Extramammary Paget’s disease: Updates in the workup and management

Objective:Extramammary Paget’s disease(EMPD)is a rare cutaneous malignant disease.Due to its rarity,there is a paucity of data regarding best treatment strategy.EMPD primarily affects apocrine gland-bearing skin areas such as the vulva,scrotum,and penis.Our objective was to provide a present-day rationale for diagnosis,pathogenesis,and treatment of EMPD with a focus on recent progress in workup and management of the disease.Methods:Literature on EMPD until February 2022 was assessed through PubMed,MEDLINE databases,and Google scholar.A narrative review of the most relevant articles was provided.Results:EMPD usually presents with indolent growth while usually being diagnosed primarily as carcinoma in situ.The foundation of EMPD treatment centers around prompt and accurate diagnosis,wide local or Mohs micrographic surgical excision with proper management towards the margin status,and careful consideration for lymphadenectomy in patients with regionally positive disease.Conventional chemotherapies are alternative treatments modality for patients with distant metastases;however,they sometimes have suboptimal efficacy.At present,there is no agreement regarding adjuvant or systemic therapies,although recent studies have shown several insights into the molecular pathogenesis,tumor biology,and genomics of the development and advancement of EMPD,which may lead to novel and targeted treatment approaches for metastatic EMPD in the future.Conclusion:Patients with EMPD should seek care from physicians with expertise in disease management and patient counseling.These patients should be surveilled with close follow-up to evaluate them for disease recurrence or progression.Global collaborations with groups such as the Global Society for Rare Genitourinary Tumors,and especially patient support groups are crucial in designing clinical trials to help elucidate more robust data in this orphan disease.

An autopsy case of metastatic extramammary Paget’s disease treated with multimodality treatment including anti-HER2 therapy: What is the clinical and pathological significance of trastuzumab to the patient?

Advanced Extramammary Paget’s disease (AEMPD) shows a poor prognosis despite multimodality therapy. In recent years, it is suggested that anti-HER2 therapy may be promising for HER2-positive AEMPD. We herein present an autopsy case of a patient with AEMPD treated with multimodality treatment including anti-HER2 therapy. A 78-year-old man who diagnosed with AEMPD died after surgery and systemic chemotherapy including anti-HER2 therapy (trastuzumab). The metastatic skin lesions were immnohistologically HER2-positive. While the patients were administrated trastuzumab plus taxan (docetaxel, and paclitaxel) regimen, the metastatic skin lesion decreased, however, brain metastases were found in his brain and trastuzumab is discontinued. The skin metastasis rapidly spread over his body, leading to weakness, and he eventually died. At autopsy, the lesions of EMPD were extended distant organs including brain, although each metastasis was small and asymptomatic. The wide lesion of skin metastasis was exacerbated after discontinuation of trastuzumab, and transudate was observed due to the extensive necrosis and erosion. Our autopsy findings showed one progressive pattern of AEMPD, and indicated what is the clinical and pathological significance of anti HER2 therapy for HER2-positive AEMPD.

Extramammary Paget’s Disease Covered the Left Nipple and Areola

We present a case of a 71-year-old woman suffering from mammary Paget,s disease and having a 10-years history of an irregular, widespread erosion accompanied by itching and burning on the skin of her left chest, extending to the breast. The erosion had steadily enlarged and had become increasingly tender. The nipple and areola of the left breast disappeared and could not be recognized. No abnormality of the right nipple, areola, and covering skin and no supernumerary nipple were seen. Mammography and ultrasonography could not be performed because of severe pain and erosive wetness. Histopathology of a surgical biopsy specimen showed epidermal infiltration by large, round, clear atypical cells scattered individually or in small clusters and distributed horizontally throughout the epidermis. The cytoplasm of these large cells was pale and vacuolated and was equivalent to that in nipple cells in Paget,s disease, and a diagnosis of mammary Paget,s disease was made. We performed total mastectomy of the left breast with wide excision of the Paget lesion of the left chest and axillary lymph node sampling. Histological examination of the specimen showed typical distribution of Paget,s cells;however no ductal carcinoma in situ was found in the mammary ducts and invasive growth was not recognized beyond the basal membrane of the lesion. From this evidences, we established a diagnosis of large, irregulaly shaped unusual mammary Paget,s disease, not of breast cancer origin, covering the left breast, areola, and nipple.

The Disturbance of Melanogenesis and Melanosome Transfer in the Leukoderma Lesions of Extramammary Paget’s Disease

We frequently encounter characteristic color variation including hypopigmentation, hyperpigmentation, and erythema in extramammary Paget’s disease (EMPD) lesions. Owing to unclear hypopigmentation, the lesional border of EMPD can be poorly defined and it is likely insufficient to perform its complete resection. Although the existence of Toker’s cells and lack of lesional bFGF production have been reported to cause hypopigmentation inside of EMPD lesions, exact mechanisms of hypopigmentation in EMPD are not fully explored. We experienced three EMPD patients with obviously hypopigmented EMPD macules and histopathologically confirmed a reduced number of melanocytes on the hypopigmented macules and their loss on the erythematous plaques or nodules. An ultrastructural analysis on the hypopigmented lesions revealed disturbance of melanosome maturation and melanosome transfer to the adherent Pagets’ cell on the basal layer. No Paget’s cells even adhered to remaining melanocytes with dendrites contained matured melanosome and a few number of matured melanosome complexes were observed in basal keratinocytes. In the present study, we hypothesize that severe disturbance of not only melanogenesis but also melanosome transfer to surrounding Paget’s cells and basal keratinocytes may cause characteristic hypopigmentation in EMPD. Future bioanalysis would reveal molecular mechanisms for hypopigmentation in EMPD.

CLINICAL ANALYSIS AND TREATMENT OF 14 CASES OF EXTRAMAMMARY PAGET'S DISEASE

Objective To diffrentiate extramammary Paget’s disease (EPD) clinically and histologically from other skin diseases. Methods Clinical analysis and excisional treatment of 14 patients with EPD were reviewed from 1987 to 1997. Results of 14 patients, 12 involved scrotum and penis, one in the groin and the other one in the syrianal region. All were positive for cytokeratin and negative for S-100 protein. Follow-up showed 3 recurrences who had positive surgical margin biopsy. One died of other diSease. Conclusion Surgery is the first choice for treatment of EPD. Negative margin must he achieved to prevent local recurrence.

Extramammary Paget’s Disease Manifested by Intraepithelial Adenocarcinoma of the Vulva and Anus Combined with Invasive Adenocarcinoma of the Ampullary Part of the Rectum

The Object of the Study: The author of the given paper describes an unusual combination of two diseases: extramammary Paget’s disease manifested by intraepithelial adenocarcinoma of the vulva and anus combined with invasive adenocarcinoma of the ampullary part of the rectum and describes the atypical manifestations of these diseases. The Content: The content of this research paper includes a description of the patient, an analysis of the clinical picture, diagnostic methods and therapeutic interventions used, a report of the following disease, and the result of the presented case. The Result of the Research Work: The result of the research work is the analysis of a clinical case with two different tumors, where such a combination of tumors is rarely described in the literature. Moreover, no large specific sample with this combination of diseases is available. Patient Characteristics: The given case report describes a patient of the Palliative Care Unit of the Gerontology Clinic with a primary diagnosis of C20-rectal adenocarcinoma in the background of the anal canal, perineal skin Paget’s disease, stage IV. The presented complications of the patient’s primary diagnosis are multiple metastases in the liver;status post palliative chemotherapy;hepatomegaly;metastases to abdominal lymph nodes, inguinal lymph nodes;metastases at Th12, L4 level;pain syndrome. The presented above combination of diagnosed diseases is very rare. Applied Diagnostics: In October 2021, it was performed diagnostic manipulation: biopsy and the pathologist have provided a microscopic description. The first tissue fragment had a pronounced electrothermal lesion and the epithelial structures were not valuable. The second skin tissue fragment was covered with hyperplastic and acanthotic epithelium;its basal and middle layers contained multiple large cells proliferates extending into the medial epidermis, and the cytoplasm of these cells reacted positively with PAS (Periodic Acid Schiff reaction). It needs to be noted that the patient had previously had several years of biopsies from the perineal and anal epidermis, where Paget’s disease had also been diagnosed. The performed immunohistochemistry showed these cells to be CK20 positive, CK7 rare positive and p16 negative. The following pathohistological findings were made: morphological and immunohistochemical picture is consistent with Paget’s disease. According to the ICD-10, the patient was diagnosed with C51 malignant neoplasm of the female external genitalia. Using imaging diagnostics, it became clear that the patient’s rectal adenocarcinoma had progressed to metastatic stage with distant liver metastases in the background of anal canal, perineal skin Paget’s disease. Therapeutic Plan of the Patient: Based on the patient’s main diagnoses, the complications of the principal diagnosis, the patient’s overall severe condition, pain syndrome, age and comorbidities, palliative chemotherapy was approved as a therapeutic option in council of doctors. Monitoring and Outcome of the Patient: The patient’s general condition was becoming worse over time, and she was diagnosed with exitus latalis in December 2022. At that time, the patient was discharged from hospital and was on palliative care at home under the control of her family physician.

外阴Paget′s病临床分析

目的研究外阴Paget's病的诊断、病理、治疗和预后.方法回顾性总结和分析1960年～2002年期间在中国医科院肿瘤医院治疗的7例外阴Paget's病,病例的症状、病变部位、病理、治疗方法以及随诊情况.结果7例Paget's病患者平均年龄67.3岁(54～81岁);外阴病变和瘙痒是主要的症状,从最初症状到确诊平均时间3.4年.所有患者初治均为手术治疗,2例行外阴单纯切除术,5例行外阴根治术.术后病理:2例浸润到真皮层;4例合并上皮下腺癌.复发5例,距初治时间平均为16.2个月,其中4例行放疗或化疗,另1例未治.平均随访时间41.1个月.3例死亡,均为浸润性病变或合并上皮下腺癌.结论外阴Paget's病患者的诊断较困难,手术是主要的治疗方法,外阴Paget's病易复发,有浸润性病变或伴上皮下腺癌者预后差.

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。

乳腺外Paget′s病的诊治附——21例报告及文献复习

目的 探讨乳腺外Paget′s病的诊治方案及其注意事项。方法 分析 2 1例乳腺外Paget′s病的临床资料、诊治经过及随访结果。结果 2 1例均经病理检查证实。 18例获随访 ,其中 3例手术后 1年复发 ;2例术后 2～ 3年死于广泛转移 ;2例术后 5年死于其他疾病 ;11例 5年无复发。结论 本病易诊为湿疹等 ,对难治性湿疹样改变应早期活检 。

Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget’s disease with curative responses

Background:Although the most commonly recommended treatment for melanoma and extramammary Paget’s disease(EMPD)of the genital region is wide surgical excision of the lesion,the procedure is highly invasive and can lead to functional and sexual problems.Alternative treatments have been used for local control when wide local exci-sion was not feasible.Here,we describe four patients with genital malignancies who were treated with boron neutron capture therapy(BNCT).Methods:The four patients included one patient with vulvar melanoma(VM)and three with genital EMPD.They underwent BNCT at the Kyoto University Research Reactor between 2005 and 2014 using para-boronophenylalanine as the boron delivery agent.They were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin/mucosal doses.Results:All patients showed similar tumor and normal tissue responses following BNCT and achieved complete responses within 6 months.The most severe normal tissue response was moderate skin erosion during the first 2 months,which diminished gradually thereafter.Dysuria or contact pain persisted for 2 months and resolved com-pletely by 4 months.Conclusions:Treating VM and EMPD with BNCT resulted in complete local tumor control.Based on our clinical expe-rience,we conclude that BNCT is a promising treatment for primary VM and EMPD of the genital region.

CK5/6和CK14在乳房外Paget病的分布

目的观察细胞角蛋白5/6(CK5/6)及14(CK14)在乳房外Paget病中的表达特点,并探讨其生物学意义。方法应用免疫组化二步法分别检测34例乳房外Paget病患者皮损及20例正常对照皮肤中CK5/6及CK14的表达情况。结果 CK5/6和CK14在乳房外Paget病中阳性表达,两者主要在表皮全层弥漫性表达,表达率分别为91.17%和88.24%。结论 CK5/6和CK14在乳房外Paget病的组织来源方面起到一定的启示作用,推测乳房外Paget病的肿瘤细胞可能来源于异常分化的基底细胞层表皮干细胞。

乳房外Paget病伴多脏器转移1例

报道1例乳房外Paget病伴右腹股沟淋巴结、肝、肺、胸腰椎、颅骨及骨髓转移的患者。原发皮损位于右侧阴囊,最后因呼吸循环衰竭而死亡。

Paget病的临床病理分析

目的 探讨Paget病的临床及病理形态学特点 ,提高对Paget病的诊治水平。 方法 回顾性分析 9例Paget病患者的临床资料及病理资料。结果 9例Paget病 ,男性患者 4例 ,女性 5例 ,年龄 40～ 82岁 ,平均 63岁。发生部位 :乳头乳晕 5例 ,乳房外 4例。镜下Paget细胞呈巢样、腺样或散在分布于表皮内。细胞体积大 ,呈圆形或椭圆形 ,胞质丰富而透亮 ,核大深染 ,核分裂相易见。免疫组化结果 :EMA、CK 7阳性 ,HMB 45阴性。结论 该病的诊断主要依据组织病理及免疫组织化学检查 ,手术是惟一有效的治疗措施 ,病灶必须彻底切除 。

原发性乳房外Paget病中E钙黏蛋白的检测

目的观察乳房外Paget病中E钙黏蛋白的表达并分析其在肿瘤侵袭过程中的意义。方法应用免疫组化方法分别对28例原发性原位乳房外Paget病(A组)和17例原发性侵袭性乳房外Paget病(B组)标本中的E钙黏蛋白进行检测。结果原发性原位乳房外Paget病标本中E钙黏蛋白的表达较周边正常皮肤标本中表达下调,其中28例原发性原位乳房外Paget病标本中,E钙黏蛋白阴性表达的占28.6%(8/28),低表达的占46.4%(13/28),高表达的占25.0%(7/28),17例原发性侵袭性乳房外Paget病标本表达分别为17.6%(3/17),58.8%(10/17),23.6%(4/17),9例肿瘤边缘正常皮肤和2例正常阴囊皮肤中E钙黏蛋白全部高表达,正常皮肤组与两组乳房外Paget病中E钙黏蛋白的表达差异有显著性(P<0.01),而两组乳房外Paget病之间的表达差异无显著性(P>0.05)。结论E钙黏蛋白表达的下调与原发性乳房外Paget病的发病有关,但可能与侵袭过程没有必然的联系。

原发性乳腺外Paget病49例临床病理分析

探讨原发性乳腺外Paget病的临床病理特征。方法回顾性统计分析49例原发性乳腺外Paget病的临床病理特征并行免疫组化染色。结果患者男性36例,女性13例,年龄47~93岁,平均68.3岁。临床主要表现为皮肤湿疹样改变或新生物,并有瘙痒、疼痛等表现,多累及生殖器或肛周等会阴部位。大体见皮损呈湿疹样红斑、融合性丘疹并可伴渗液、糜烂等改变。镜下表皮全层内见数目不等的Paget细胞浸润,呈单个散在、巢团状或假腺样分布,部分病例可见病变累及皮肤附属器,小部分病例可见肿瘤浸润真皮;Paget细胞呈圆形或卵圆形上皮样,胞质丰富,淡染或透明,核大有异型。免疫组化:49例CK7均(+),部分p16(+),CK5/6和p63(-)。32例获得随访资料,其中复发8例。结论乳腺外Paget病发病率低,好发于老年男性会阴部,临床需与良性皮肤病鉴别。Paget细胞具有特殊的组织形态特点,免疫表型可以帮助鉴别诊断其他多种表皮内原位肿瘤。

对侧阴囊旋转皮瓣修复阴部乳房外Paget病

目的 为一侧阴囊和腹股沟乳房外Paget病彻底切除后修复提供安全可靠的皮瓣。 方法 根据阴囊皮肤的应用解剖学基础 ,设计对侧阴囊旋转皮瓣修复阴部乳房外Paget病切除后创面。 结果 5例患者皮瓣全部存活 ,随访 3个月至 5年 ,术区外形和功能恢复良好 ,未见复发 ,效果满意。结论 阴囊旋转皮瓣血供安全 ,操作方便简单 ,容易成活 。

乳房外Paget病的研究进展

乳房外Paget病是一种少见的表皮内腺癌。检查方法有组织病理、免疫组化、非侵入性检查(包括皮肤镜和反射式共聚焦激光扫描显微镜)。Mohs显微外科手术被认为是首选治疗方法,其他疗法有咪喹莫特、光动力疗法、曲妥珠单抗以及全身化学疗法等。本文对乳房外Paget病的流行病学、发病机制和诊治等内容进行综述,以期提高临床诊治水平。

Pin1在乳房外Paget病的表达及意义

目的:分析Pin1染色后乳房外Paget病组和对照组切片中Pin 1的表达及意义。方法:采用免疫组化染色的方法,对27例乳房外Paget病和10例正常皮肤标本进行Pin1免疫组化染色,并将乳房外Paget病组按照浸润深度分成三组分别观察。结果:乳房外Paget病组阳性率74.07%,其中51.85%为高表达,对照组阳性率30%,均为低表达,差异具有统计学意义(P<0.05)。乳房外Paget病标本按照浸润深度分成三组进行比较,差异来自对照组与乳房外Paget病各组之间,在乳房外Paget病组内部进行两两比较无统计学意义。结论:Pin1在正常皮肤组织中不表达或极低表达,在乳房外Paget病患者皮损中的表达增高。

原发性乳房外Paget病中雄激素受体的表达

目的探讨雄激素受体（AR）在原发性乳房外Paget病组织中的表达及其与疾病侵袭性间的关系。方法应用免疫组化方法．检测20例原位乳房外Paget病、18例侵袭性乳房外Paget病石蜡组织切片中AR的表达情况。结果38例原发性乳房外Paget病中男26例，女12例，年龄（45～84）岁，平均年龄为64岁。AR在原发性乳房外Paget病中明显表达，AR高表达率为58％（22／38）；其中，AR在侵袭性及原位乳房外Paget病中的高表达率分别为78％（14／18）和40％（8／20），相比具有统计学意义（X2值为5．401．P值为0．020）。结论AR的异常表达与原发性乳房外Paget病的发生发展及侵袭性可能有关。

误诊为乳房外Paget病的阴茎基底细胞癌1例

报告1例阴茎基底细胞癌误诊为乳房外Paget病。患者男,83岁,阴茎根部斑块、结节伴瘙痒9年,加重伴破溃3年。皮肤科检查:阴茎根部左侧可见一约4.5 cm×2.5 cm暗红色斑块,其上见散在结节及较厚黄褐色痂壳附着。下腹部、腹股沟、阴囊见大片红斑及绿豆至黄豆大暗红色丘疹,部分皮疹上见点状糜烂,覆淡黄色鳞屑。临床诊断:乳房外Paget病。皮损组织病理检查:真皮内见大量嗜碱性肿瘤细胞团块,部分与表皮相连,肿瘤细胞核大深染,在团块边缘排列呈栅栏状,外周有收缩间隙。最终诊断:基底细胞癌。手术切除斑块后,行3次光动力治疗。随访至今20个月,未见复发。