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) がん研有明病院 乳腺センター

著者: 岩瀬拓士2) 名古屋第一赤十字病院 乳腺・内分泌外科

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:2019/02/07
患者向け説明資料

概要・推奨   

疾患のポイント:
  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、乳頭の変化は1点の乳管口を中心として円状に広がり()、進行すると乳輪部皮膚に進展し、乳頭が平坦化する()。
  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。
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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。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
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。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(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[2021年]
岩瀬拓士 : 特に申告事項無し[2021年]
監修:中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]

改訂のポイント:
  1. 乳癌取り扱い規約 第18版
  1. 2015年次 乳癌登録集計結果
に基づき改訂を行った。

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。
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 

著者: Stephanie M Wong, Rachel A Freedman, Emily Stamell, Yasuaki Sagara, Jane E Brock, Stephen D Desantis, Mehra Golshan
雑誌名: 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  Ann Surg Oncol. 2015 Oct;22(10):3308-16. doi: 10.1245/s・・・
著者: Piotr Sek, Antoni Zawrocki, Wojciech Biernat, Janusz H Piekarski
雑誌名: 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  Histopathology. 2010 Oct;57(4):564-71. doi: 10.1111/j.1・・・
著者: Joseph M Anderson, Reshma Ariga, Hema Govil, Kenneth J Bloom, Darius Francescatti, Vijaya B Reddy, Victor E Gould, Paolo Gattuso
雑誌名: 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  Appl Immunohistochem Mol Morphol. 2003 Jun;11(2):120-4.・・・
著者: Elżbieta Marczyk, Anna Kruczak, Aleksandra Ambicka, Katarzyna Mularz, Agnieszka Harazin-Lechowska, Julia Moskal, Andrzej Sokołowski, Jerzy Mituś, Janusz Ryś
雑誌名: 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  Pol J Pathol. 2011 Dec;62(4):229-35.
著者: David L Wachter, Peter W Wachter, Peter A Fasching, Matthias W Beckmann, Carolin C Hack, Marc-Oliver Riener, Arndt Hartmann, Johanna D Strehl
雑誌名: 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  Arch Pathol Lab Med. 2018 Aug 20;. doi: 10.5858/arpa.20・・・
著者: Mujgan Caliskan, Giovanna Gatti, Irina Sosnovskikh, Nicole Rotmensz, Edoardo Botteri, Simona Musmeci, Gabriela Rosali dos Santos, Giuseppe Viale, Alberto Luini
雑誌名: 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  Breast Cancer Res Treat. 2008 Dec;112(3):513-21. doi: 1・・・
著者: G H Sakorafas, K Blanchard, M G Sarr, D R Farley
雑誌名: 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  Cancer Treat Rev. 2001 Feb;27(1):9-18. doi: 10.1053/ctr・・・

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