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Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget’s Disease of the Vulva

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Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget’s Disease of the Vulva

We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in . 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

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Efficacy of Abemaciclib in the Management of Refractory Metastatic Extramammary Paget’s Disease

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Efficacy of Abemaciclib in the Management of Refractory Metastatic Extramammary Paget’s Disease

Published systemic therapy options for metastatic extramammary Paget's disease have largely been anecdotal due to the rarity of this disease, which has precluded the ability to conduct clinical trials. We describe the favorable response of a 72-year-old man with extramammary Paget's disease, whose disease has been controlled with the CDK4/6 inhibitor, abemaciclib. The rationale behind the selection of this therapy is discussed.

Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget’s Disease of the Vulva

We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore.

Extramammary Paget Disease

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.

Extramammary Paget’s Disease and Melanoma: 2 Cases of Double Cancers

Extramammary Paget’s Disease and Melanoma: 2 Cases of Double Cancers

Extramammary Paget’s disease (EMPD) is a rare intraepidermal neoplastic disease. There is a well-known relationship between EMPD and underlying malignancy. However, only a few cases of EMPD and cutaneous melanoma have been reported previously. In this case report we present 2 cases of such double cancers: one as a collision tumor, the other at separate sites. We discuss the pathogenesis, treatment, and importance of a thorough clinical and radiological examination and review the literature.

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Co-occurrence of apocrine adenocarcinoma and invasive mammary-type ductal carcinoma in extramammary Paget disease of the axilla

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Co-occurrence of apocrine adenocarcinoma and invasive mammary-type ductal carcinoma in extramammary Paget disease of the axilla

Extramammary Paget disease (EMPD) is an uncommon malignancy that occurs in apocrine gland-rich areas of the body. EMPD of the axilla is rare, but a few cases have been reported. Some cases of EMPD have been reported with underlying apocrine adenocarcinoma; rarely, mammary-type ductal carcinoma can accompany EMPD. Here, we report a very rare case of EMPD with apocrine adenocarcinoma and invasive mammary-type ductal carcinoma.

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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.

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

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

Signi!cant developments in understanding the pathogenesis of EMPD have been made, especially of the genomic aberrations associated with EMPD. This has allowed for the development and use of therapeutic options which may improve outcomes for patients with EMPD.

Extramammary Paget disease shows differential expression of B7 family members B7-H3, B7-H4, PD-L1, PD-L2 and cancer/ testis antigens NY-ESO-1 and MAGE-A

Extramammary Paget disease shows differential expression of B7 family members B7-H3, B7-H4, PD-L1, PD-L2 and cancer/ testis antigens NY-ESO-1 and MAGE-A

Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma of the anogenital region most commonly treated with surgical excision. Surgical margin clearance is often problematic and recurrence rates remain high indicating the need for additional therapeutic options. Topical immunomodulators have been used with reported success suggesting EMPD may respond to other immunotherapies. This study investigates EMPD protein expression of targetable B7 family members and cancer/testis antigens (CTAs) B7-H3, B7-H4, PD-L1, PD-L2, MAGE-A, and NY-ESO-1 and components of antigen presenting machinery B2M and MHC-I.

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Paget disease of the vulva an analysis of 24 cases

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Paget disease of the vulva an analysis of 24 cases

Paget's disease can arise in the breast (mammary Paget disease) or in other locations (extramammary Paget disease) such as anogenital skin in both males and females (Paget disease of the vulva [PDV]). Underlying adenocarcinoma can be found in some cases. This study aims to report clinical aspects, surgical procedures, outcomes, and recurrences of patients with PDV.

A retrospective chart review was conducted on patients with pathologically confirmed diagnosis of PDV managed at the Department of Obstetrics and Gynecology, University of Bari, and the “Giovanni Paolo II” National Cancer Institute in Bari, between 1998 and 2018.

Records of 24 cases of PDV were examined. Median age of the patients at diagnosis was 69.3 (range 38–84), diagnosis of synchronous cancer was made in 2 cases and in 2 other cases of metachronous disease. Three patients had previously been diagnosed with other oncological diseases. All patients underwent surgery including wide local excision (6), simple vulvectomy (8), and extended vulvectomy (10). Lymphadenectomy was performed in 2 cases and reconstructions with advancement flaps in 7 cases. Four patients were found to have invasive disease and 1 had inguinal node involvement. Positive margins were found in 11 patients. Wound dehiscence and urethral stenosis were found in 4 and 1 case each. Eight recurrences (33.33%) were observed, regardless of positive surgical margins. PDV has a low rate of malignancy but a high rate of recurrence.

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.

A primer on extramammary Paget’s disease for the urologist

A primer on extramammary Paget’s disease for the urologist

Extramammary Paget’s disease (EMPD) is a rare and lethal intraepithelial malignancy that remains poorly understood. No standardized guidelines or consensus statements exist with regards to the diagnostic evaluation, therapeutic approaches and follow-up management. Complete surgical excision with negative margins has been accepted as the mainstay of treatment for EMPD to decrease the risk of local recurrence and to maximize durable cure. While the debate on the surgical approach between wide local excision (WLE) and Mohs micrographic surgery (MMS) continues, several studies have demonstrated the ability of WLE to be performed safely and effectively and to yield equally satisfactory outcomes with similar rates of recurrence to MMS. Patients undergoing surgical excision often require complex closures with skin grafting or local flaps to close genital defects.

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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.

Identification of genetic alterations in extramammary Paget disease using whole exome analysis

Identification of genetic alterations in extramammary Paget disease using whole exome analysis

Exome analysis revealed recurrent somatic mutations in several genes, including TP53, PIK3CA, and ERBB2. We identified additional candidate exons by searching the COSMIC database for exons that are frequently mutated in other adenocarcinomas. We obtained 19 exons in 12 genes as candidate exons, and performed target amplicon sequencing in samples obtained from EMPD patients. New somatic mutations in the TP53 gene were identified in six EMPD patients. Single nucleotide polymorphism analysis revealed multiple chromosomal alterations in three EMPD specimens, and two specimens exhibited amplification of chromosome 12p13 and losses of 3p21–24, 7q22 and 13q12–21.

【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。

Combination Cisplatin‐Epirubicin‐Paclitaxel Therapy for Metastatic Extramammary Paget's Disease

Combination Cisplatin‐Epirubicin‐Paclitaxel Therapy for Metastatic Extramammary Paget's Disease

xtramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.

In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane‐ and/or platinum‐based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.

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Serum cytokeratin 19 fragment 21‐1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget's disease

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Serum cytokeratin 19 fragment 21‐1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget's disease

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma affecting the genitals and axillary regions. As metastasis of these tumours is itself rare, solid disease management strategies have not been established. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) levels have been identified as candidate biomarkers for tumour progression in EMPD; however, neither the accuracy of, nor correlation between, these markers have been examined in EMPD patients.

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