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 collected 151 patients with invasive extramammary Paget's disease. The rate of LN metastasis in patients without lymphadenopathy was 15%. On the other hand, patients with lymphadenopathy had LN metastasis in 80%. No difference in survival between patients with or without SLN metastasis. Patients with lymphadenopathy showed worse survival than those with positive SLN.
We report a 74‐year‐old Japanese man with triple extramammary Paget's disease; the genital and both of the axillar regions were simultaneously involved. Literature review revealed that 27 cases of triple extramammary Paget's disease have been reported in Japan, but there are no reports of triple extramammary Paget's disease from countries other than Japan, although 2 cases of double extramammary Paget's disease are reported. In all 28 cases, including our case, the genital lesion preceded the axillary lesions. All cases except one were male and only the exceptional female case was reported to have an the invasive tumor in the dermis. We speculate that extramammary Paget's disease may appear multi‐centrically.
We retrospectively analyzed the efficacy of combination chemotherapy consisting of infusions of 5-fluorouracil (5-FU, 600 mg/m2/body, 5 days/week) and cisplatin (5–10 mg/body, 5–7 days/week) administered intravenously for 8–24 h (low-dose FP). The overall survival ranges (medians) were 5–51 months (12) in all 22 patients, 6–51 months (13) in the 13 patients showing complete response or PR, and 5–12 months (11) in the 6 SD patients. The reported palliative effects of low-dose FP include control of pain and improvement of lymphedema.
Extramammary Paget’s disease (EMPD) is a rare cancer. Although EMPD is usually noninvasive and treated with local therapy, once metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD) cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40%) in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options.
Metastatic Extramammary Paget’s Disease (EMPD) is a rare cancer that currently has no validated treatment. Regimens including FECOM (5-FU, epirubicin, carboplatin, vincristine, and mitomycin C), trastuzumab in HER-2 expressing disease, 5-FU/cisplatin, or single agent docetaxel have been used in different case reports with varying levels of efficacy. A 58 year-old gentleman with EMPD diffusely metastatic to bone with bone marrow invasion presented with worsening shortness of breath and was found to have significant pancytopenia and disseminated intravascular coagulation (DIC). He was started on low-dose heparin for the DIC and weekly paclitaxel. Initially requiring daily transfusions of platelets and packed red blood cells, his shortness of breath improved after two doses of paclitaxel, and he became transfusion-independent after only three doses of paclitaxel. Carcinoembryonic Antigen (CEA) levels have been shown to correlate with tumor progression and parallel disease course. This patient’s pre-paclitaxel CEA of 62.1 ng/mL was also observed to decrease to 20.6 ng/mL after three doses. With no current validated chemotherapy regimen, this case can help guide consideration of paclitaxel in future treatment of metastatic EMPD.
Extramammary Paget's disease (EMPD) is an intraepithelial carcinoma usually occurring on the skin or mucosa of the perineum. Clinically, it resembles eczema or dermatitis, and misdiagnosis and treatment delays are common. The treatment of choice for EMPD is a wide excision with adequate margins. Wide excision with intraoperative frozen biopsy and Mohs micrographic surgery are common methods; however, these are associated with a high recurrence rate and long operation time, respectively.
Methods
Between January 2010 and June 2013, 21 patients diagnosed with EMPD underwent mapping biopsy. Biopsy specimens were collected from at least 10 areas, 2 cm from the tumor margin. When the specimens were positive for malignancy, additional mapping biopsy was performed around the biopsy site of the positive result, and continued until no cancer cells were found. Based on the results, excision margins and reconstruction plans were established preoperatively.
Results
The patients (18 male, 3 female) had a mean age of 66.5 years (range, 50-82 years). Almost all cases involved in the perineal area, except one case of axillary involvement. Permanent biopsy revealed one case (4.8%) of positive cancer cells on the resection margin, in which additional mapping biopsy and re-operation was performed. At the latest follow-up (mean, 27.4 months; range, 12-53 months), recurrence had not occurred.
Conclusions
Preoperative mapping biopsy enables accurate resection margins and a preoperative reconstructing plan. Additionally, it reduces the operation time and risk of recurrence. Accordingly, it represents an effective alternative to Mohs micrographic surgery and wide excision with intraoperative frozen biopsy.
Toker cells are epithelial clear cells found in the areolar and nipple areas of the breast, vulvar region, and other apocrine gland–bearing areas of the skin. Toker cells have been implicated in the pathogenesis of clear cell papulosis, cutaneous hamartoma with pagetoid cells, and rare cases of primary extramammary Paget disease (EMPD) but not in secondary EMPD with underlying adenocarcinoma. The pathogenesis of primary EMPD is not well defined. We report a case of multicentric primary EMPD with evidence of Toker cell proliferation and nonaggressive biologic behavior in a 63-year-old white man. A detailed description of the morphologic and biologic features of Toker cells and their possible carcinogenetic links also are discussed. Based on the observation and follow-up of our patient, we hypothesize that multicentric primary EMPD starts with Toker cell hyperplasia and can potentially evolve to carcinoma in the genital region.
Extramammary Paget disease (EMPD), which was first described by Crocker1 in a patient with erythematous patches on the penis and scrotum, is morphologically identical to mammary Paget disease (MPD) of the nipple. The principal difference between EMPD and MPD is anatomic location.
In our study, EMPD was more common in male than in female patients (ratio: 3.9:1), which contrasts with findings from studies performed in Western populations. As a result of this pattern of male predominance, the most common sites of disease were the scrotum, penile shaft, and pubic area. A total of 27 associated malignancies were identified in 26 (14.4%) of 181 patients, which included stomach cancer (n = 6), rectal cancer (n = 3), colon cancer (n = 3), anal cancer (n = 2), pancreatic can- cer (n = 2), liver cancer (n = 2), and other cancers (n = 9). Of the eight patients who tested positive for CK20, five (62.5%) had an accompanying internal malig- nancy. Of the 11 patients who tested negative for CK20, two (18.2%) had a true associated malignancy. Of the 193 patients diagnosed with EMPD, 58% underwent conventional wide excisions and 11.2% had MMS. Nine- teen (33.3%) of the 57 patients in the conventional exci- sion group showed recurrence, but only two (12.5%) of the 16 patients in the MMS group experienced recur- rence. Of the 181 patients for whom follow-up data were available, 88 (48.6%) belonged to the ANED group, 41 (22.6%) to the AWD group, nine (5.0%) to the DOD group, two (1.1%) to the DOAC group, 12 (6.6%) to the DOUD group, and 29 (16%) to the FUL group. These findings have important implications for the management and treatment of Korean EMPD patients.
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.
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