) is a rare malignant dermatosis with poorly defined outcomes. We investigated clinical characteristics of invasive EMPD at different anatomic sites and by subject demographics to determine prognostic factors for overall survival (OS). All patient data were collected from the Surveillance, Epidemiology, and End Results (SEER) program, 1973–2013, of the U.S. National Cancer Institute. Patients with invasive EMPD of skin, vulva/labia, vagina, scrotum/penis, or other sites were included. After excluding patients with unknown radiation status, data of 2001 patients were analyzed. Primary endpoint was EMPD mortality by anatomic sites. Independent variables included patients’ demographic data, concurrent malignancy (ie, non-EMPD related cancers), tumor size, distant metastasis, and surgery and/or radiation or not. Multivariate regression analysis showed that mortality was significantly higher in patients with vaginal EMPD than in patients with vulvar/labial EMPD (adjusted hazard ratio [aHR] = 3.26, p < 0.001). Patients with distant metastasis had higher mortality than those without (aHR = 3.36, p < 0.001). Patients who received surgery had significantly lower mortality than those who did not receive surgery (aHR = 0.77, p = 0.030), and those treated with radiation had significantly higher mortality than those who did not receive radiation (aHR = 1.60, p = 0.002). Older age was associated with significantly increased mortality (aHR = 1.09, p < 0.001), and mortality was significantly higher in males than in females (aHR = 1.42, p = 0.008). In conclusion, among EMPD patients, mortality is higher in patients with vaginal EMPD than in those with vulvar/labial EMPD and higher in those who are older, those with concurrent malignancy or distant metastasis. Mortality is also higher in males than in females. Surgery is a protective factor and radiation is a risk factor for OS. Greater understanding of EMPD clinical characteristics, and considering EMPD in differential diagnosis of chronic genital and perianal dermatoses may provide support for early EMPD diagnosis and definitive surgical treatment.

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Extramammary Paget Disease

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Extramammary Paget Disease

Extramammary Paget disease (EMPD) is a rare dermatologic condition that frequently presents in areas where apocrine sweat glands are abundant, most commonly the vulva, although perineal, scrotal, perianal, and penile skin may also be affected. Lesions clinically present as erythematous, well-demarcated plaques that may become erosive, ulcerated, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life. Professionals disagree about many aspects of EMPD, for example, the prevalence of concurrent vulvar adenocarcinoma or invasive EMPD, association with regional and distant cancers, and recurrence rates following surgical excision. Early recognition is imperative because the diagnosis is frequently delayed and there is a high incidence of associated invasive disease.

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Successful treatment of metastatic extramammary Paget's disease with pemetrexed monotherapy systemically and 5-fluorouracil topically

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Successful treatment of metastatic extramammary Paget's disease with pemetrexed monotherapy systemically and 5-fluorouracil topically

Abstract 
Advanced extramammary Paget's disease does not have a standardized treatment guideline as its incidence is low and has been rarely reported in literature. Here we describe a case of metastatic extramammary Paget's disease successfully treated with topical 5-fluorouracil (5-FU) and systemic pemetrexed. The therapy was safe without any appreciable adverse effects like diarrhea, rash, neutropenia or fatigue; maintaining remission for more than 6 months. Thus, we propose 5-FU and pemetrexed as the first-line therapy for advanced extramammary Paget's disease, especially for aged patients with unresectable skin lesions.

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Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

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Evidence-Based Screening Recommendations for Occult Cancers in the Setting of Newly Diagnosed Extramammary Paget Disease

To identify the rates of associated and occult cancers in patients with extramammary Paget disease (EMPD) discovered using cancer screening methods at a tertiary medical center; to propose evidence-based cancer screening guidelines at the time of diagnosis of EMPD; and to clarify terminology associating EMPD with underlying malignancies.

All patients diagnosed with EMPD should undergo cancer screening. At minimum, evaluation should include age-appropriate screening and the addition of urine cytology, mammography, and prostate-specific antigen blood test—if not already performed—may be of particular use. An algorithm for evaluation of patients with newly diagnosed EMPD is proposed.

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Metastatic Extramammary Paget’s Disease: Pathogenesis and Novel Therapeutic Approach

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Metastatic Extramammary Paget’s Disease: Pathogenesis and Novel Therapeutic Approach

Metastatic EMPD is an aggressive skin adenocarcinoma with poor prognosis. Since current chemotherapeutic regimens are only moderately effective, improving clinical outcomes is imperative. The basic and translational research to date has provided an insight into the mechanisms promoting metastasis of EMPD that provide potential therapeutic targets for new drug development. Seemingly, Paget cells augment the ability of proliferation and survival by activating the RAS–RAF–MEK–ERK signaling, PI3K–AKT–mTOR signaling, or androgen–AR signaling. In addition, the interaction of Paget cells with other cells, such as LECs and CD163+Arg1+ macrophages in a tumor through the CXCR4–SDF-1 signaling and RANKL–RANK signaling, respectively, could establish a favorable tumor microenvironment to promote metastasis of Paget cells. Furthermore, recent genomic analysis of MMR has revealed that a decent percentage of EMPD comprises MMR-deficient EMPD cases that might achieve durable clinical response by an anti-PD-1 antibody. Hence, we are now beginning to understand multiple aspects involved in the pathogenesis of metastatic EMPD, and these findings will be sure to lead to better treatments for patients with metastatic EMPD in the future.

 

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Efficacy of low-dose 5-fluorouracil/cisplatin therapy for invasive extramammary Paget’s disease

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Efficacy of low-dose 5-fluorouracil/cisplatin therapy for invasive extramammary Paget’s disease

Extramammary Paget's disease (EMPD) is one of the cutaneous adenocarcinomas. The effective chemotherapy for advanced EMPD has not been established. This study was designed to evaluate the efficacy of combination 5‐fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week) for invasive EMPD. Seventeen EMPD patients with multiple metastases who visited our dermatology clinic between October 2004 and May 2016 (mean age, 76.9 years; 10 men, seven women) were retrospectively analyzed. Eight EMPD patients underwent low‐dose 5‐fluorouracil/cisplatin therapy and nine patients chose best supportive care. The average number of treatment cycles was 12.3. All patients had a confirmed response, four (50%) showed a partial response, two (25%) stable disease and two progressive disease. The median times to progression‐free and overall survival were 25.0 and 77.4 weeks, respectively. There was no severe (grade 3 and 4) adverse event. Although not significant, the survival of the patients treated with low‐dose 5‐fluorouracil/cisplatin therapy showed a trend toward improved survival as compared with best supportive care (P = 0.08, log–rank test). This regimen had low risk and relatively high disease control rate, suggesting that this regimen be recommended as one of the treatment options for advanced EMPD.

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Genito-Urinary Extramammary Pagets disease: Recognition and outcomes of distinct histological subtypes

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Genito-Urinary Extramammary Pagets disease: Recognition and outcomes of distinct histological subtypes

Introduction & Objectives: Genito-Urinary Extramammary Pagets Disease (EMPD) is a rare neoplasm that occurs in regions abundant in apocrine glands, or as a secondary intraepithelial spread of EMPD associated with another underlying carcinoma. The former occurs on peno-scrotal skin and can be in-situ or invasive. The latter occurs primarily on the inner precpuce or glans. Management and prognosis differ between these subtypes.

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Extramammary Paget Disease of the Vulva: A Case Series Examining Treatment, Recurrence, and Malignant Transformation.

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Extramammary Paget Disease of the Vulva: A Case Series Examining Treatment, Recurrence, and Malignant Transformation.

Patients with EMPD in this series have a high rate of recurrence. Many undergo multi-modal therapy often with multiple providers. However, patients experience relatively long disease-free intervals with a low rate of associated malignancy. We propose an algorithm for management that focuses on symptom control and minimizing morbidity of treatment intervention once invasive disease has been excluded.

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Chemokine Receptors CXCR4 and CXCR7 are Associated with Tumor Aggressiveness and Prognosis in Extramammary Paget Disease

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Chemokine Receptors CXCR4 and CXCR7 are Associated with Tumor Aggressiveness and Prognosis in Extramammary Paget Disease

Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer-specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD.

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