Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

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

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Apocrine Carcinoma of the Groin Possibly Associated with Extramammary Paget's Disease

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Apocrine Carcinoma of the Groin Possibly Associated with Extramammary Paget's Disease

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.

In vivo confocal microscopy in the daily practice of the dermatologic surgeon

In vivo confocal microscopy in the daily practice of the dermatologic surgeon

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.

Failure of Extensive Extramammary Paget Disease of the Inguinal Area to Clear With Imiquimod Cream, 5%

Failure of Extensive Extramammary Paget Disease of the Inguinal Area to Clear With Imiquimod Cream, 5%

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: 20 Years of Experience in Chinese Population

Extramammary Paget’s Disease: 20 Years of Experience in Chinese Population

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.

Recurrence of periumbilical Paget disease after fresh Mohs treated with slow Mohs with CK-7

Recurrence of periumbilical Paget disease after fresh Mohs treated with slow Mohs with CK-7

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).

Successful Intra-Arterial Chemotherapy for Extramammary Paget’s Disease of the Axilla in a Patient with Parkinson’s Disease

Successful Intra-Arterial Chemotherapy for Extramammary Paget’s Disease of the Axilla in a Patient with Parkinson’s Disease

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.

Full Recovery of Recurrent Extramammary Paget’s Disease of the Vulva (REMPD-V) After Imiquimod Treatment (PDF)

Full Recovery of Recurrent Extramammary Paget’s Disease of the Vulva (REMPD-V) After Imiquimod Treatment (PDF)

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.

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Extramammary Paget's disease Outline

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Extramammary Paget's disease Outline

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.

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Photodynamic Therapy Following Carbon Dioxide Laser Enhances Efficacy in the Treatment of Extramammary Paget’s Disease

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Photodynamic Therapy Following Carbon Dioxide Laser Enhances Efficacy in the Treatment of Extramammary Paget’s Disease

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.  

Depigmented genital extramammary Paget's disease: a possible histogenetic link to Toker's clear cells and clear cell papulosis

Abstract

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.

Treatment of limited extent extramammary Paget's Disease with 5 percent imiquimod cream

Treatment of limited extent extramammary Paget's Disease with 5 percent imiquimod cream

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.

Extramammary Paget's Disease Resistant to Surgery and Imiquimod Monotherapy But Responsive to Imiquimod Combination Topical Chemotherapy With 5-Fluorouracil and Retinoic Acid: A Case Report

Extramammary Paget's Disease Resistant to Surgery and Imiquimod Monotherapy But Responsive to Imiquimod Combination Topical Chemotherapy With 5-Fluorouracil and Retinoic Acid: A Case Report

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.

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Prognosis and Management of Extramammary Paget’s Disease and the Association with Secondary Malignancies

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Prognosis and Management of Extramammary Paget’s Disease and the Association with Secondary Malignancies

Male-to-female ratio was 4:29, and median age was 70 years. Median followup was 68 months, and no patient died from EMPD. The lesion was predominantly found on the vulva (76%). Patch-like, nonconfluent growth was present in 45% of patients, and no patient had pathologic lymph nodes. The most common signs and symptoms were irritation or pruritus (73%) and rash (61%). The presence of patches, invasive tumor growth, or a second malignancy were significantly associated with a higher recurrence rate. The type of operation, either local excision or hemivulvectomy, was not related to the time to recurrence. Complete gross resection was achieved in 94% of cases. Fifty-six percent of patients had microscopically positive margin and this correlated with a significantly higher recurrence rate (p 􏰀 0.002). The tumor recurred clinically in 14 of 33 patients (42%) after a median of 152 months (range 5 to 209 months). In those patients, between one and six reexcisions were performed. In 14 of 33 patients with EMPD (42%), 16 concurrent secondary malignancies were found. Overall survival rates for EMPD patients were similar to those of the general population.

Mammary and extramammary Paget's disease

Mammary and extramammary Paget's disease

Mammary and extramammary Paget’s disease are uncommon intraepithelial ad- enocarcinomas. Both conditions have similar clinical features, which mimic inflammatory and infective diseases. His- tological diagnostic confusion can arise between Paget’s disease and other neo- plastic conditions aVecting the skin, with the most common diVerential diagnoses being malignant melanoma and atypical squamous disease. The glandular diVer- entiation of both mammary Paget’s dis- ease and extramammary Paget’s disease is indicated by morphological appear- ances, the presence of intracellular mucin in many cases, and positive immunohisto- chemical staining for glandular cytokerat- ins, epithelial membrane antigen, and carcinoembryonic antigen. This article provides an overview of mammary and extramammary Paget’s disease and dis- cusses recent evidence regarding the cell of origin. The concepts of primary and secondary Paget’s disease are presented and the diVerential diagnosis is discussed with reference to immunohistochemical markers that might be of diagnostic value. 

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Perianal extramammary paget's disease associated with primary linitis plastica of the rectum: Report of a case

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Perianal extramammary paget's disease associated with primary linitis plastica of the rectum: Report of a case

We report herein a case of perianal extramammary Paget's disease associated with primary linitis plastica of the rectum. An 82-year-old woman was admitted to our hospital for investigation and treatment of a perianal eczematous lesion. A skin biopsy of the lesion revealed perianal extramammary Paget's disease and a barium enema demonstrated diffuse narrowing with an irregular contour at the ampulla recti. Under a suspected diagnosis of linitis plastica of the rectum, an abdominoperineal resection was performed to resect both the rectal and perianal lesions with regional lymphadenectomy. Grossly, marked narrowing and wall thickness were observed at the lower rectum, and a histological diagnosis of signet ring cell carcinoma was confirmed. The perianal eczematous lesion revealed many atypical cells with clear cytoplasm, being Paget cells, throughout the entire epidermis. Sparse distributions of signet ring cells were also observed in the subcutaneous tissue beneath the perianal eczematous lesion. The pathogenesis of perianal extramammary Paget's disease in this patient was therefore considered to be an intraepidermal extension of primary linitis plastica of the rectum.

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Ultrastructural study of extramammary Paget's disease -- histologically showing transition from bowenoid pattern to Paget's disease pattern.

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Ultrastructural study of extramammary Paget's disease -- histologically showing transition from bowenoid pattern to Paget's disease pattern.

Histological, immunohistochemical, and ultrastructural studies were performed on two cases of histologically unusual extramammary Paget's disease. Histologically, the central area of the lesions showed a bowenoid pattern, and the peripheral area showed typical extramammary Paget's disease. The transition zone showed an intermediate pattern. All these areas were positive for CEA and EMA, and negative for S-100 protein. Ultrastructurally, in the intermediate pattern, the tumour cells had abundant cytoplasmic glycogen, and the widened intercellular spaces contained numerous glycogen particles, which were probably secreted by the tumour cells. It is well known that eccrine glands, but not apocrine glands, secrete glycogen particles. Therefore, the present findings suggest that some cases of extramammary Paget's disease are a proliferation of germinative cells with eccrine gland differentiation.

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