Studies
Extramammary Paget’s disease (EMPD) is rare and as such medical studies and research on EMPD is often difficult to find. Due to limited participation, EMPD studies can differ in conclusions.
We found no reliable evidence to inform decisions about different interventions for women with Paget’s disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well-designed non-randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking.
Extramammary Paget’s disease (EMPD) is a rare neo-plastic pathology involving the vulva, scrotum, and peri-anal areas, and it is characterized by a slow and insidious course. EMPD may also be associated with internal malignancy, and its clinical presentation features long-standing pruritic lesions, eczema-like, refractory to any therapy. The therapeutic approach depends on the extent of involvement; wide surgical excision is the first choice among treatments, but other forms of therapy, alone or in combination, include imiquimod 5%, photodynamic therapy, Mohs surgery as well as external beam radiotherapy and Brachytherapy. In the present paper a new therapeutic alternative is proposed: Dermo-Beta-Brachytherapy (DBBT) with 188Re.
Skin cancer is the most common type of cancer worldwide. In the United States, the incidence is rising, with over two million people diagnosed each year [1]. More cases of skin cancer are diagnosed each year than breast, prostate, lung, and colon cancer combined. The lifetime risk of developing skin cancer is estimated to be 20%[2]. Although nonmelanoma skin cancer is rarely fatal and associated with a very low mortality rate, melanoma can be highly fatal. Approximately 76,000 individuals will be diagnosed with invasive melanoma in 2012 [3]. Skin cancer can be easily cured with early detection and excision. Early detection is essential, especially for melanoma, which has a grim prognosis once it has metastasized. Today, detection requires a biopsy to definitively determine if a lesion is malignant or benign.
Extramammary Paget’s Disease (EMPD) is a rare neoplastic lesion, which represents less than 1% of vulvar neoplasms. The lesion generally appears as eczema and the most frequently reported symptom is the itch. Also because of these poor clinical features, there is usually a delay in its diagnosis, based on the typical biopsy histological pattern. It has a good prognosis in absence of malignancy, but can result in a heavy quality of life impairment because of frequent recurrence with necessity of ablative therapies and anxiety for possible cancerization. Rarely EMPD can be invasive or associated to adenocarcinoma or other kinds of cancer. The first choice therapy is the surgical excision, with inguinal lymphadenectomy in case of infiltrative disease. However, many other conservative therapies, including the topical use of antiblastic, immuno-modulating, and hormone-modulating drugs, are used against EMPD even if still off label. After completion of this article, the reader should be able to recall the clinical manifestations of the EMPD, the histological pattern which allows its diagnosis, and to state the options for a treatment, which should be conservative and at the same time as radical as possible.
Invasive extramammary Paget’s disease (EMPD) is relatively rare and is reported to be highly metastatic to lymph nodes or even other organs, including bone. Histologically, EMPD shows significant numbers of lymphocytes around the tumor mass, suggesting the possible development of novel immunomodulatory therapy for EMPD by targeting these infiltrating lymphocytes. Previously, bisphosphonates (BPs) were administered for the treatment of malignancy, especially osteolytic bone disease. Recent reports also suggested that BPs might have a direct antitumor effect through several pathways beyond their beneficial effect on bone metastasis. Among them, the abrogation of immunosuppressive cells, myeloid derived suppressor cells (MDSC), by BPs might be one of the optimal methods to induce an antitumor immune response both locally and at sites remote from the tumor. In this study, we employed immunohistochemical staining for immunosuppressive macrophages and cytotoxic T cells in the lesional skin of patients with noninvasive EMPD and those with invasive EMPD.
Regulatory T cells (Tregs), identified by the expression of CD4, CD25 and Foxp3, together with immunosuppressive macrophages, such as CD163+ M2 macrophages, are involved in maintaining peripheral tolerance. The aim of this study was to elucidate the involvement of Tregs and CD163+ macrophages in invasive and non-invasive extramammary Paget's disease. The presence of CD4+CD25+Foxp3+ Tregs, CD163+ M2 macrophages and matrix metalloproteinase-9+ cells was examined immunohistologically in fixed sections of lesional skin from 10 patients with non-invasive extramammary Paget's disease and 7 patients with invasive extramammary Paget's disease. Fewer CD4+CD25+Foxp3+ Tregs were observed in non-invasive extramammary Paget's disease than in invasive extramammary Paget's disease. In contrast, higher numbers of CD163+ macrophages and metalloproteinase-9+ cells were detected only in invasive extramammary Paget's disease. These findings suggest that the induction of immunosuppressive cells in extramammary Paget's disease differs according to the tumour stage.
This report addresses the appropriate use of Mohs micrographic surgery (MMS) in the treatment of cutaneous neoplasms. In the United States in 2006, there were an estimated 3.5 million nonmelanoma skin cancers diagnosed, and it is projected that there will be nearly 4 million new cases of nonmelanoma skin cancer diagnosed in the United States each year.1 Similarly, the incidence of melanoma in situ continues to increase with an estimated 55,560 to be newly diagnosed in 2012,2 with many of these likely to be of the lentigo maligna (LM) subtype.3
Because of this epidemic of skin cancer and an increase in the number of dermatologists trained in MMS, the use of this treatment modality has expanded significantly in recent years. In fact, the use of MMS increased by 400% from 1995 to 2009, and currently 1 in 4 skin cancers is being treated with MMS.4 As the incidence of skin cancer continues to climb and the field of MMS continues to advance, dermatologists, primary care providers, Mohs surgeons, and the health care community in general will need to understand how to best use MMS in the treatment of skin cancer.
Extramammary Paget’s disease is a rare cutaneous malignant neoplasm. The genetic and epigenetic mechanisms underlying its pathology remain unknown. In this study, we investigated the expression levels, and mutation and methylation status of a common tumor suppressor gene, deleted in liver cancer 1 (DLC1), and an oncogene, PIK3CA, in tumor (n=132) and normal tissues (n=20) from unrelated patients. The presence of epigenetic and genetic lesions was then correlated to the patient pathology data to determine the potential role of these genes in extramammary Paget’s disease etiology and progression. The DLC1 gene was found to be downregulated in 43 (33%) tumors, as compared with immunohistochemistry results from normal tissues. Methylation-sensitive, high-resolution melting analysis indicated that the DLC1 promoter was hypermethylated in 51 (39%) extramammary Paget’s disease tumors. This hypermethylation was associated with significantly decreased DLC1 levels (P=0.011), and had a strong positive correlation with advanced age (P=0.002). PIK3CA mutations were detected by direct sequencing in 32 (24%) tumors, the majority of which were invasive. Furthermore, PIK3CAmutations significantly correlated with DLC1 hypermethylation. Thus, aberrant DLC1 methylation and PIK3CA mutations may have important roles in extramammary Paget’s disease pathogenesis, and may represent potential molecular targets for therapy
Apocrine carcinoma is a rare malignancy with invasive potential. It presents as painless, slow-growing, firm or cystic, red nodules with focal ulcerations. The tumor is capable of hematogenous dissemination to the liver, lungs, and bone as well as lymphatic spread. In addition, apocrine carcinomas cause intra-epidemial pagetoid spread. We report a case of an apocrine carcinoma related with extensive extramammary Paget's disease (EMPD). The relationship between apocrine carcinoma and EMPD remains to be understood. Co-existing cases with apocrine carcinoma and EMPD are discussed to better understand the relationship between these two malignant apocrine tumors.
RCM is emerging as a promising and versatile tool to assist dermatologic surgeons in the diagnosis and approach of cutaneous tumors. Compared with dermoscopy, it has demonstrated increased sensitivity and specificity in the clinical diagnosis of melanocytic lesions and doubtful dermoscopies, and many other applications are being studied. Nevertheless, it is important to note that traditional histopathology remains the gold standard for the definitive diagnosis of skin lesions.
RCM still has many limitations, which have been mitigated as more research is performed, and the device has been improved. In 2007, a consensus conference was organized to standardize concepts, and in 2009 an Internet-based study invol- ving six reference centers was conducted to evaluate the repro- ducibility of those concepts and the derived terminology. 53, 54
The examination of a single lesion takes 5-15 minutes. A clinical examination and dermoscopy are essential to determine what should be assessed by RCM, for lesions with fewer altera- tions in the initial tests are more likely to present fewer charac- teristic findings using RCM.40
Another important limitation to be overcome with techni- cal improvements in the near future is the visualization of the dermis, given that the reflection of the light only allows viewing to a depth of 350 m only (i.e., papillary or superficial reticular dermis).
However, while dermoscopy has probably already reached its full diagnostic accuracy potential, we expect great advances in RCM in the next few years.1 As was the case for dermoscopy, we expect RCM become part of the dermatologists’ daily practice as an auxiliary method in the diagnosis and treatment of skin cancer.
Of the 27 published cases that describe imiquimod treatment of EMPD, 6 report treatment failure (22%), but factors that may contribute to treatment failure are not well understood. In the present patient, treatment with imiquimod may have been complicated by variable lesion thickness, which inhibited uniform penetration of imiquimod, or the presence of invasive disease not detected on initial biopsy. The efficacy of imiquimod to treat extensive invasive EMPD has not been demonstrated, and surgical approaches remain the most appropriate treatment for invasive disease. Variable responses to topical imiquimod use among patients suggest that other factors may be important in determining response to therapy.
Surgical management of extramammary Paget disease (EMPD) remains a therapeutic mainstay, but alternative treatments for primary limited cutaneous EMPD in the anogenital area that avoid cosmetic and functional defects after extensive tissue removal are under investigation. Local recurrence of EMPD can be significant,1 highlighting the insidious nature of EMPD and the need to identify more effective treatments. The topical immunomodulator imiquimod, 5%, has been reported to induce clinical and histologic resolution of superficial EMPD,2-12 but several cases of imiquimod failure have also been described.13-17 Herein, we present a case of genital EMPD considered to be limited to in situ disease at the beginning of treatment with topical imiquimod that proved refractory, with demonstration of invasive disease during treatment. We also review the current literature (articles published in English and obtained through PubMed, Ovid, and GoogleScholar searches conducted between July 1, 2009, and August 31, 2010) regarding successes (n = 21) and failures (n = 6) of imiquimod therapy for EMPD and present characteristics that could portend treatment failure.
Extramammary Paget’s disease is an uncommon intra-epidermal carcinoma of apocrine gland-bearing skin. The most frequently involved anatomical sites include the scrotum, penis, vulva, and perineal and perianal region. Other rare sites of involvement, such as the eyelids [1], axilla, and external auditory canal [2], have been reported. There have been case reports describing ectopic EMPD occurring in areas devoid of apocrine gland, but they are exceedingly rare [3].
In the majority of the cases, the disease is limited to the epidermis. However, it is well known that EMPD has the potential of dermal invasion [4]. Moreover, its association with underlying internal malignancies remained one of the most interesting characteristics of the disease. Data in the literature come from small series and case reports only, especially on Chinese patients.
Extrammamary Paget disease (EMPD) is an uncommon neoplasm that often involves the skin of the genital or perianal regions. There are no clearly established guidelines for treatment, but surgical excision with wide margins (3-5 cm) or Mohs micrographic surgery (MMS) are the techniques of choice when there is no association with an underlying neoplasm. We present a case of EMPD in an unusual location (periumbilical skin). This was treated with fresh MMS, but reappeared, necessitating a second MMS (slow).
Extramammary Paget’s disease (EMPD) is a rare intraepithelial neoplasm occurring less frequently in men and even more rarely in the axilla. A 59-year-old man with severe Parkinson’s disease presented with axillary EMPD. The neurological comorbidity made treatment of the EMPD problematical and prompted us to propose locoregional intra-arterial chemotherapy in single short sessions. Two innovative chemotherapeutic macrocomplexes were used: doxorubicin incorporated in large liposomes and the taxane paclitaxel incorporated in albumin nanoparticles. A therapeutic response was seen right from the first treatment and was macroscopically close to complete after four cycles. Five months after the end of treatment the patient had minimal visible disease and had enjoyed a distinct improvement in quality of life, with no noteworthy complications related to the intra-arterial chemotherapy with percutaneous transfemoral catheterization.
Although rare, extramammary Paget’s disease (EMPD) is a serious condition because underlying internal malignancy may accompany super cial cutaneous lesions.Extramammary Paget disease is characterised by a chronic eczema-like rash of the skin around the anogenital regions of males and females. Under the microscope it looks very similar to the more common type of mammary Paget ́s disease that occurs on the breast. Extramammary Paget disease most commonly occurs in women aged between 50-60 years. Although surgical excision is the generally accepted standard of care for EMPD. The EMPD-V recurrence rates are high despite aggressive surgical intervention, treatment with topical imiquimod 5 percent cream has reportedly been ef cacious in clearing lesions. We report the case of a 72-year-old woman with biopsy-proven EMPD-V of the thigh treated successfully with imiquimod application thrice weekly for 6 weeks.
This cancer shares many histologic similarity with Paget's disease of the breast. Clinically, patients present with itchy pink to red scaly areas, resembling a chronic eczema. There may be scattered islands of white hyperkeratosis. These areas may be scattered and multicentric, involving the vulva and perineum. It is a slow growing and progressive cancer which requries a wide local excision. In addition, there are occasional cases which are really underlying invasive adenocarcinomas which have secondarily spread to the overlying skin in 10-20% of cases. Underlying adenocarcinoma in 10-20% of cases represent secondary metastasis to the skin, not true extramammary Paget's disease. In these cases, the pathologist must perform a diligent search to identify a primary adenocarcinoma.
Surgical resection is the first-choice therapy for extramammary Paget’s disease, but extensive resection is highly invasive and non-surgical treatments are sometimes preferred. Although photodynamic therapy (PDT) has been used for extramammary Paget’s disease for some time, recurrence and residual tumour cells are common. In the present study, five patients with extramammary Paget’s disease with a total of eight lesions first underwent carbon dioxide (CO2) laser abrasion, followed by 3 h of occlusive application of aminolaevulinic acid (ALA) and then 100 J/cm2 irradiation with a 630-nm excimer dye laser. This combination treatment regime was repeated every 2 weeks for a total of 3 times. Group 1 comprised two patients (five lesions) who received CO2 laser and ALA-PDT only. Group 2 comprised three patients (three lesions) who received CO2 laser and ALA-PDT for residual tumour cells following surgery. Follow-up examinations showed that seven lesions in five patients had not recurred after 12 months, suggesting the efficacy of the present method.
Background: The histogenesis of extramammary Paget's disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget's disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker's clear cell/CCP hypothesis.
Methods: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4 x 3 cm hypopigmented-depigmented patch on the root of the penis.
Results: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD.
Conclusions: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.
Although there is not extensive experience with the use of topical imiquimod 5 percent in the treatment of EMPD, the reported cases of successful use of this agent in limited extent EMPD are promising. Larger scope, randomized controlled trials are needed to determine the true safety and efficacy of imiquimod in comparison to the other therapy modalities currently used to manage EMPD. To the best of our knowledge, the treatment of EMPD of the thigh with imiquimod is not reported elsewhere in the literature, and we report our case as further evidence of the potential role imiquimod may play in this disorder.
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