Depigmented extramammary Paget's disease

BACKGROUND: Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. OBJECTIVES: To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. METHODS: All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. RESULTS: Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. CONCLUSIONS: Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.     

乳房外Paget病治疗进展

乳房外Paget病的治疗主要包括广泛局部切除、Mohs显微手术、放射疗法、光动力疗法、激光治疗、化学疗法、咪喹莫特和5-氟尿嘧啶等方法.对于保留局部组织和降低疾病复发率,Mohs显微手术更有优势,对于其他治疗的研究,结果各不相同.本文就乳房外Paget病的治疗进展进行综述.     

乳房外Paget病皮损中黏蛋白1和黏蛋白2的表达

目的 探讨黏蛋白1(MUC1)和黏蛋白2(MUC2)在乳房外Paget病(EMPD)中的表达情况.方法 生物素蛋白免疫组化法(SP法)检测19例EMPD皮损及19例美容切除术后正常皮肤组织上MUC1与MUC2的表达.结果 19例EMPD皮损常规HE染色显示,3例伴低分化腺癌,6例呈浸润性,10例为上皮内.MUC1在3例伴腺癌Paget病中有2例呈阳性表达,6例浸润性和10例上皮内Paget病均呈阳性表达.MUC2在3例伴腺癌Paget病和6例浸润性Paget病均呈阳性表达,在10例上皮内Paget病中有2例呈阳性表达.MUC1与MUC2在正常皮肤组织呈阴性表达.MUC1在上皮内Paget病中的表达显著高于伴腺癌Paget病和浸润性Paget病(P＜0.05).MUC2在伴腺癌Paget病和浸润性Paget病中的表达显著高于上皮内Paget病(P＜0.05).MUC1和MUC2的表达无明显相关性(r=-0.5,P＞0.05).结论 MUC1在EMPD中呈普遍表达,MUC2在伴有腺癌和浸润性EMPD中呈阳性表达.

Abstract：

Objective To study the expressions of mucin (MUC) 1 and 2 in extramammary Paget's disease(EMPD) lesions. Methods Tissue specimens were obtained from the lesions of 19 patients with EMPD and normal skin of 19 human controls during cosmetic surgery. Streptavidin-perosidase (SP) technique was used to detect the expressions of MUC1 and MUC2 in these specimens. Results As haematoxylin-eosin (HE) staining showed, 3 cases were accompanied by poorly differentiated adenocarcinoma, 6 were invasive Paget's disease and 10 were intraepithelial EMPD. MUC1 was expressed in 2 cases accompanied by poorly differentiated adenocarcinoma, and in all the cases of invasive and intraepithelial EMPD; MUC2 was observed in all the cases of adenocarcinoma-complicated EMPD and invasive EMPD, but only in 2 of 10 cases of intraepithelial EMPD.Neither MUC1 nor MUC2 was observed in normal control specimens. A significant increase was observed in the expression of MUC1 in lesions of intraepithelial EMPD compared with invasive EMPD and adenocarcinoma-complicated EMPD (both P ＜ 0.05), and in the expression of MUC2 in lesions of invasive EMPD and adenocarcinoma-complicated EMPD compared with intraepithelial EMPD (both P ＜ 0.05). The expression of MUC1 was uncorrelated to that of MUC2 (r= -0.5, P＞ 0.05). Conclusions MUC1 is generally expressed in the lesions of EMPD, while MUC2 is expressed in those of adenocarcinoma-complicated EMPD and invasive EMPD.     

乳房外Paget病反射式共聚焦显微镜和皮肤镜图像特征分析

目的:分析乳房外Paget病(EMPD)反射式共聚焦显微镜(RCM)和皮肤镜特征。方法:回顾性分析我院16例经组织病理证实为乳房外Paget病的RCM、皮肤镜影像资料。结果:16例患者反射式共聚焦显微镜特征均表现为低折光大而圆的Paget细胞散在或成巢分布。16例皮肤镜表现均出现乳红色背景、亮白色无结构区和点-球状血管。结论:本研究中EMPD患者有共同的皮肤镜和RCM特征,皮肤镜和RCM可作为EMPD早期诊断及治疗随访的辅助工具。     

Comparative genomic hybridization in epithelioid sarcoma

BACKGROUND: Epithelioid sarcoma is a rare mesenchymal neoplasm of unknown histogenesis. Data on genome-wide surveys for chromosomal aberrations in epithelioid sarcoma are limited. OBJECTIVES: To investigate genetic aberrations in epithelioid sarcoma. METHODS: We analysed seven cases of epithelioid sarcoma (classic type, three cases and proximal type, four cases) by comparative genomic hybridization (CGH), and correlated findings with the results of additional immunohistochemical study. RESULTS AND CONCLUSIONS: CGH analysis showed DNA copy number changes at one to five different genomic sites in six of seven cases (86%). The majority of the changes were gains. The most frequent gain was at 22q (six cases). Other recurrent changes include gains of 12q24-qter (four cases), 17 (four cases), and 5q32-qter (three cases). High-level homology was seen in chromosomal aberration in both types. In addition, expression of interleukin-2 receptorbeta, located in 22q, was revealed by immunohistochemical method in six cases with gain of 22q, suggesting it may play a role in epithelioid sarcoma tumorigenesis.     

47例Paget病临床与组织病理分析

本文回顾性分析了47例Paget病的临床及病理表现,其中乳房Paget病17例,均为女性,平均发病年龄54.2岁,平均病程19.6个月;乳房外Paget病30例(男28例,女2例),平均发病年龄68.2岁;平均病程61.96个月。皮损均表现为界清的红斑,表面有渗出、糜烂和结痂。皮损组织病理可见典型的散在或成巢分布的Paget细胞,免疫组化肿瘤细胞表达CK7、CEA、CKpan。45例患者早期误诊为"湿疹"。     

Photodynamic therapy for the treatment of extramammary Paget's disease

BACKGROUND: Surgical and ablative treatment modalities for extramammary Paget's disease (EMPD) have high recurrence rates and can be associated with significant morbidity. OBJECTIVES: To evaluate photodynamic therapy (PDT) for the treatment of EMPD. METHODS: We conducted a retrospective review of notes and histology of five men with anogenital, groin and axillary EMPD treated with PDT at Roswell Park Cancer Institute between 20 April 1995 and 1 February 2001. RESULTS: Sixteen EMPD lesions were treated with topical aminolaevulinic acid (ALA)-PDT. Eleven of these lesions had failed previous Mohs micrographic surgery, excision or laser ablation. When evaluated 6 months after one treatment with ALA-PDT, eight of 16 (50%) sites achieved a complete clinical response (CR); six of eight CRs were in lesions that had failed prior conventional therapies. Three of the eight CRs (37.5%) recurred at 9, 10 and 10 months. One patient who was partially responsive to topical ALA-PDT subsequently received systemic Photofrin(R)-PDT, with a complete clinical and histological response at 1 year. Functional and cosmetic outcome was excellent in all patients. CONCLUSIONS: PDT is an effective treatment for EMPD. Recurrence rates are high with topical ALA-PDT, but comparable with standard therapies. Topical ALA-PDT causes little scarring and is preferred for superficial disease and mucosal surfaces. Systemic Photofrin(R)-PDT may be better suited for bulky disease. While further studies are indicated, PDT is well tolerated and appears to be a useful therapy for EMPD.     

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease

Background We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget’s disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy‐ and nutrient‐sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin‐dependent kinases, is a key regulator of G₁–S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT–mTOR–p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. Objective To investigate the immunohistochemical staining of the AKT–mTOR–p70S6K pathway in EMPD and to evaluate the relationships among the components. Methods Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)‐AKT, p‐mTOR, p‐4E‐binding protein 1 (p‐4EBP1), p‐p70S6K/S6K1, p‐ribosomal protein S6 (p‐S6) and CDK2. Ten normal skin samples served as a control. Results Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1, p‐S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1 and p‐S6 and CDK2. Conclusions The activation of the AKT–mTOR–p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT–mTOR–p70S6K pathway might be a potential therapeutic target in EMPD.     

Mohs显微手术治疗乳房外Paget病42例

目的:评价Mohs治疗乳房外Paget病的疗效。方法:42例乳房外Paget病患者沿皮损周围2 cm行Mohs手术切除,确认边缘结果阴性之后行皮瓣或植皮闭合。术后31例患者使用光动力,每周1次,共4次。11例外用咪喹莫特乳膏,每日1次,共半年,随访8~36个月。结果:6例患者复发,复发率14.3%,其中4例为术后光动力治疗患者,2例为术后外用咪喹莫特乳膏。结论:EMPD进行Mohs显微描记手术结合光动力治疗或外用咪喹莫特乳膏有效。     

三种性激素受体在原发性乳房外Paget病中的表达及意义

目的 研究探讨3种性激素受体在原发性乳房外Paget病中表达的特点及意义.方法 免疫组化法检测雄激素受体、雌激素受体和孕激素受体在30例原发性乳房外Paget病中的表达.结果 30例原发性乳房外Paget病中19例雄激素受体表达阳性.阳性率为63.3％,其中25例男性患者中阳性率为72％,5例女性患者中阳性率为20％.所有病例中雌激素受体和孕激素受体均阴性表达.结论 原发性乳房外Paget病有性激素依赖性,雄激素及其受体可能参与原发性乳房外Paget病的发生和发展.     

The Roswell Park Cancer Institute experience with extramammary Paget's disease

Extramammary Paget's disease (EMPD) is a rare intraepithelial neoplasm. Common sites of occurrence include the vulva, perianal region, perineum and scrotum. Despite frequent recurrences, surgery is the standard treatment. This study examines the recurrence rate for EMPD treated by conventional surgical management. Alternative and multimodal therapeutic approaches are reviewed. This retrospective analysis included all 30 patients treated for EMPD at Roswell Park Cancer Institute (RPCI) between 1970 and 1998. Following conventional surgical treatment, 44% of our patients developed recurrence. Vulvectomy provided the lowest recurrence rate, but involved extensive tissue loss and functional debility. Multimodal treatment using Mohs' micrographic surgery and photodynamic therapy has been used at RPCI to manage EMPD with minimal tissue loss and no functional impairment. Surgical treatment offers a moderate chance of EMPD cure. Long-term multimodal approaches require close follow-up, but may conserve both tissue and function.     

16例乳房外Paget病临床回顾

对１６例乳房外Ｐａｇｅｔ病的临床、治疗及预后进行了回顾。结果提示，乳房外Ｐａｇｅｔ病多发生于老年人，主要发生于外阴部皮肤，典型皮损为湿疹样境界清楚的红斑，少数病例伴有相关内脏恶性肿瘤，治疗首选局部扩大切除，预后相对良好。     

Mammary and extramammary Paget''s disease

Paget's disease is an intra-epidermal adenocarcinoma seen over the nipple/areola (mammary Paget's disease) or in extramammary body zones, such as the anogenital and perineal skin and the axilla. Mammary and extramammary Paget's disease share many common clinicopathological features but also show several differences, namely, with regard to pathogenesis and association with underlying malignancies. Indeed, mammary Paget's disease is as a rule associated with an underlying breast carcinoma whereas association of extramammary Paget's disease with underlying (skin or visceral) malignancies occurs much less frequently. We review here the main clinicopathological and therapeutic features of mammary and extramammary Paget's disease.     

乳房外Paget病一例

患者男,54岁,阴囊及股部赘生物4个月.皮肤科检查:右侧腹股沟及阴囊见多个红色或皮色的结节和肿块,直径为0.5 cm×0.5 cm～8 cm×8 cm,呈疣状或圆顶状,部分表面糜烂,有少许脓性分泌物,伴恶臭.该患者在以往的皮损基础上出现新生物,伴有恶臭,根据患者的临床表现及病史考虑为鳞状细胞癌,给予进一步检查,经皮损组织病理和免疫组化的检查诊断为原发性乳房外Paget病.实验室检查HPV为阴性.

Abstract：

A 54-year-old man presented with neoplasms on the groin and scrotum for 4 months.Physical examination revealed multiple, erythematous or skin-colored, verrucous-like or dome-shaped nodules and neoplasms measuring 0.5 to 8 cm in diameter on the right groin and scrotum. Erosions were observed on the surface of some lesions with purulent secretion and stench. The neoplasms arose in previous lesions with stench. The patient was initially diagnosed with squamous cell carcinoma according to the clinical manifestation and medical history, but histopathological and immunohistochemical examination confirmed a diagnosis of primary extra-mammary Paget's disease. PCR was negative for low- or high-risk human papilloma virus types in this patient.     

Two cases of vulval pigmented extramammary Paget's disease: histochemical and immunohistochemical studies

We describe two Japanese female patients with pigmented extramammary Paget's disease (EMPD); one patient had a dark brown plaque and the other had a reddish patch with a pigmented area, both affecting the vulval region. Histochemical and immunohistochemical examinations confirmed EMPD with melanocyte colonization; plump tumour cells with a large nucleus and pale cytoplasm that were positive for CAM 5.2 and CEA proliferated singly or in nests in the epidermis, and scattered among the tumour cells were many dendritic cells with a large amount of melanin that were positive for HMB-45 and S-100 protein. Fontana-Masson (FM) stain showed many positive cells with well-developed dendritic processes within and around tumour nests. Histochemical and immunohistochemical studies of non-pigmented EMPD cases on the same region showed that HMB-45 positive cells were sparse or not detected at all, and that also FM staining-positive cells were decreased or not detected, and their dendritic processes were poorly formed. The present study suggests that there might be heterogeneity in EMPD in terms of relationships between Paget's cells and melanocytes.     

Fusion of single-photon emission computed tomography and computed tomography images of sentinel lymph nodes in extramammary Paget's disease of the scrotum

We describe a new method for the fusion of single-photon emission computed tomography (SPECT) and multidetector computed tomography (MDCT) images using an acrylic resin marker containing 99 m-Tc phytate and viewing software (Fusion Viewer Version 1.0 for Windows). This method provided the fusion of SPECT and CT images in a short time and made it easy to identify the sentinel lymph nodes in the patient with extramammary Paget's disease of the scrotum.     

Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget's disease

Background  Metastatic penoscrotal extramammary Paget's disease (EMPD) has seldom been reported in the literature.
Objectives  To improve the knowledge of the clinicopathological characteristics, management and outcome in patients with this disease.
Methods  The medical records and pathological slides of 10 patients with metastatic EMPD and 33 patients with nonmetastatic disease were reviewed. Immunohistochemical staining for epithelial cadherin (E-cadherin) was performed in the primary skin disease. All the 10 patients received 5-fluorouracil- or docetaxel-based chemotherapy.
Results  The most common sites of metastases were lymph nodes followed by bone. Patients with metastatic EMPD were more likely to be young and had elevated carcinoembryonic antigen (CEA) levels. Dermal or deeper invasion, lymphovascular embolization and negative expression of E-cadherin were important pathological predictors of metastatic potential. In invasive EMPD, lymphovascular embolization but not expression of E-cadherin was significantly associated with the risk of metastases. In three patients, ¹⁸F-fluorodeoxyglucose positron emission tomography (PET)–computed tomography (CT) scans revealed occult lymph node metastases which were overlooked at conventional CT examinations. Two patients had complete response to the chemotherapy, three had partial response and five had progressive disease. The 2-year overall survival rate was 48% in patients with metastatic EMPD. In those patients with significantly elevated CEA level, the value of CEA paralleled the disease course.
Conclusions  Metastatic EMPD tended to have dermal invasion and lymphovascular embolization. PET–CT scans were helpful in detecting distant metastases. 5-Fluorouracil- or docetaxel based-chemotherapy was effective in some patients. Serum CEA level can be a useful biomarker for monitoring disease course.     

Distal phalangeal metastasis of extramammary Paget's disease

A rare case of phalangeal metastasis of extramammary Paget's disease in a 68-year-old man is described. The patient developed an erythematous, slightly elevated area in the pubic region. A biopsy specimen demonstrated numerous, large, rounded cells with ample pale-staining cytoplasm proliferating in the epidermis. With a diagnosis of extramammary Paget's disease, he underwent wide local excision and inguinal node dissection. Eleven months postoperatively, the patient developed a tender, red, swollen right ring finger. Bone X-ray showed that the distal phalanx of the ring finger had completely dissolved. Histopathological examination demonstrated proliferation of tumor cells in the adipose tissue. They had poorer and darker cytoplasm than the Paget's cells in the epidermis of the pubic region. Immunohistochemically, these cells showed the same staining pattern as did the Paget's cells at the primary site. Accordingly, the patient was diagnosed with distal phalangeal metastasis of extramammary Paget's disease. Two weeks after the appearance of the distal phalangeal metastasis, the patient died of cancerous pleurisy. It has been reported that patients with phalangeal metastasis have a very poor prognosis.     

Metastatic extramammary Paget's disease treated with paclitaxel and trastuzumab combination chemotherapy

In the treatment of metastatic breast cancer, trastuzumab, a recombinant monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is effective when tumor cells overexpress HER2 protein. Although some cases of extramammary Paget's disease (EMPD) also express HER2 protein, no case of EMPD has been reported to be treated with trastuzumab. A 75-year-old man who suffered from EMPD of the scrotum and inguinal region underwent a local excision and lymph node dissection. Tumor cells invaded the dermis and lymph nodes. Although he was postoperatively treated with adjuvant chemotherapies, metastatic skin lesions appeared and spread over his left thigh, rapidly and widely. Tumor cells disseminated along lymph vessels in the dermis and overexpressed HER2 protein. We administered paclitaxel and trastuzumab according to a protocol for HER2-positive metastatic breast cancers. The skin metastasis dramatically decreased during the regimen and a histopathological examination showed that most of HER2-positive tumor cells diminished. Six months later, metastases were found in the central nervous system (CNS), but no other metastases were found in the skin, visceral organs or lymph nodes. Trastuzumab and paclitaxel-combination with the assessment of central nervous system lesions should be considered as an option for the treatment of HER2-positive EMPD.     

Mammary and extramammary Paget's disease

Paget''s disease, described by Sir James Paget in 1874, is classified as mammary and extramammary. The mammary type is rare and often associated with intraductal cancer (93-100% of cases). It is more prevalent in postmenopausal women and it appears as an eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration and inversion of the nipple. It must be distinguished from erosive adenomatosis of the nipple, cutaneous extension of breast carcinoma, psoriasis, atopic dermatitis, contact dermatitis, chronic eczema, lactiferous ducts ectasia, Bowen''s disease, basal cell carcinoma, melanoma and intraductal papilloma. Diagnosis is histological and prognosis and treatment depend on the type of underlying breast cancer. Extramammary Paget''s disease is considered an adenocarcinoma originating from the skin or skin appendages in areas with apocrine glands. The primary location is the vulvar area, followed by the perianal region, scrotum, penis and axillae. It starts as an erythematous plaque of indolent growth, with well-defined edges, fine scaling, excoriations, exulcerations and lichenification. In most cases it is not associated with cancer, although there are publications linking it to tumors of the vulva, vagina, cervix and corpus uteri, bladder, ovary, gallbladder, liver, breast, colon and rectum. Differential diagnoses are candidiasis, psoriasis and chronic lichen simplex. Histopathology confirms the diagnosis. Before treatment begins, associated malignancies should be investigated. Surgical excision and micrographic surgery are the best treatment options, although recurrences are frequent.