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.

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; = 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 (= 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

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)

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

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.

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.

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

Question  Can a combination of fluorouracil and calcipotriene creams be used safely and effectively as a treatment for refractory extramammary Paget disease (EMPD)?

Findings  In this case series, we report 3 cases of refractory EMPD treated with a topical combination of fluorouracil and calcipotriene. The treatment was well tolerated and was followed by clinical improvement in all cases with demonstrated histopathological response in 2 of the cases.

Meaning  Topical combination of fluorouracil and calcipotriene may be a viable palliative treatment option for patients with refractory EMPD.

Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

Background

Extramammary Paget's disease (EMPD) is a rare skin cancer with relative high frequencies of germline and somatic mismatch repair (MMR) genes mutations. However, the methylation and expression of these genes have not been validated in EMPD.

Objective

This study aims to confirm the methylation and expression of MMR genes in EMPD.

Serum cell‐free DNA levels are useful marker for extramammary Paget's disease

Although carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are useful marker for extramammary Paget's disease (EMPD), the serum CEA and CYFRA levels are not elevated in most EMPD patients without metastasis. Therefore, further useful biomarkers are needed for the detection of EMPD including early lesions. Cell‐free DNA (cfDNA) has attracted attention as an indicator of clinical conditions in several cancers, and we studied the clinical implications of cfDNA for EMPD. The serum cfDNA levels were significantly elevated in EMPD patients with or without metastasis compared to those in healthy controls. And serum cfDNA was a better diagnostic marker for the presence of EMPD compared to serum CYFRA. Moreover, the post‐operative serum cfDNA levels were significantly lower than those from the pre‐operative samples, and the change in serum cfDNA levels reflected the clinical courses of EMPD patients treated with chemotherapy. Taken together, serum cfDNA levels may be useful marker for the diagnosis and disease progression in EMPD.

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.

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.

Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report

Background

Anal canal cancer occasionally accompanies extramammary Paget disease. Although most of them are squamous cell carcinoma, anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease has never been reported.

Conclusions

This is a clinically significant case, as it reveals novel pathological features about anal canal cancer with secondary Paget disease and successfully treated with modified FOLFOX6. Careful pathological investigation and appropriate treatment choice are needed for this rare cancer.

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.

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.

Prognostic Factors of Extramammary Paget’s Disease

Most patients with extramammary Paget’s disease (EMPD) show a good prognosis; however, some patients develop fatal metastases. Early detection is important for improving prognosis, due to the difficulties associated with the treatment of distant EMPD metastases. Several studies have emphasized the importance of the invasion level of the primary lesion for predicting the presence of metastasis, and deeper invasion or increased thickness is correlated with poorer prognosis. Vascular tumor invasion of the primary lesion can also predict the risk of metastasis. Lymph node metastasis is a strong indicator for poor prognosis, and the number of lymph node metastases affects patient outcome, in that there is a significant difference in survival between patients with zero or one lymph node metastasis and those with more than two lymph node metastases. Serum markers may be able to predict the presence of systemic metastases, and carcinoembryonic antigen and cytokeratin 19 fragment 21-1 reflect disease progression and may be clinically valuable. Although several genetic alterations have been determined for EMPD, factors determining prognosis should be further explored.

Mayo Clinic: Prospective Registry of Gynecologic Patients With Extramammary Paget's Disease Study

The Mayo Clinic (Rochester, MN, USA) is currently recruiting women with vulvar Extramammary Paget's Disease for an EMPD study. This includes EMPD of the vulva, vagina or perianal EMPD. The 25-year study will allow physicians to better understand EMPD. The researchers also want to learn more about the microorganisms (microbiome) that live on or near the areas of skin affected by EMPD, in order to better understand this condition. Tumor tissues will be obtained in order to perform tumor molecular profiling to identify targetable somatic mutations in EMPD. This EMPD study is for women only. More information on the Prospective Registry of Gynecologic Patients With Extramammary Paget's Disease study can be found here

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.

A total of 161 patients met the inclusion criteria. Most (59.6%) were female patients, and the mean age at the time of EMPD diagnosis was 70.8±10.1 years. Most (82%) of the 161 patients had at least 1 cancer screening test performed, though screening practices varied widely. Of those screened for an underlying malignancy, 17 distant, noncontiguous malignancies were identified in 15 patients (11.4%), with prostate (n=5), urinary tract (n=5), and breast (n=2) malignancies found most frequently. Most malignancies were identified by urine cytology, mammography, and prostate-specific antigen blood test. Of all patients, 37 (23.0%) had an underlying contiguous malignancy identified by pathology.

131 Mutational landscape of extramammary Paget disease

Extramammary Paget disease (EMPD) is a rare malignancy of the skin. Because of the scarcity of the cases, genomic alterations in EMPD are poorly characterized. To address this issue, we have interrogated 39 EMPD samples and patients blood with exome sequencing. The mutational load of EMPD was moderately high; the median prevalence of somatic mutations was above 3 mutations per megabase, a number comparable to the one of kidney renal cell carcinoma. Our study identified several putative driver events. ERBB2 mutation, as well as amplification, is frequent in our samples and likely the key driver of EMPD. The mutations are enriched in the tyrosine kinase domain of ERBB2, and are likely to cause functional alteration of the gene product. This observation is in line with previous papers reporting the efficacy of trastuzumab for EMPD. Other cancer genes including ERBB3KMT2CMLL4, and COL1A1 are also frequently mutated in EMPD. Driver mutation analysis by OncodriveFM identified potential novel cancer genes that are previously unreported in other cancer types. Copy number analysis identified recurrent somatic copy number aberrations. Frequent deletion peaks included CDKN2A and TSC2, both of which were important tumor suppressor genes. Mutational signature analysis showed that APOBEC3B activation, coupled with aging, was driving the somatic mutations in EMPD. We also identified evidence of APOBEC3B activation including kataegis and strand bias in the EMPD genome. In conclusion, our study provides the comprehensive landscape of somatic mutations in EMPD as well as insights into the mechanisms behind the carcinogenesis of EMPD. We have identified putative driver mutations including ERBB2 and ERBB3, which are readily targeted. We also suggest that EMPD may be treated with cancer immunotherapy, for the moderately high mutational load observed in EMPD is associated with the response to cancer immunotherapy in other cancer types. These insights provide rationale for use of systemic treatments in patients with EMPD.

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.

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.