今日の臨床サポート

乳房パジェット病

著者: 植弘奈津恵1) がん研究会有明病院 乳腺センター

著者: 岩瀬拓士2) 日本赤十字社 愛知医療センター名古屋第一病院 乳腺外科

監修: 中村清吾 昭和大学医学部外科学講座乳腺外科学部門

著者校正/監修レビュー済:2022/10/26
参考ガイドライン:
  1. 日本乳癌学会:乳癌診療ガイドライン 疫学・診断編/治療編2022年版
患者向け説明資料

概要・推奨   

  1. パジェット病は、乳癌が乳頭・乳輪の表皮内に進展することにより難治性の湿疹様変化を呈したものをいう。
  1. パジェット病は必ず乳頭から始まり、円状に広がる。また、難治性で経過が長いことが特徴であるため、症状の出現時期や広がり方、治療歴を聴取することが重要である。
  1. パジェット病には90%以上の症例で乳管癌が存在しているため、治療は原則として乳房切除術を行う。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
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尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
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(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
植弘奈津恵 : 特に申告事項無し[2022年]
岩瀬拓士 : 特に申告事項無し[2022年]
監修:中村清吾 : 講演料(第一三共,中外製薬,メディコン),研究費・助成金など(アストラゼネカ,協和キリン,第一三共,島津製作所,大鵬薬品工業,日本化薬,持田製薬),奨学(奨励)寄付など(エーザイ,コニカミノルタ,中外製薬)[2022年]

改訂のポイント:
  1. 乳癌診療ガイドライン2022年版に基づき、加筆・修正を行った。

病態・疫学・診察

疾患情報  
  1. パジェット病は、乳癌が乳頭・乳輪の表皮内に進展することにより難治性の湿疹様変化を呈したものをいう。
  1. 乳癌が主乳管内を進展して乳頭部皮膚に達するため、乳頭部では主乳管開口部を中心として円状に広がる。
  1. 非浸潤癌、浸潤癌のいずれでも起こり得るが、「乳癌取扱い規約」では、非浸潤癌もしくは間質浸潤が存在する場合には微小浸潤までをパジェット病とし、1㎜を超える浸潤が指摘される場合は浸潤癌に分類している[1]
  1. 病理学的には乳頭・乳輪の表皮内に大型の明るい泡沫状の胞体と、大きく目立つ核を持つパジェット細胞がみられることが特徴である。
  1. 発生頻度は全乳癌の1~2%とされている[2]が、日本では「乳癌取扱い規約」上のパジェット病の頻度は0.3%である[3]。SEER dataを用いた解析では、2011年のパジェット病の年齢調整罹患率は0.44であり、非浸潤癌および浸潤癌を伴うパジェット病の罹患率は2001年より減少傾向にある[4]
  1. パジェット病の80%以上の症例でパジェット細胞および併存する非浸潤癌、浸潤癌がHER2陽性を呈する[5][6][7][8]
  1. 治療は原因となる乳癌の状態に応じて選択する。
 
  1. 男性でも乳房パジェットになるが、非常にまれである。(参考文献:[9][10][11][12][13][14]
  1. 乳房パジェットはまれな疾患であり、男性乳癌も全乳癌の約1%とまれな疾患であるため、その発生は非常にまれである。SEER dataを用いた解析では1973年から2012年までで120例あり、全男性乳癌のうち1.45%であったと報告されている[14]。治療方針は通常の男性乳癌と同様に乳房切除術を基本とする。
問診・診察のポイント  
  1. パジェット病は必ず乳頭から始まり、円状に広がる。また、難治性で経過が長いことが特徴であるため、症状の出現時期や広がり方、治療歴を聴取することが重要である。

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文献 

Stephanie M Wong, Rachel A Freedman, Emily Stamell, Yasuaki Sagara, Jane E Brock, Stephen D Desantis, Mehra Golshan
Modern Trends in the Surgical Management of Paget's Disease.
Ann Surg Oncol. 2015 Oct;22(10):3308-16. doi: 10.1245/s10434-015-4664-3. Epub 2015 Jul 23.
Abstract/Text PURPOSE: We examined the incidence and modern national trends in the management of Paget's disease (PD), including the use of breast-conserving surgery (BCS), mastectomy, axillary surgery, and receipt of radiotherapy.
METHODS: Using surveillance, epidemiology and end results (SEER) data, we identified 2631 patients diagnosed with PD during 2000-2011. Of these patients, 185 (7%) had PD of the nipple only, 953 (36.2%) had PD with ductal carcinoma in situ (PD-DCIS), and 1493 (56.7%) had PD with invasive ductal carcinoma (PD-IDC). Trends in age-adjusted incidence, primary surgery, sentinel lymph node biopsy (SLNB), and axillary lymph node dissection were examined. Multivariable logistic regression was used to evaluate factors associated with receipt of BCS and radiotherapy.
RESULTS: A decrease in the age-adjusted incidence of PD occurred from 2000 to 2011 (-4.3% per year, p < 0.05). The overall rates of mastectomy in the PD only, PD-DCIS, and PD-IDC groups were 47, 69, and 88.9%, respectively. Only in the PD-IDC group did the proportion of patients undergoing BCS increase significantly, from 8.5% in 2000 to 15.7% in 2011 (p = 0.01). Of those who underwent axillary surgery, the proportion of patients undergoing SLNB increased from 2000 to 2011. In adjusted analyses, Paget's subgroup, older age, central tumor location, low/intermediate grade, tumor size <2.0 cm, SEER region, and year of diagnosis after 2006 were significantly associated with receipt of BCS.
CONCLUSIONS: The incidence of Paget's disease has decreased over time while modern trends in local therapy suggest that BCS, SLNB, and adjuvant radiotherapy remain underutilized.

PMID 26202552
Piotr Sek, Antoni Zawrocki, Wojciech Biernat, Janusz H Piekarski
HER2 molecular subtype is a dominant subtype of mammary Paget's cells. An immunohistochemical study.
Histopathology. 2010 Oct;57(4):564-71. doi: 10.1111/j.1365-2559.2010.03665.x.
Abstract/Text AIMS:   To test the hypothesis that the similarity of the molecular subtypes of Paget's cells to the molecular subtypes of the underlying breast carcinomas favours the epidermotrophic theory of the origin of Paget's cells.
METHODS AND RESULTS:   The immunohistochemical expression of markers that define particular molecular subtypes of breast carcinomas were analysed. The whole analysis was performed by means of tissue microarrays in mammary Paget's disease and in the underlying breast carcinoma(s). Human epidermal growth factor receptor type 2 (HER2)-overexpression subtype [oestrogen receptor (ER(-) ); HER2(+) ] was a dominant molecular subtype of Paget's cells (37 of 43 analysed cases; 86%). Luminal B (ER(+) ; HER2(+) ) and luminal A (ER(+) ; HER(-) ) subtypes were identified in 12% and 2% of cases, respectively. None of the analysed tumours presented a basal-like phenotype. A similar distribution of molecular subtypes was identified in the underlying in situ breast carcinomas (HER2 subtype, 82%; luminal A, 6%; luminal B, 6%; basal-like, 6% of cases) and in the invasive component (HER2 subtype, 84%; luminal A, 8%; luminal B, 8%; basal-like, 0% of cases).
CONCLUSIONS:   HER2 molecular subtype is the dominant, but not the sole subtype seen in Paget's cells of the nipple. A similar distribution of molecular subtypes in both Paget's cells and in the underlying carcinomas strongly suggests their common origin.

© 2010 Blackwell Publishing Limited.
PMID 20955381
Joseph M Anderson, Reshma Ariga, Hema Govil, Kenneth J Bloom, Darius Francescatti, Vijaya B Reddy, Victor E Gould, Paolo Gattuso
Assessment of Her-2/Neu status by immunohistochemistry and fluorescence in situ hybridization in mammary Paget disease and underlying carcinoma.
Appl Immunohistochem Mol Morphol. 2003 Jun;11(2):120-4.
Abstract/Text HER-2/Neu overexpression is seen in 20% to 30% of invasive breast carcinomas and has been reported in as many as 80% of high-grade infiltrating carcinomas. Earlier studies have suggested that 100% of the tumor cells in mammary Paget disease show overexpression of HER-2 protein. We undertook this study to assess HER-2 status of mammary Paget disease and of the underlying breast carcinoma, when present, by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Formalin-fixed, paraffin-embedded tissue from 20 cases of mammary Paget disease were analyzed for HER-2 status by IHC and FISH. IHC for estrogen receptor (ER) was also performed. The patients ranged in age from 34 to 88 years, with a mean age of 62 years. Eighty percent of the cases showed strong overexpression (3+) of HER-2 protein by IHC, and all of these cases showed more than 5-fold amplification of the HER-2 gene by FISH. The remaining 4 cases, which were negative for HER-2/Neu by IHC, showed no amplification by FISH. All of the latter cases expressed ER, whereas no case that overexpressed HER-2 expressed ER. Sixteen cases had an underlying tumor, which was in situ in 6 cases. The underlying tumors were identical to the Paget disease with respect to their HER-2/Neu overexpression by both IHC and FISH. HER-2 overexpression was identified in 80% of our cases of Paget disease. There was 100% concordance between HER-2 protein overexpression by immunohistochemistry and gene amplification in both the Paget and the underlying tumor. Moreover, all of the cases negative for HER-2 overexpression expressed ER, whereas those positive for HER-2 did not.

PMID 12777994
Elżbieta Marczyk, Anna Kruczak, Aleksandra Ambicka, Katarzyna Mularz, Agnieszka Harazin-Lechowska, Julia Moskal, Andrzej Sokołowski, Jerzy Mituś, Janusz Ryś
The routine immunohistochemical evaluation in Paget disease of the nipple.
Pol J Pathol. 2011 Dec;62(4):229-35.
Abstract/Text Paget disease (PD) of the nipple with coexisting intraductal (DCIS) and invasive carcinoma of the breast comprises 0.6-1.8% of all malignant epithelial neoplasms of this organ. Unlike invasive ductal carcinoma, there are many controversies concerning histological features of PD and the significance of the immunohistochemical characteristics of this neoplasm, which limits the optimal treatment protocols. Therefore, we decided to verify the immunohistochemical markers of PD basing on the retrospective analysis of postoperative material from 69 patients treated surgically. Microscopic examination revealed partial (7 cases) or total (62 cases) replacement of the squamous epithelium of the nipple with nests of atypical glandular cells spreading in an area ranging from 0.2 to 2.5 cm. DCIS coexisting with the PD lesions was present in all examined patients, and infiltrating carcinoma occurred in 31 (44.9%) patients. Both intraepidermal and DCIS components presented c-erbB2 overexpression. Positive estrogen and progesterone receptor staining was observed only in 7 (10.1%) and 2 (2.7%) tumours, respectively. Ki-67 proliferation index of PD cells ranged from 10% to 30%, whereas in DCIS it varied from 4% to 20%. The value of Ki-67 index exceeding 25% in the intraepidermal component of PD was associated with worse overall survival rate.

PMID 22246908
David L Wachter, Peter W Wachter, Peter A Fasching, Matthias W Beckmann, Carolin C Hack, Marc-Oliver Riener, Arndt Hartmann, Johanna D Strehl
Characterization of Molecular Subtypes of Paget Disease of the Breast Using Immunohistochemistry and In Situ Hybridization.
Arch Pathol Lab Med. 2018 Aug 20;. doi: 10.5858/arpa.2017-0578-OA. Epub 2018 Aug 20.
Abstract/Text CONTEXT: - Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast.
OBJECTIVES: - To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present.
DESIGN: - We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated, invasive carcinoma of the breast, if present.
RESULTS: - The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated, invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases.
CONCLUSIONS: - Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated, invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated, invasive carcinoma and the luminal and triple-negative subtypes underrepresented.

PMID 30124327
F Serour, S Birkenfeld, E Amsterdam, O Treshchan, M Krispin
Paget's disease of the male breast.
Cancer. 1988 Aug 1;62(3):601-5.
Abstract/Text Histologically proved Paget's disease of the breast with negative hormonal receptor assay in a 73-year-old man induced a review of the 27 valuable cases of the literature. Our patient is disease-free, eight years after treatment by modified radical mastectomy and adjuvant irradiation. Peak incidence of the disease is between 50 and 70 years of age. The most frequent presenting signs reported are ulcerations and eczematous lesions of the nipple (71.4%) with discharge and bleeding in 39.3% of the cases. Other findings are a palpable mass (42.8%) and involved axillary lymph nodes (53.5%). The treatment of choice is shown to be radical or modified radical mastectomy with adjuvant radiotherapy. To date, no proof exists of the value of hormone receptors assays and routine adjuvant hormone therapy is not practiced.

PMID 2839285
S T O'Sullivan, G T McGreal, A Lyons, L Burke, J G Geoghegan, M P Brady
Paget's disease of the breast in a man without underlying breast carcinoma.
J Clin Pathol. 1994 Sep;47(9):851-2.
Abstract/Text A case of histologically confirmed Paget's disease of the breast in a 72 year old man, without underlying breast carcinoma, is reported. This report raises questions about the pathogenesis of this condition and suggests that Paget's disease is an independent, intraepidermal carcinoma rather than a direct extension of intraductal carcinoma of the breast to the nipple and areola.

PMID 7962657
D C Desai, E J Brennan, N Z Carp
Paget's disease of the male breast.
Am Surg. 1996 Dec;62(12):1068-72.
Abstract/Text A histopathologically proven case of Paget's disease of the breast in a 47-year-old male induced a review of the 32 cases in the world's literature. Paget's disease usually presents in the 5th and 6th decades of life without any obvious racial predilections. The most frequent presenting signs include ulceration, eczema, nipple discharge, bleeding, and crust formation. At the time of presentation, 50 per cent of the patients have a palpable breast mass, positive lymph nodes, or both. When entertaining the diagnosis of Paget's disease of the breast using morphologic characteristics of the cells, the diagnosis of malignant melanoma and Bowen's disease (intraepithelial squamous cell carcinoma) must be included in the differential diagnosis. Certain differences will be seen between these three entities based on specific cell staining and the uptake of certain tumor markers. There is no evidence that this disease behaves differently in males versus females, but the 5-year survival for males is worse: 20 to 30 per cent in males versus 30 to 50 per cent in females. The treatment of this disease must focus on the pathology of the underlying tumor. Current treatment involves modified radical mastectomy or radical mastectomy for Stage I and II tumors. Adjuvant chemotherapy, radiation, and tamoxifen are also used depending on the nodal and receptor status of the tumor.

PMID 8955252
T El Harroudi, F Tijami, A El Otmany, A Jalil
Paget disease of the male nipple.
J Cancer Res Ther. 2010 Jan-Mar;6(1):95-6. doi: 10.4103/0973-1482.63561.
Abstract/Text Breast cancer occurring in the mammary gland of men is infrequent. It accounts for 0.8% of all breast cancers, which is less than one per cent of all newly diagnosed male cancers and 0.2% of male cancer deaths. However, Paget disease of the male nipple is extremely rare. We report a single case of Paget disease with infiltrative ductal carcinoma of the breast in a 61-year-old man.

PMID 20479557
Scott J Adams, Rani Kanthan
Paget's disease of the male breast in the 21st century: A systematic review.
Breast. 2016 Oct;29:14-23. doi: 10.1016/j.breast.2016.06.015. Epub 2016 Jul 6.
Abstract/Text Paget's disease of the breast is characterized by eczematous changes of the nipple-areolar complex and is associated with an underlying in situ or invasive breast carcinoma in most cases. Histologically, Paget's disease is identified by epithelial cells with abundant basophilic or amphophilic, finely granular cytoplasm with a large, centrally situated nucleus, most abundant in the lower epidermal layers. Due to the rarity of the condition among breast cancers, compounded by the rarity of breast cancer in men, understanding of the disease's presentation, course, and optimal treatment in men is largely derived from case reports and extrapolation of findings from studies in female patients. Paget's disease must be differentiated from other conditions including eczema, Bowen's disease, squamous cell carcinoma, and melanoma. Recognition of Paget's disease clinically and pathologically is critical as the superficial lesion may be the only sign of an underlying ductal carcinoma and its presence may be of prognostic significance. This article provides an update on cases of Paget's disease of the breast in men reported in the published literature together with a comprehensive analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Data, 1973-2012. Current understanding and management of the disease in the context of male patients is reviewed. However, additional research is required to further understand the overall pathogenesis and molecular profile of Paget's disease to provide improved insight for personalized, precision-based therapeutic options.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27394005
Mujgan Caliskan, Giovanna Gatti, Irina Sosnovskikh, Nicole Rotmensz, Edoardo Botteri, Simona Musmeci, Gabriela Rosali dos Santos, Giuseppe Viale, Alberto Luini
Paget's disease of the breast: the experience of the European Institute of Oncology and review of the literature.
Breast Cancer Res Treat. 2008 Dec;112(3):513-21. doi: 10.1007/s10549-007-9880-5. Epub 2008 Feb 1.
Abstract/Text BACKGROUND: Paget's disease of the breast is an uncommon presentation of breast malignancy, accounting for 1-3% of all the breast tumors and presents in different histopathologic patterns: in association with an underlying invasive or non invasive carcinoma, or without any underlying neoplasia. In the literature, different methods are used for the treatment. Mastectomy with or without axillary dissection has been considered as the standard treatment procedure for many years. Several studies have already shown that breast conservation with radiation therapy is an oncologically safe option. Regarding the axillary approach, several studies have documented the presence of positive sentinel lymph node even in Paget's disease alone. The objective of this study was to retrospectively analyze outcome of patients affected by Paget's breast disease and to define our institutional experience.
PATIENTS AND METHODS: Between May 1996 and February 2003, 114 patients with confirmed Paget's disease of the breast were retrieved and underwent surgery at the European Institute of Oncology of Milan, Italy. The median age of the patients was 54 years at the time of the diagnosis. In our study, the histopathological examination of the operated specimen revealed one hundred seven patients with Paget's disease associated with an underlying invasive or non invasive carcinoma, and seven patients without underlying carcinoma. Patients underwent either conservative breast surgery or mastectomy, with or without sentinel lymph node biopsy and/or axillary surgery. Each patient was evaluated after surgery at a multidisciplinary meeting to selecting systemic therapy.
RESULTS: Seven patients had "pure" Paget's disease of the breast and one hundred seven had the disease associated with an underlying carcinoma. As surgical techniques 71 mastectomies and 43 breast conserving surgeries have been performed. Complete axillary dissection was done in patients with clinically positive lymph node and/or sentinel lymph node biopsy positive. Sentinel lymph node biopsy was performed in nineteen patients with invasive component and five were positive and underwent axillary dissection. Eleven sentinel lymph node biopsies were done in patients with non invasive component and none of them was positive. Adjuvant systemic therapies were based on the final tumor, node and metastasis stage: thirty patients received adjuvant chemotherapy alone, fourteen received endocrine treatment alone, twenty-six patients were evaluated to receive both chemo and endocrine therapy. The median duration of follow up was 73 months and was updated in the last 6 months. Five patients developed local recurrence, one had regional recurrence, another two had loco-regional recurrences and fourteen had distant metastasis as a first event. Malignancy-related deaths were censored in the statistical analyses cancer for and due to another tumor in eleven patients. Additionally, deaths were not related to malignancy totally in thirteen patients.
CONCLUSIONS: Screening examination and imaging techniques are fundamental. Breast conserving surgery combined with breast irradiation for patients with invasive and non invasive breast carcinoma has become the treatment of first choice. All surgical conservative approaches should include the complete nipple-areolar complex and margins of resected specimen free of tumor. Thanks to the evolution of the conservative approach, good cosmetic result can be obtained. To be informed about the axillary lymph node status and to avoid the patient to have a second surgical approach, sentinel lymph node biopsy should be performed.

PMID 18240020
G H Sakorafas, K Blanchard, M G Sarr, D R Farley
Paget's disease of the breast.
Cancer Treat Rev. 2001 Feb;27(1):9-18. doi: 10.1053/ctrv.2000.0203.
Abstract/Text Paget's disease of the breast is a rare disorder of the nipple-areola complex that is often associated with an underlying in situ or invasive carcinoma. A change in sensation of the nipple-areola, such as itching and burning, is a common presenting symptom. Objectively, eczematoid changes of the nipple-areola complex are common. The later stages of Paget's disease of the breast are characterized by ulceration and destruction of the nipple-areola complex. Eczematoid changes of the nipple-areola complex and persisting soreness or itching, without obvious reason, is a suspicious symptom for Paget's disease of the breast and calls for thorough evaluation, including mammography. Exfoliative cytology with demonstration of Paget's cells may be useful, but a negative finding does not exclude Paget's disease of the breast. Surgical biopsy is the diagnostic standard and therefore the diagnosis should always be confirmed by open (surgical) biopsy. The histogenesis of Paget's disease of the breast continues to be debated. The epidermotropic theory holds that Paget's cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis. According to the in situ transformation theory, the Paget's cells arise as malignant cells in the nipple epidermis independent from any other pathologic process within the breast parenchyma. This theory has been proposed to explain those cases in which there is no underlying mammary carcinoma or when there is a carcinoma remote from the nipple-areola complex. Each of these theories is plausible; however, treatment approaches differ markedly depending on the theory of histogenesis. Mastectomy has been considered the standard of care in the management of patients with Paget's disease of the breast. Nowadays, however, some patients with Paget's disease of the breast are candidates for breast-conserving therapy. Patients must be selected carefully on an individual basis. Until there is a better understanding of the relationship of Paget's disease of the breast to the underlying cancer the surgeon should understand the natural history and behaviour of this lesion and be aware of both the risks of under- and over-treating patients with Paget's disease of the breast.

Copyright 2001 Harcourt Publishers Ltd.
PMID 11237774
R K Gupta, J Simpson, C Dowle
The role of cytology in the diagnosis of Paget's disease of the nipple.
Pathology. 1996 Aug;28(3):248-50.
Abstract/Text Although rare, eczematous skin changes ascribed to Paget's disease of the nipple nevertheless warrant timely diagnosis. However this may occasionally be delayed due to a reluctance to proceed to traditional diagnostic techniques of wedge biopsy, surgical excision or punch biopsy. In this communication we describe 11 cases of unilateral mammary Paget's disease, in which an unequivocal cytodiagnosis was made from nipple scrapings. In five of these cases an underlying ductal carcinoma of the breast was simultaneously diagnosed by fine needle aspiration (FNA) cytology of a palpable breast lump. All 11 cases were subsequently proven histologically to be Paget's disease. Despite the fact that the use in dermatology of scrape smears and fine needle aspiration cytology remains somewhat unpopular, it is suggested that the screening of any eczematous skin change of the nipple should be considered using the simple, reliable and non-invasive technique of scrape cytology.

PMID 8912355
M E Lucarotti, J M Dunn, A J Webb
Scrape cytology in the diagnosis of Paget's disease of the breast.
Cytopathology. 1994 Oct;5(5):301-5.
Abstract/Text Eczema of the nipple is an important symptom presenting to the general surgeon in the out-patient department. The diagnosis of Paget's disease of the nipple has traditionally been made by incision biopsy necessitating at least a local anaesthetic. We present 14 patients with nipple skin change, in whom the technique of scrape cytology was used to identify patients with Paget's disease. In our series eight cases of Paget's disease were successfully identified by scrape cytology with no false negatives or positives. We suggest that this is a quick, easy, non-invasive method of screening eczema of the nipple in the out-patient clinic.

PMID 7529588
Francesco Sardanelli
Overview of the role of pre-operative breast MRI in the absence of evidence on patient outcomes.
Breast. 2010 Feb;19(1):3-6. doi: 10.1016/j.breast.2009.11.003.
Abstract/Text The role of pre-operative breast MRI is outlined on the basis of the existing evidence in favor of a superior capability in comparison with mammography and sonography to detect ipsilateral and contralateral malignant lesions and to evaluate the disease extent, including the extensive intraductal component associated with invasive cancers. Patients with a potential higher anticipated benefit from pre-operative MRI can be identified as those: with mammographically dense breasts; with a unilateral multifocal/multicentric cancer or a synchronous bilateral cancer already diagnosed at mammography and sonography; with a lobular invasive cancer; at high-risk for breast cancer; with a cancer which shows a discrepancy in size of >1 cm between mammography and sonography; or under consideration for partial breast irradiation. More limited evidence exists in favor of MRI for evaluating candidates for total skin sparing mastectomy or for patients with Paget's disease. Irrespective of whether the clinical team routinely uses preoperative MRI or not: women newly diagnosed with breast cancer should always be informed of the potential risks and benefits of pre-operative MRI; results of pre-operative MRI should be interpreted taking into account clinical breast examination, mammography, sonography and verified by percutaneous biopsy; MRI-only detected lesions require MR-guidance for needle biopsy and pre-surgical localization, and these should be available or potentially accessible if pre-operative MRI is to be implemented; total therapy delay due to pre-operative MRI (including MRI-induced work-up) should not exceed one month; changes in therapy planning resulting from pre-operative MRI should be decided by a multidisciplinary team.

Copyright (c) 2009 Elsevier Ltd. All rights reserved.
PMID 20159456
Kathrin A Frei, Harald M Bonel, Marie-Francoise Pelte, Nola M Hylton, Karen Kinkel
Paget disease of the breast: findings at magnetic resonance imaging and histopathologic correlation.
Invest Radiol. 2005 Jun;40(6):363-7.
Abstract/Text OBJECTIVES: The purpose of this article is to describe magnetic resonance imaging (MRI) findings in patients with Paget disease of the breast and to evaluate mammography and MRI of the breast in the diagnosis of associated breast cancer.
MATERIALS AND METHODS: Nine patients with biopsy-proven Paget disease of the nipple underwent preoperative mammography and MRI of the breast to evaluate underlying breast cancer. All patients underwent subsequent surgery. The patients' charts and imaging studies were retrospectively reviewed. Imaging findings were correlated to results of histopathology.
RESULTS: Histopathology confirmed Paget disease of the nipple in all 9 patients and diagnosed associated ductal carcinoma in situ (DCIS) in the retroareolar lactiferous ducts in 8 of 9 patients (88%). MRI showed abnormal nipple enhancement in these 8 patients with an ill-defined thickened nipple-areolar complex. DCIS elsewhere in the breast was diagnosed in 4 of 9 patients (45%) corresponding to nonfocal enhancement in all 4 patients at MRI of the breast (100%).
CONCLUSIONS: Paget disease of the breast associated with underlying DCIS can be diagnosed at MRI of the breast and therefore impact management decisions.

PMID 15905723
Mary Morrogh, Elizabeth A Morris, Laura Liberman, Kimberly Van Zee, Hiram S Cody, Tari A King
MRI identifies otherwise occult disease in select patients with Paget disease of the nipple.
J Am Coll Surg. 2008 Feb;206(2):316-21. doi: 10.1016/j.jamcollsurg.2007.07.046. Epub 2007 Oct 29.
Abstract/Text INTRODUCTION: For patients with Paget disease (PD) of the nipple, preoperative imaging to detect and evaluate the extent of an underlying malignancy can facilitate appropriate treatment planning. The purpose of this study was to evaluate the role of breast MRI in this setting.
STUDY DESIGN: Using ICD-9 codes for "breast symptoms," we identified 2,294 patients without a current cancer diagnosis seen at our institution (1995 to 2006). Sixty-nine patients (3%) had nipple changes suspicious for PD as the only physical finding. Skin/nipple biopsy confirmed PD in 39 of 69 (57%) patients. Thirty-four patients were eligible for review.
RESULTS: Surgical pathology identified cancer in 32 of 34 (94%) patients (7 invasive ductal carcinoma, 25 ductal carcinoma in situ). Nineteen (59%) cancers were confined to the central quadrant of the breast (unifocal). Preoperative imaging (mammography 34 of 34, MRI 13 of 34) detected 15 of 32 (49%) cancers. Mammography detected 11 cancers, accurately demonstrating extent of disease in 9 of 11 patients. MRI detected seven cancers, accurately demonstrating extent of disease in six of seven patients. After positive mammography (n = 11), MRI (n = 5) did not change management. After negative mammography (n = 23), MRI (n = 8) detected otherwise occult disease in 4 of 8 patients, accurately demonstrating extent of disease in 4 of 4 patients and ruling out an underlying cancer in 1 of 1 patient.
CONCLUSIONS: Ninety-four percent of patients with biopsy-proved PD as the only physical finding had an underlying cancer and 59% had unifocal disease. Negative preoperative imaging did not reliably exclude an underlying cancer, but the increased sensitivity of MRI detected otherwise occult disease. In the setting of negative mammography, MRI can facilitate treatment planning for patients with PD.

PMID 18222386
Giampiero Capobianco, Bernardino Spaliviero, Salvatore Dessole, Pier Luigi Cherchi, Vincenzo Marras, Guido Ambrosini, Francesco Meloni, Giovanni Battista Meloni
Paget's disease of the nipple diagnosed by MRI.
Arch Gynecol Obstet. 2006 Aug;274(5):316-8. doi: 10.1007/s00404-006-0160-0. Epub 2006 Apr 19.
Abstract/Text BACKGROUND: Paget's disease of the breast is a rare manifestation of breast carcinoma.
CASE REPORT: The patient presented with a red lesion of the left nipple-areola complex. Breast physical examination, ultrasonography and mammography were normal bilaterally. Magnetic resonance imaging (MRI) correctly depicted Paget's disease of the nipple. Before surgery the patient underwent biopsy of the lesion that showed Paget's disease of the breast associated with an underlying ductal carcinoma in situ. The patient underwent left mastectomy and unilateral axillary lymph node dissection. The patient refused the breast-conserving surgery because she was afraid that she could have a recurrence of the carcinoma. Microscopy of the lesion confirmed the MRI diagnosis.
CONCLUSION: MRI was very useful and accurate to diagnose Paget's disease of the breast without palpable mass, ultrasonographic and mammographic findings.

PMID 16622685
Goro Amano, Mioko Yajima, Yasunori Moroboshi, Yoshiki Kuriya, Noriaki Ohuchi
MRI accurately depicts underlying DCIS in a patient with Paget's disease of the breast without palpable mass and mammography findings.
Jpn J Clin Oncol. 2005 Mar;35(3):149-53. doi: 10.1093/jjco/hyi044.
Abstract/Text Breast-conserving therapy must be carefully indicated among patients with Paget's disease of the breast, because the disease is often associated with an underlying in situ or invasive carcinoma, even when there are no palpable mass or mammography findings. We report a 52-year-old woman who complained of skin color change of her right nipple for 11 months. No mass was palpable in her breasts, and mammography did not show any density or calcification. Nipple biopsy revealed Paget's disease of the breast with ductal carcinoma in situ (DCIS) in the breast epithelium just beneath the nipple. Magnetic resonance imaging (MRI) of the breast demonstrated diffuse segmental enhancement in two different quadrants. According to the pattern of enhancement, the lesions depicted by MRI were diagnosed as an extensively spreading type of DCIS. Based on informed consent, the patient received a total mastectomy. The histopathological examination demonstrated non-invasive ductal carcinoma with comedo-necrosis. The histological mapping with subserial sectioning demonstrated an extent of the lesions that corresponded accurately to the lesions defined by MRI. We conclude that MRI may play an important role in selecting candidates for breast-conserving therapy out of those patients with mammary Paget's disease with no clinical evidence of an underlying breast carcinoma.

PMID 15741305
Elina Siponen, Katja Hukkinen, Päivi Heikkilä, Heikki Joensuu, Marjut Leidenius
Surgical treatment in Paget's disease of the breast.
Am J Surg. 2010 Aug;200(2):241-6. doi: 10.1016/j.amjsurg.2009.07.044.
Abstract/Text BACKGROUND: The aim of this study was to evaluate the outcomes of surgical treatment of Paget's disease of the breast, with special emphasis on magnetic resonance imaging (MRI) and sentinel node biopsy (SNB).
METHODS: The study included 58 consecutive patients with Paget's disease treated from 1995 to 2006.
RESULTS: Twenty-five patients had ductal carcinoma in situ, and 31 had invasive carcinoma. MRI was performed in 14 patients, with positive findings in 7 patients, 5 of whom had negative findings on conventional imaging. The overall mastectomy rate was 76%. Eighteen patients underwent SNB, and 26 patients underwent full or partial axillary clearance. Fourteen patients had no axillary surgery. One patient had local recurrence after breast conservation, and another had axillary recurrence after negative results on SNB. Six patients had distant metastases. Four patients died of breast cancer.
CONCLUSIONS: Paget's disease is frequently associated with peripheral or multicentric cancer. MRI may be helpful when considering breast conservation or omitting axillary nodal staging.

2010 Elsevier Inc. All rights reserved.
PMID 20678619
Hyeon Sook Kim, Jee Hyun Seok, Eun Suk Cha, Bong Joo Kang, Hak Hee Kim, Young Jin Seo
Significance of nipple enhancement of Paget's disease in contrast enhanced breast MRI.
Arch Gynecol Obstet. 2010 Aug;282(2):157-62. doi: 10.1007/s00404-009-1244-4. Epub 2009 Oct 17.
Abstract/Text PURPOSE: To evaluate significance of nipple enhancement of Paget's disease in contrast enhanced (CE) breast MRI.
METHODS: Ten patients of biopsy proven Paget's disease were included in this study. Preoperative mammogram and ultrasonogram (US) were obtained in all 10 patients, and 8 patients underwent CE breast MRI prior to surgery. Mammographic and US findings were reviewed retrospectively. On MRI, morphology (flattening or asymmetry or thickening) and enhancement of pathologically involved nipple were analyzed comparing with the opposite side, and also reviewed the abnormal enhancing lesion in the breast parenchyma.
RESULTS: Morphologic changes of the nipple were detected in 2 out of 10 patients by mammogram and 6 out of 10 patients by US. On MRI, morphologic change was also revealed in 7 patients and abnormal enhancement of involved nipple was observed in all 8 patients. Associated parenchymal enhancing lesions were proved to be DCIS (7 out of 10) and invasive ductal carcinoma (2 out of 10). Remaining one patient had no underlying breast parenchymal malignancy.
CONCLUSION: CE breast MRI allows for the correct detection of nipple involvement of Paget's disease even when clinical information or mammographic/US findings are not provided.

PMID 19838723
Elizabeth Marcus
The management of Paget's disease of the breast.
Curr Treat Options Oncol. 2004 Apr;5(2):153-60.
Abstract/Text Paget's disease of the breast is a relatively rare condition, accounting for 1% to 3% of primary breast cancers. It is associated with an underlying carcinoma, invasive or noninvasive (ductal carcinoma in situ), in most of the cases. Primary treatment is surgical with adjuvant therapy being dictated by the stage and nature of the underlying tumor. Modified radical mastectomy is the standard of care with breast conservation appropriate in a select group of patients with Paget's disease. This select group includes patients that are diagnosed with nipple-areola changes alone without evidence of a palpable mass or mammographic abnormality. In this group of patients, breast conservation offers local recurrence rates comparable to rates in patients with invasive or noninvasive cancers. In patients diagnosed with associated palpable masses or mammographic abnormalities suggestive of cancer, the recurrence rates are higher and mastectomy is warranted.

PMID 14990209
N Bijker, E J Rutgers, L Duchateau, J L Peterse, J P Julien, L Cataliotti, EORTC Breast Cancer Cooperative Group
Breast-conserving therapy for Paget disease of the nipple: a prospective European Organization for Research and Treatment of Cancer study of 61 patients.
Cancer. 2001 Feb 1;91(3):472-7.
Abstract/Text BACKGROUND: The purpose of the current study was to assess the outcome of breast-conserving therapy by means of a cone excision and radiotherapy in patients with Paget disease of the nipple without associated invasive breast carcinoma.
METHODS: Between 1987 and 1998, 61 eligible patients were registered in the European Organization for Research and Treatment of Cancer Study 10873. The majority of patients (97%) presented without an associated palpable mass. At histologic examination, the majority (93%%) of patients had an underlying ductal carcinoma in situ (DCIS); in the remaining 7%, only Paget disease was found. Treatment was comprised of a complete excision of the nipple-areolar complex including the underlying breast tissue with tumor free margins, followed by external irradiation to the whole breast (50 gray in 25 fractions). The primary endpoint was local recurrence.
RESULTS: At a median follow-up of 6.4 years, 4 of the 61 patients developed a recurrence in the treated breast (1 patient with DCIS and 3 patients with invasive disease). One patient with an invasive local recurrence died of disseminated breast carcinoma. The 5-year local recurrence rate was 5.2% (95% confidence interval, 1.8-14.1%).
CONCLUSIONS: Breast-conserving therapy is a feasible alternative for patients with Paget disease and a limited extent of underlying DCIS. To achieve good local control, treatment should be comprised of a complete excision of the nipple-areolar complex including the underlying disease, followed by irradiation to the whole breast.

Copyright 2001 American Cancer Society.
PMID 11169928
Abstract/Text
PMID 11920556
Jennifer K Marshall, Kent A Griffith, Bruce G Haffty, Lawrence J Solin, Frank A Vicini, Beryl McCormick, David E Wazer, Abram Recht, Lori J Pierce
Conservative management of Paget disease of the breast with radiotherapy: 10- and 15-year results.
Cancer. 2003 May 1;97(9):2142-9. doi: 10.1002/cncr.11337.
Abstract/Text BACKGROUND: At 5-year follow-up, patients with Paget disease of the breast who were treated with breast-conserving surgery (BCS) and radiotherapy (RT) had excellent results. The current report provides 10- and 15-year rates of tumor control in the breast, as well as disease-free and overall survival rates following BCS and RT in a cohort of patients with Paget disease presenting without a palpable mass or mammographic density.
METHODS: Through a collaborative review of patients treated with BCS and RT from seven institutions, 38 cases of Paget disease of the breast presenting without a palpable mass or mammographic density were identified. All patients had pathologic confirmation of typical Paget cells at time of diagnosis. Thirty-six of 38 patients had a minimum follow-up greater than 12 months and constitute the study cohort. Ninety-four percent of patients underwent complete or partial excision of the nipple-areola complex and all patients received a median external beam irradiation dose of 50 Gy (range, 45-54 Gy) to the whole breast. Ninety-seven percent of patients also received a boost to the remaining nipple or tumor bed, a median total dose of 61.5 Gy (range, 50.4-70 Gy).
RESULTS: With median follow-up of 113 months (range, 18-257 months), 4 of 36 patients (11%) developed a first recurrence of disease in the treated breast only. Two of the four recurrences in the breast were ductal carcinoma in situ (DCIS) only and two were invasive with DCIS. Two additional patients had a recurrence in the breast as a component of first failure. Actuarial local control rates for the breast as the only site of first recurrence were 91% at 5 years (95% confidence interval [CI], 80-100%) and 87% (95% CI, 75-99%) at both 10 and 15 years. Actuarial local control rates for breast recurrence, as a component of first failure, were 91% (95% CI, 80-100%), 83% (95% CI, 69-97%), and 76% (95% CI, 58-94%) at 5, 10, and 15 years, respectively. No clinical factors were identified as significant predictors for breast recurrence. Five-, 10- and 15-year actuarial rates for survival without disease of 97% (95% CI, 90-100%) and 5-, 10-, and 15-year actuarial rates of overall survival of 93% (95% CI, 84-100%) at 5 years and 90% (95% CI, 78-100%) at 10 and 15 years were reported.
CONCLUSIONS: These data confirm excellent rates of local control, disease-free survival, and overall survival at 10 and 15 years following BCS and RT for Paget disease of the breast. This study continues to support the recommendation of local excision and definitive breast irradiation as an alternative to mastectomy in the treatment of patients with Paget disease presenting without a palpable mass or mammographic density.

Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11337
PMID 12712465
Kristina Dalberg, Henrik Hellborg, Fredrik Wärnberg
Paget's disease of the nipple in a population based cohort.
Breast Cancer Res Treat. 2008 Sep;111(2):313-9. doi: 10.1007/s10549-007-9783-5. Epub 2007 Oct 19.
Abstract/Text BACKGROUND: Paget's disease of the nipple is a rare form of breast cancer characterised by the presence of intraepidermal tumour cells. It is often associated with ductal carcinoma in situ (DCIS) and/or invasive cancer in the breast parenchyma. We have studied the presentation and symptoms of Paget's disease, local control and breast cancer corrected survival following breast conserving surgery or mastectomy.
PATIENTS AND METHODS: The study is based on 223 women with histological verified Paget's disease of the nipple diagnosed between 1976 and 2001 at 13 Swedish hospitals. All women s charts were reviewed. All recurrences and deaths were registered. A comparison was made for differences in breast cancer-corrected survival (BCS) and disease-free survival (DFS) in univariate analyses.
RESULTS: The median follow-up was 12 (4-28) years. In a vast majority (98%), the main presenting symptom was eczema or ulceration of the nipple. The diagnosis of an underlying breast malignancy was established in 79% of the women before surgery. A cone excision of the nipple-areola complex was performed in 43 women and 169 women had a mastectomy. Eleven elderly women were not operated. One hundred and seventeen women had a non-invasive Paget of which 40 had an underlying DCIS. Invasive cancer was seen in 68 women. In 38 cases the histopathological report did not state if the tumour was invasive or not. Thirty-three women died from breast cancer. In operated women BCS and DFS at 10 years were 87% and 82%, respectively. The 10-year BCS for non-operated patients (n = 11) was 34%. At 10 years, the cumulative local recurrence rate was 9%, 8% among women undergoing mastectomy and 16% among those treated with breast conserving surgery. In univariate analysis the type of surgery, cone excision or mastectomy, had no statistically significant impact on BCS or DFS. Risk factors for breast cancer death and recurrence were having an underlying invasive cancer compared with an in situ carcinoma and having a palpable tumour in the breast.
CONCLUSION: The main presenting symptoms were eczema or ulceration of the nipple. Patients with non invasive Pagets disease of the nipple had an excellent cancer outcome. Selected patients with Paget's disease of the nipple were treated with breast conserving surgery with survival rates similar to those achieved with mastectomy.

PMID 17952590
Kazumi Kawase, Dominick J Dimaio, Susan L Tucker, Thomas A Buchholz, Merrick I Ross, Barry W Feig, Henry M Kuerer, Funda Meric-Bernstam, Gildy Babiera, Frederick C Ames, S Eva Singletary, Kelly K Hunt
Paget's disease of the breast: there is a role for breast-conserving therapy.
Ann Surg Oncol. 2005 May;12(5):391-7. doi: 10.1245/ASO.2005.05.026. Epub 2005 Mar 29.
Abstract/Text BACKGROUND: The optimal surgical management of Paget's disease of the breast remains to be defined. Mastectomy has been the standard of care, but several institutions have recently advocated breast-conserving surgery, particularly for patients with minimal disease. In an effort to develop rational treatment guidelines, we examined our institutional experience with Paget's disease of the breast.
METHODS: Patients with Paget's disease of the breast who had surgical therapy at our institution between 1949 and 1993 were reviewed. In addition to patient and tumor characteristics, charts were reviewed for treatment modalities, locoregional recurrence patterns, and survival. Subgroups were compared for differences in survival in both univariate and multivariate analyses.
RESULTS: A total of 104 patients met the study criteria. The most common presenting symptoms were nipple discharge and eczematous changes of the nipple/areola complex. Ninety-seven patients (93.2%) had an underlying invasive or noninvasive cancer associated with Paget's disease. Ninety-two patients (88.5%) underwent mastectomy, and 12 (11.5%) had a breast-conserving procedure. On univariate analysis, patients with age <60 years at diagnosis, stage II disease, positive lymph nodes, invasive disease, or a palpable mass had significantly lower 10-year disease-specific and recurrence-free survival. There were four locoregional recurrences (three after mastectomy and one after breast conservation). There were no significant differences in overall, disease-specific, or recurrence-free survival according to the type of surgery.
CONCLUSIONS: Paget's disease of the breast is almost always associated with an underlying breast cancer. Breast-conserving approaches result in local control and survival rates similar to those achieved with mastectomy.

PMID 15915373
L J Pierce, B G Haffty, L J Solin, B McCormick, F A Vicini, D E Wazer, A Recht, M Strawderman, A S Lichter
The conservative management of Paget's disease of the breast with radiotherapy.
Cancer. 1997 Sep 15;80(6):1065-72.
Abstract/Text BACKGROUND: The purpose of this study was to evaluate the feasibility of breast-conserving therapy involving limited surgery and definitive radiotherapy as a treatment for Paget's disease, and to determine the disease free and overall survival associated with this approach.
METHODS: The authors retrospectively reviewed the charts of all patients treated during the period 1980-1994 for Paget's disease of the breast who did not present with a palpable mass or mammographic density. Through a collaborative review, 30 cases were identified. A biopsy confirming the presence of typical Paget's cells was performed on all patients. All patients received external beam radiotherapy to the breast, with a median dose of 50 gray (Gy). Ninety-seven percent received a boost to the remaining nipple or tumor bed, with a median dose to the tumor bed of 61.5 Gy.
RESULTS: The median follow-up for surviving patients was 62 months. Three patients (10%) developed a recurrence in the breast as the only site of first failure, and 2 additional patients (7%) experienced failure in the breast as a component of first failure. The median time to local failure was 69 months. The 5- and 8-year actuarial estimates of local failure as the only site of first failure were 9% (95% confidence interval [CI], 0-20%) and 16% (95% CI, 0-31%), respectively. Of the 5 patients with local failures, 3 were among 22 patients (14%) who underwent complete resection of the nipple or nipple-areola complex, compared with 2 failures among 6 patients (33%) after partial resection (P = 0.29). There were no failures among 2 patients who had a biopsy only. Four of 5 local failures were salvaged by mastectomy, and 3 of these patients were free of disease after a median follow-up of 52 months. The 5- and 8-year estimates of disease free survival for the overall series were both 95% (95% CI, 87-100%); cause specific overall survival was 100% at 8 years.
CONCLUSIONS: Breast-conserving therapy involving complete resection of the nipple-areola complex followed by definitive radiotherapy is a viable alternative to mastectomy in the treatment of Paget's disease. High rates of disease free and cause specific survival, in addition to adequate local control, justify consideration of a conservative approach.

PMID 9305706
Seema Seetharam, Ian S Fentiman
Paget's disease of the nipple.
Womens Health (Lond Engl). 2009 Jul;5(4):397-402. doi: 10.2217/whe.09.23.
Abstract/Text Paget's disease of the nipple is an unusual epidermal presentation of underlying breast cancer. It presents as eczematous change or erythematous ulceration, but may also be an incidental histological finding in a mastectomy specimen. Approximately half of the underlying cancers are invasive, the remainder being ductal carcinoma in situ, and only rarely is there no associated malignancy. Routine clinical and mammographic assessment may significantly underestimate the extent of disease, but MRI may increase the sensitivity in detecting occult malignancy. Mastectomy maximizes local control; however, selected cases can be treated by nipple conisation with radiotherapy. Sentinel node biopsy is the standard of care for axillary staging in the clinically and ultrasonically node-negative case. Almost all invasive cases overexpress human EGF receptor-2 and, therefore, are likely to benefit from adjuvant chemotherapy and herceptin.

PMID 19586431
S Helme, K Harvey, A Agrawal
Breast-conserving surgery in patients with Paget's disease.
Br J Surg. 2015 Sep;102(10):1167-74. doi: 10.1002/bjs.9863. Epub 2015 Jul 14.
Abstract/Text BACKGROUND: Paget's disease of the breast is a rare condition that is associated with underlying breast cancer in the majority of patients. The conventional treatment for Paget's disease has been mastectomy, but there is an increasing trend to consider breast-conserving surgery (BCS) in selected patients. Owing to the uncommon nature of the disease, research studies tend to be small and retrospective. This systematic review presents the published evidence regarding BCS for patients with Paget's disease with a focus on patient selection and oncological safety.
METHODS: A search of Ovid and PubMed databases was conducted to identify all papers published regarding BCS for Paget's disease.
RESULTS: The search identified 172 papers of which 43 were clinically relevant. BCS is a safe alternative to mastectomy, provided a clear surgical margin is achieved and adjuvant radiotherapy used. However, patients with Paget's disease should be assumed to have underlying breast cancer, and these cancers tend to have poor biological profiles. When BCS is considered, careful preoperative investigation should be undertaken to identify the presence and extent of an underlying cancer. These cancers can be mammographically occult, multifocal or multicentric. Although the evidence is limited, there may be a role for MRI in selecting patients with Paget's disease for BCS.
CONCLUSION: Patients with Paget's disease are candidates for breast conservation with appropriate preoperative investigations. Oncological outcomes are equivalent to those of mastectomy if surgical margins are achieved and adjuvant radiotherapy is given.

© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.
PMID 26175231
Yufeng Yao, Li Sun, Yan Meng, Yan Zhuang, Lin Zhao, Qiao Yu, Chengshuai Si
Breast-Conserving Surgery in Patients With Mammary Paget's Disease.
J Surg Res. 2019 Sep;241:178-187. doi: 10.1016/j.jss.2019.03.025. Epub 2019 Apr 24.
Abstract/Text BACKGROUND: We aimed to analyze the association between Paget's disease (PD) and breast cancer (BC) subtypes and compare the effect of breast-conserving surgery (BCS) as a local treatment with mastectomy for PD.
MATERIALS AND METHODS: Data of patients with histologic type International Classification of Diseases-0-3 8540-8543 who were treated from 1973 to 2014 were retrieved from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute. A chi-square test was used to identify differences in categorical data among different groups. Overall survival (OS) was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, sequential landmark analysis, and propensity score-matched analysis.
RESULTS: The study cohort included 5398 patients. Triple-negative BC accounted for the fewest patients with PD-only (1/22, 4.54%), Paget's disease-ductal carcinoma in situ (PD-DCIS) (3/48, 6.25%), and Paget's disease-invading ductal carcinoma (PD-IDC) (23/352, 6.53%). According to the results of the log-rank test and Cox analysis, the 10-year OS rates were similar for the BCS and mastectomy subgroups among patients with PD-DCIS or PD-IDC. Furthermore, there were no significant differences in survival benefits among the different surgeries after propensity score matching. Landmark analyses for OS of patients with PD-DCIS or PD-IDC surviving more than 1, 3, and 5 y showed no significant differences in survival. There were statistical differences in 10-year OS rates for patients with PD-DCIS or PD-IDC who underwent radiation therapy, or not, following BCS (both, P < 0.001).
CONCLUSIONS: For patients with PD-DCIS or PD-IDC, breast conservation therapy with lumpectomy and radiation is an effective local treatment strategy, compared with mastectomy.

Copyright © 2019 Elsevier Inc. All rights reserved.
PMID 31026796
A Fourquet, F Campana, P Vielh, P Schlienger, D Jullien, J R Vilcoq
Paget's disease of the nipple without detectable breast tumor: conservative management with radiation therapy.
Int J Radiat Oncol Biol Phys. 1987 Oct;13(10):1463-5.
Abstract/Text Between 1960 and 1984, 20 selected patients with Paget's disease of the breast confined to the nipple were treated conservatively with radiotherapy alone (17/20 pts) or limited surgery and radiotherapy (3/20 pts). Median follow-up was 7.5 years. No patients died of breast disease. Three patients had recurrence in the treated breast, and were treated by mastectomy. All recurrences were located in the nipple or areola and were all Paget's disease, without associated intraductal or invasive carcinoma. No axillary node recurrences occurred. The actuarial 7-year probability of living free of disease with breast preserved was 81%. Among the 15 patients who had a minimum follow-up of 3 years, without recurrence, 12 (80%) had a good cosmetic result. These results suggest that radiation therapy could be an effective alternative to radical surgery in the treatment of patients with Paget's disease of the nipple without concomitant breast tumor.

PMID 3040645
A D Stockdale, J D Brierley, W F White, A Folkes, A Y Rostom
Radiotherapy for Paget's disease of the nipple: a conservative alternative.
Lancet. 1989 Sep 16;2(8664):664-6.
Abstract/Text The case records of 28 patients with Paget's disease of the nipple treated by radio-therapy alone were reviewed retrospectively. 16 of 19 patients who had no palpable underlying tumour and who were mammographically normal at the time of original treatment remain free of disease with a median follow-up of 5 years 3 months. In this selected group, radical radiotherapy with small fields localised to the involved skin is an effective alternative to mastectomy.

PMID 2570909
Christine Laronga, Danielle Hasson, Susan Hoover, John Cox, Alan Cantor, Charles Cox, W Bradford Carter
Paget's disease in the era of sentinel lymph node biopsy.
Am J Surg. 2006 Oct;192(4):481-3. doi: 10.1016/j.amjsurg.2006.06.023.
Abstract/Text BACKGROUND: Paget's disease of the breast is an uncommon cancer. "Breast cancer" management has evolved to include sentinel lymph node biopsy (SLNB). Our objective is to determine utilization of SLNB in the surgical algorithm of Paget's disease.
METHODS: After institutional review board approval, a database review of patients with Paget's disease was conducted. Patient demographics, tumor characteristics, treatment including use of SLNB, and survival were reviewed. Patient characteristics and outcomes were analyzed by using contingency table chi-square, pooled t tests, and log-rank tests for comparisons.
RESULTS: Fifty-four patients with Paget's disease were identified and divided into 2 cohorts (18 no SLNB and 36 SLNB). The mean age was 66 years for the no-SLNB group and 60 years for the SLNB group (P = .17). Paget's disease only was present in 33%, Paget's disease + DCIS in 41%, and Paget's disease + invasive cancer in 26%. The mean invasive tumor size was 1.62 cm in the no-SLNB group and 1.59 cm in the SLNB group (P = .96). For invasive disease, ER/PR status was similar, but Her2 was more likely to be overexpressed in SLNB (P = .04). Surgery choice ranged from "no surgery" to lumpectomy to mastectomy. Axillary staging was performed in 45 of 54 patients, with 11% in both cohorts having nodal disease. A sentinel lymph node was identified in 97% of patients. Five-year overall and disease-free survival was 100% in the no-SLNB group and 88% in the SLNB group (P = .97) and 76% in the no-SLNB group and 84% in the SLNB group (P = .88), respectively.
CONCLUSIONS: Paget's disease remains rare but should be treated similar to other "breast cancer." SLNB should be performed to evaluate the axilla when invasive disease is identified or a mastectomy is planned.

PMID 16978954
P Sukumvanich, D J Bentrem, H S Cody, E Brogi, J V Fey, P I Borgen, M L Gemignani
The role of sentinel lymph node biopsy in Paget's disease of the breast.
Ann Surg Oncol. 2007 Mar;14(3):1020-3. doi: 10.1245/s10434-006-9056-2.
Abstract/Text BACKGROUND: Sentinel lymph node (SLN) biopsy has become a standard of care for axillary lymph node staging in breast cancer and appears suitable for virtually all patients with clinically node-negative (cN0) invasive disease. However, its role in Paget's disease of the breast, a condition in which invasion may or may not be present, remains undefined.
METHODS: Among 7,083 consecutive SLN biopsy procedures, we retrospectively identified 39 patients with Paget's disease of the breast. Nineteen patients had no associated clinical/radiographic features ("Paget's only"), and 20 patients had associated clinical/radiographic findings ("Paget's with findings").
RESULTS: The mean ages for the Paget's alone and with findings groups were 63.6 and 49.6 years, respectively. The use of breast conservation therapy was 32% in the Paget's alone group and 10% in the Paget's with findings group. Invasive carcinoma was found in 27% of patients in the Paget's alone group and 55% of patients in the Paget's with findings group. The success rate of SLN biopsy was 98%, and the mean number of SLNs removed was 3 in both groups. In the entire cohort of Paget's disease, 28% (11/39) of the patients had positive SLNs (11%, Paget's alone; 45%, Paget's with findings).
CONCLUSION: In our "Paget's only" cohort, invasive cancer was found in 27% of cases and positive SLNs in 11%. SLN biopsy should be considered in all patients with Paget's disease of the breast, whether associated clinical/radiographic findings are present.

PMID 17195914

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