GATA3 is a sensitive marker for primary genital extramammary paget disease: an immunohistochemical study of 72 cases with comparison to gross cystic disease fluid protein 15


GATA-binding protein 3 (GATA3) has been identified as a sensitive marker for breast carcinoma but its sensitivity in primary genital extramammary Paget diseases (EMPDs) has not been well studied.


Positive GATA3 staining was seen in all 71 (100%) intraepithelial diseases, 25/26 (96%; female 10/10, male 15/16) invasive adenocarcinomas and 14/15 (93%; female 3/3, male 11/12) metastatic adenocarcinomas, respectively. Positive GCDFP15 staining was seen in 46/71 (65%; female 28/34 or 82%, male 18/37 or 49%) intraepithelial diseases, 20/26 (77%; female 9/10, male 11/16) invasive adenocarcinomas, and 12/15 (80%; female 2/3, male 10/12) metastatic adenocarcinomas, respectively (GATA3 versus GCDFP15: p < 0.01 for both intraepithelial disease and invasive adenocarcinoma, p = 0.28 for metastatic adenocarcinoma). In positive-stained cases, GATA3 stained more tumor cells than GCDFP15 (79% versus 25% for intraepithelial disease, 71% vs 34% for invasive adenocarcinoma, 73% vs 50% for metastatic adenocarcinoma, p < 0.01 for all 3 components).


Our findings indicate that GATA3 is a very sensitive marker for primary genital EMPDs and is more sensitive than GCDFP15.

Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget’s Disease

Park et al. report their experience in the management of extramammary Paget’s Disease (EMPD) of the penoscrotal region and specifically compare outcomes among cohorts of men with the disease who either did or did not undergo mapping biopsies prior to their definitive surgical procedure. The rationale for the study and this comparison is that Paget’s disease initially spreads insidiously through the epidermis, sometimes in a single-cell fashion, and establishing the diagnosis can be very difficult subsequent to intraoperative frozen sections. Thus, several studies have described the use of outpatient mapping biopsies under more permanent section pathology techniques to facilitate the diagnosis and to ‘clear’ the surgical margins (references 19–21 in the article). This should theoretically lead to a lower incidence of positive frozen section margins intraoperatively, a lower incidence of positive permanent section margins, and lower recurrence rates for patients.

Reflectance confocal microscopy can spare biopsies in previously treated patients with extramammary Paget disease

Oriol Yélamos, MD 1, 2

1.     Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY

2.     Dermatology Department, Hospital Clínic, Universitat de Barcelona, Barcelona

Extramammary Paget disease or EMPD is a rare skin cancer that presents with a red patch in the vulva or anus in women, and in the scrotum, penis and anus in men. Diagnosing EMPD is challenging because the entire area affected by the disease is not visible with the naked eye, or can be misdiagnosed with other skin conditions such as infection or inflammation. This is particularly important when monitoring treatment response, as treatments can irritate the skin and look identical (red patch) to residual EMPD.

Reflectance confocal microscopy or RCM is an imaging system which uses a light source that does not damage the skin and that allows to see cells on the superficial layers on the skin. RCM has been used to diagnose EMPD as one can see the cancer cells in the skin in real time. However, RCM has not been evaluated to identify if EMPD remains active after therapy. Recently we have published in JAMA Dermatology the first study using RCM in patients with previously treated EMPD. We studied 5 patients with previously treated EMPD (4 men and 1 woman). We evaluated 22 sites in the skin suspicious for EMPD using RCM and later obtaining a skin biopsy of these sites. We have found that if we saw EMPD using RCM, in all the cases (9 out 9) the biopsy revealed active EMPD. On the other hand, in the cases where we did not see cancer using RCM, there was a small chance of missing active EMPD (3 out of 13 sites). We believe this may happen because EMPD cells may form small groups of cells that can be difficult to see with RCM, especially in cases which had received therapy, or may be located too deep to be seen with RCM.

Our study has shown that RCM can be very useful to identify EMPD after treatment, and eventually if one sees EMPD on RCM, biopsies may not be necessary and can be spared in such a sensitive location. However, because there is a small chance of missing disease recurrence if RCM does not see cancer, biopsies may be needed in this setting. To sum up, we believe that by assessing previously treated EMPD with RCM, our patients will need less biopsies to know if their disease is still active or not, and whether further treatment is required.


Yélamos O, Hibler BP, Cordova M, Hollmann TJ, Kose K, Marchetti MA, Myskowski PL, Pulitzer MP, Rajadhyaksha M, Rossi AM, Jain M. Handheld Reflectance Confocal Microscopy for the Detection of Recurrent Extramammary Paget Disease. JAMA Dermatol. 2017 May 10. doi: 10.1001/jamadermatol.2017.0619

Extramammary Paget`s Disease: A Real Challenge for Geriatricians

Extramammary Paget’s Disease (EMPD) is a rare intraepithelial adenocarcinoma. It mostly affects women in their seventies. EMPD develops principally in the apocrine genital, anal, and axillary zones [1]. We conducted a retrospective study at the University Hospital of Reims over a period of 20 years (1994- 2014). 9 patients were included of which 7 were female. The median age of onset was 78 years (60-91). The diagnosis time ranged from a few months to 5 years prior to diagnosis. Vulvar localization remains by far the most common localization. 6 patients, all females, had pruritus (vulvar); 2 (22%) felt pain from the lesions.

Topical Imiquimod in Treating Patients With Recurrent Paget's Disease of the Vulva

RATIONALE: Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing. Applying topical imiquimod to the vulva may be an effective treatment for recurrent Paget's disease.

PURPOSE: This clinical trial is studying how well topical imiquimod works in treating patients with recurrent Paget's disease of the vulva.

OBJECTIVES: To assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease.

Podoplanin expression in peritumoral keratinocytes predicts aggressive behavior in extramammary Paget's disease.

BACKGROUND: Recent studies have demonstrated podoplanin expression in several tumors, which has been associated with lymph node metastasis and poor prognosis. Podoplanin expression in peritumoral cells such as cancer-associated fibroblasts also correlates with tumor progression in several cancers. However, podoplanin expression and its association with extramammary Paget's disease (EMPD) remain unclear.

OBJECTIVE:  In this study, we examined whether the presence of podoplanin expression in tumor cells or peritumoral basal keratinocytes correlated with aggressive behavior in patients with EMPD and investigated the mechanisms of podoplanin-mediated tumor invasion in this disorder.

Tumor Wide Horizontal Invasion Predicts Local Recurrence for Scrotal Extramammary Paget’s Disease

Extramammary Paget’s disease (EMPD) is a rare malignancy, and little was known about its prognostic factors and optimal treatment. In the current study, we aimed to discuss clinical and pathological features of scrotal EMPD and determine the prognostic factors for cancer-specific survival and local recurrence. A total of 206 patients with scrotal EMPD lesions surgically treated at our institute were studied. All clinical and pathological data were reviewed. Immunohistochemical staining of TP53 and Ki67 was examined as well. At the last follow-up, 175 patients (84.95%) were alive. Twelve patients (5.83%) had died of the disease due to distant metastases. Fifteen patients (7.28%) developed local recurrences of scrotal EMPD. Ki67 expression was significantly elevated in patients with wide horizontal invasion (P = 0.003). In univariate analysis, high invasion level, presence of nodule, presence of lymphovascular invasion, adnexa invasion, lymph node metastasis and high p53 expression were significant factors for poor cancer-specific survival. In multivariate analysis, high p53 expression was significantly correlated with poor cancer-specific survival. Wide horizontal invasion was independently correlated with local recurrence-free survival of scrotal EMPD. In conclusion, wide horizontal invasion is an independent risk factor for local recurrence-free survival in the patients with scrotal EMPD.

Mechanisms of immune evasion in extramammary Paget disease

mmune evasion by cancer is a well-recognized mechanism that promotes tumour growth and metastases which in recent years has been shown to be amenable to therapeutic exploitation. Extramammary Paget disease (EMPD) is a rare form of skin cancer affecting apocrine glands in anogenital regions. The prognosis of the disease is good if treated early by surgical removal of the tissue, with a 5-year survival rate close to 95%.[1] The prognosis is worse for invasive disease, partly due to the lack of definitive treatment options in this setting.[2] Understanding the mechanisms of EMPD evolution has the potential to identify new treatment targets for this entity. In this edition of the BJD, Fujimura et al.[3] have looked into a suspected link between Langerhans cells (LCs) and regulatory T-cell (Treg) activity in EMPD that could contribute to the immunosuppressive environment that supports tumour growth and invasion by immune evasion.

Serum cytokeratin 19 fragment 21-1 is a useful tumor marker for the assessment of extramammary Paget's disease.

Cytokeratin 19 fragment 21-1 (CYFRA 21-1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21-1 could be a useful marker for extramammary Paget's disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21-1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21-1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21-1. Furthermore, CYFRA 21-1 was reduced in association with post-treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow-up period. CYFRA 21-1 was re-elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21-1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.

Mayo Clinic Cancer Center Experience of Metastatic Extramammary Paget Disease 1998-2012

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy. The most common presentation of EMPD is the vulva followed by perianal involvement. Most cases are localized to the dermis with treatment focused on surgery, topical treatment or radiotherapy. Recurrence is frequent despite therapies utilized. Metastatic extramammary Paget disease is uncommon and, as such, standard treatment guidelines do not exist. This study sought to evaluate the treatment regimens and outcomes of patients treated at a Mayo Clinic Center from 1998-2012. Cancer registry inquiry revealed 261 patients with report advanced Paget disease during these years. Ten cases of metastatic EPMD were identified with sufficient documentation for review. This review reveals support for utilizing localized radiation therapy for bulky disease sequentially with systemic chemotherapy consisting of carboplatin and paclitaxel or irinotecan. Further studies are necessary to define the optimal treatment regimen.

A matter of margins: Surgical and pathologic risk factors for recurrence in extramammary Paget's disease

Medical records of patients seeking care for EMPD from 1/1992–9/2015 were reviewed. Follow-up was restricted to 5 years following primary surgery. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method. Risk factors were evaluated for an association with recurrence and positive margins, respectively, using Cox proportional hazards regression and logistic regression.

Inclusion of males allowed us to examine the influence of a different surgical approach (MMS) on margin status and recurrence rates in EMPD. In contrast to prior studies including solely vulvar EMPD, we observed strong association between margin status and recurrence risk. Risk of positive margins was significantly higher after WLE compared to MMS. MMS should be explored to improve outcomes in gynecologic patients with EMPD.

Primary invasive triple extramammary Paget's disease with regional lymph node metastasis

Extramammary Paget's disease (EMPD) is a rare intraepidermal carcinoma and predominantly involves apocrine gland-bearing areas, such as anogenital regions and axillae. EMPD usually involves a solitary area and, less often, two areas in the same patient (double EMPD). The simultaneous involvement of bilateral axillae and anogenital region, called triple extramammary Paget's disease (TEPD), is an extremely rare subgroup of diseases that has been reported mostly from studies conducted in Japan. Because of its rarity, the clinical course, pathology/immunohistochemical staining features, and prognosis of TEPD are still unclear. Herein, to our knowledge, we present the first case of primary invasive TEPD with regional lymph node metastasis in Taiwan, and review the literature.

Mohs with CK-7 staining: 98% 5-year cure rate for extramammary Paget disease

Mohs surgery with cytokeratin-7 immunohistochemistry staining effected complete removal of extramammary Paget disease and resulted in a 5-year, 95% recurrence-free cure rate.

The results are significantly better than the often-cited 77% cure rate seen with Mohs surgery alone, Dr. Ali Alexander Damavandy said at the annual meeting of the American College of Mohs Surgery.

“These are statistically significant and clinically substantial results,” said Dr. Damavandy, a procedural dermatology fellow at the University of Pennsylvania, Philadelphia. “With this method you can tell a patient that in 5 years, he has a 95% chance of still not having the tumor. The high recurrence-free rate we have seen supports the view that Mohs surgery with cytokeratin-7 [CK-7] immunohistochemistry should be considered the curative treatment of choice for both primary and recurrent extramammary Paget disease of the skin.”

Primary extramammary invasive Paget’s vulvar disease: what is the standard, what are the challenges and what is the future for radiotherapy?


Primary invasive Extramammary Paget’s vulvar disease is a rare tumor that is challenging to control. Wide surgical excision represents the standard treatment approach for Primary invasive Extramammary Paget’s vulvar disease. The goal of the current study was to analyze the appropriate indications of radiotherapy in Primary invasive Extramammary Paget's vulvar disease because they are still controversial.


We searched the Cochrane Gynecological Cancer Group Trials Register, Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE database up to September 2015. Radiotherapy was delivered as a treatment in various settings: i) Radical in 28 cases (range: 60–63 Gy), ii) Adjuvant in 25 cases (range: 39–60 Gy), iii) Salvage in recurrence of 3 patients (63 Gy) and iv) Neoadjuvant in one patient (43.3 Gy). A radiotherapy field that covered the gross tumor site with a 2–5 cm margin for the microscopic disease has been used. Radiotherapy of the inguinal, pelvic or para-aortic lymph node should be considered only for the cases with lymph node metastases within these areas.


Radiotherapy alone is an alternative therapeutic approach for patients with extensive inoperable disease or medical contraindications. Definitive radiotherapy can be used in elderly patients and/or with medical contraindications. Adjuvant radiotherapy may be considered in presence of risk factors associated with local recurrence as dermal invasion, lymph node metastasis, close or positive surgical margins, perineal, large tumor diameter, multifocal lesions, extensive disease, coexisting histology of adenocarcinoma or vulvar carcinoma, high Ki-67 expression, adnexal involvement and probably in overexpression of HER-2/neu. Salvage radiotherapy can be given in inoperable loco-regional recurrence and to those who refused additional surgery. 

A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget's disease


Eight patients from two institutions were enrolled. Complete clinical and histologic response was achieved in 6 (75%) patients by the 12-week follow-up appointment. Of the two remaining patients, one had a complete clinical response but no significant histologic response; the other patient was removed from the study protocol secondary to intolerable local irritation. Two patients continue to have no evidence of disease after a median follow-up of 35 months. Five are alive with disease. No patients progressed to invasive cancer while receiving therapy.

Paget disease of the vulva

In this review, we provide an overview of the clinical aspects, histopathology, molecular genetics, and treatment options for Vulvar Paget’s Disease (VPD), a rare skin disease, most commonly found in postmenopausal Caucasian women. The underlying cause of VPD remains not well understood. VPD is rarely associated with an underlying urogenital, gastrointestinal or vulvar carcinoma. In approximately 25% of the cases, VPD is invasive; in these cases, the prognosis is worse than in non-invasive cases. Recurrence rates in invasive VPD are high: 33% in cases with clear margins, and even higher when surgical margins are not clear, regardless of invasion. Historically, surgical excision has been the treatment of choice. Recent studies show that imiquimod cream may be an effective and safe alternative.

Clinical and pathological characteristics of extramammary Paget’s disease: report of 246 Chinese male patients

Extramammary Paget’s disease (EMPD) is a rare cutaneous neoplasm. The aim of this study was to elaborate the clinical and pathological features of Chinese EMPD male patients. The study comprised 246 patients with EMPD at our institute from January 1993 to December 2012. Scrotum was the most common initial site. The average age of onset was 63.9 years but the mean delay in diagnosis was 3.6 years. EPMD spread exclusively to the inguinal lymph nodes and the right inguinal lymph nodes are more likely to suffered Paget cells infiltration. Accompanying malignancies were found in 20 patients. Pathological examination revealed 63 patients defined as invasive EMPD. Immunohistochemical detection showed various expression levels of EMA, CEA, CK7, HER2/neu, Ki67, P53, CK20 and S100 in tumor tissues, but negative expression of VIM, LCA and HMB45. HER2/neu protein exhibited a significant association with invasive EMPD. A novel histological type of EMPD with CK7-/S100+ was identified. Elevated serum PSA level was observed in only 16% patients. Invasive EMPD often had advanced age of onset. Metastatic EMPD showed significantly shorter in the delay in diagnosis and the greater length of skin lesion in contrast to others. This study demonstrates the clinical and pathological features of Chinese male EMPD patients, and may provide implications for the management of Chinese EMPD patients.

Extramammary Paget's disease in two brothers

Extramammary Paget's disease (EMPD), which is considered to be an adenocarcinoma of the apocrine glands, is a rare, slow-growing neoplasm. The standard treatment for local EMPD is surgical resection, however, so far, no effective treatment is found for advanced EMPD. Trastuzumab, which is a recombinant monoclonal antibody against the human epidermal growth factor receptor 2 HER2 has been proved to be effective in the treatment of advanced EMPD in some cases where HER2 protein is overexpressed. Herein, we report two cases of EMPD in two brothers. The younger brother who presented as local EMPD on the scrotum received surgical resection and had no recurrence in 15 months following. The older brother suffered from invasive EMPD also on the scrotum with inguinal region multiple metastatic lymph nodes and was treated with combination chemotherapy and Trastuzumab to target HER2 consecutively after a wide surgical excision.

Psoriasis with extramammary paget disease in a male: a case report

Psoriasis is a chronic inflammatory skin disease that is characterized by erythematous, sharply demarcated papules and plaques covered by scales [1]. Extramammary Paget disease (EMPD) is a rare neoplastic condition of the skin or its underlying appendages commonly found in the vulva, perianal region, scrotum, penis, and axilla [2]. Clinically the condition presents as a well-demarcated, thickened, pruritic, erythematous, or white scaly plaque with irregular borders [3,4]. Microscopically EMPD involves large cells with vacuolated cytoplasm and centrally located nuclei characterized as Paget cells [5]. The disease is categorized into primary or secondary EMPD with primary EMPD originating from intraepidermal cells and secondary EMPD coming from an underlying neoplasm [2,5]. However, there is no report suggesting the association of psoriasis with EMPD, or psoriasis admixed with EMPD. In this paper, we present a case of extensive psoriasis in a male combined with penoscrotal EMPD.