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乳房外パジェット病

著者: 吉野公二 がん・感染症センター 都立駒込病院 皮膚腫瘍科

監修: 戸倉新樹 掛川市・袋井市病院企業団立 中東遠総合医療センター 参与/浜松医科大学 名誉教授

著者校正/監修レビュー済:2021/05/19
参考ガイドライン:
日本皮膚科学会 :皮膚悪性腫瘍ガイドライン 第3版 乳房外パジェット病診療ガイドライン2021
患者向け説明資料

概要・推奨   

  1. 外尿道口周囲、腟壁から膣前庭部、肛門周囲を中心に乳房外パジェット病変を認める患者には、続発性乳房外パジェット病の可能性があるため、膀胱鏡、婦人科的診察、直腸肛門鏡などによる精査が勧められる(推奨度1)。
  1. 原発性と続発性乳房外パジェット病との組織学的鑑別には、サイトケラチン20(CK20)とGCDFP15 の免疫組織化学的検索が勧められる(推奨度1)。
  1. 皮疹の境界が不明瞭な乳房外パジェット病に対しては、術前にマッピング生検を考慮してもよい(推奨度1)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
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:
吉野公二 : 講演料(小野薬品,ノバルティスファーマ)[2021年]
監修:戸倉新樹 : 講演料(田辺三菱,サノフィ,マルホ,協和キリン),研究費・助成金など(ノバルティス,レオファーマ)[2021年]

改訂のポイント:
  1. GRADE systemを用い、前半に総論、後半にClinical Questionを記述している。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 乳房外パジェット病は外陰部に好発する表皮内癌であり<図表><図表>、その他肛門<図表>、腋窩<図表>にも発生する。
 
女性の外陰部乳房外パジェット病

出典

 
男性の外陰部乳房外パジェット病

出典

 
肛門部の乳房外パジェット病

肛門部に発生した乳房外パジェット病

出典

img1:  著者提供
 
 
 
腋窩の乳房外パジェット病

腋窩の境界明瞭な紅斑。乳房外パジェット病を知らなければ、見過ごしてしまうような病変である。

出典

img1:  著者提供
 
 
 
  1. 高齢者に好発し、人口高齢化に伴って患者が増加傾向にあり、当初より手術不能な超高齢患者も多くなっている。
  1. 臨床的に陰部湿疹<図表>、真菌症(白癬<図表>、カンジダ症)と誤診されやすく、不適切な外用治療が漫然と続けられているケースが多い。
  1. 表皮内癌の状態で長年にわたって緩徐に発育するが、1度浸潤を来すと高率にリンパ行性、血行性転移を来し、予後不良である。
  1. 子宮・腟、膀胱、肛門・直腸などの内部臓器の癌が皮膚に波及して、原発性の乳房外パジェット病と類似した症状を示すことがある(パジェット現象)。その場合は続発性乳房外パジェット病として明確に区別する。
 
  1. 外尿道口周囲、腟壁から膣前庭部、肛門周囲を中心に乳房外パジェット病変を認める患者には、続発性乳房外パジェット病の可能性があるため、膀胱鏡、婦人科的診察、直腸肛門鏡などによる精査が勧められる(推奨度1J)。
  1. 隣接臓器癌が表皮内を進展して皮膚側に病巣を形成する病態を続発性乳房外パジェット病と呼ぶ。膀胱移行上皮癌は外尿道口周囲に、子宮頸癌・腟癌は腟前庭部に、直腸・肛門管癌は肛門周囲に続発性乳房外パジェット病を認めることがある[1][2]。原発性とは治療内容や予後が著しく異なるため[3]、続発性が疑われる場合には隣接臓器の精査は必須である。
 
  1. 原発性と続発性乳房外パジェット病との組織学的鑑別には、サイトケラチン20(CK20)とGCDFP15 の免疫組織化学的検索が勧められる(推奨度1J)。
  1. 免疫組織化学的に原発性乳房外パジェット病はGCDFP15陽性[4]、CK20陰性[5][6]であることが知られている。直腸癌[5][7]、膀胱移行上皮癌[6][8]の続発性乳房外パジェット病ではGCDFP15陰性、CK20陽性であるため、原発性との鑑別に役立つとされる。しかし、逆の染色パターンを示す症例の報告もあるので結果の解釈には注意を要する[5][6]
問診・診察のポイント  
  1. 初期は軽微な紅斑ないし脱色素斑として始まり、徐々に拡大するにつれて湿潤・びらんを来し、瘙痒や違和感を伴う。

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文献 

著者: J J Chanda
雑誌名: J Am Acad Dermatol. 1985 Dec;13(6):1009-14.
Abstract/Text Extramammary Paget's disease is a rare cutaneous adenocarcinoma, usually of epidermal origin and glandular differentiation and frequently associated with an underlying adnexal carcinoma and perhaps with underlying internal malignancy. One hundred ninety-seven cases of extramammary Paget's disease (196 cases reported in the English literature from 1962 to 1982 and one case of my own) are reviewed. It remains a rare cutaneous malignancy that occurs primarily in elderly people. It is seen more frequently in women than in men and occurs predominantly in vulvar and perianal locations. Twenty-six percent of patients with this disease will ultimately die of it or an associated internal malignancy. Twenty-four percent of patients with the disease have an associated underlying cutaneous adnexal adenocarcinoma. These patients have a higher mortality rate--46%--than patients with extramammary Paget's disease without underlying cutaneous adnexal adenocarcinoma. Twelve percent of patients with extramammary Paget's disease have an associated concurrent underlying internal malignancy. The location of the underlying internal malignancy appears to be closely related to the location of the extramammary Paget's disease--i.e., a perianal location is associated with adenocarcinoma of the digestive system, a penile-scrotal-groin location with genitourinary malignancy, etc. A directed internal malignancy search may be of benefit in patients who are diagnosed as having extramammary Paget's disease.

PMID 3001158  J Am Acad Dermatol. 1985 Dec;13(6):1009-14.
著者: J S Metcalf, R E Lee, J C Maize
雑誌名: Arch Dermatol. 1985 Apr;121(4):532-4.
Abstract/Text A case of epidermotropic carcinoma involving the urethral meatus and the skin of the glans penis was associated with primary transitional cell carcinoma of the urinary bladder with urethral extension. The histopathologic and histochemical features were identical to those seen in extramammary Paget's disease. There was positive intracytoplasmic staining for the carcinoembryonic antigen with the use of an immunoperoxidase stain, another similarity between this neoplasm and extramammary Paget's disease. However, these staining characteristics are consistent with those of the primary bladder tumor and with staining patterns described in the literature for urothelial carcinoma.

PMID 2983621  Arch Dermatol. 1985 Apr;121(4):532-4.
著者: Victoria Shepherd, Emma J Davidson, John Davies-Humphreys
雑誌名: BJOG. 2005 Mar;112(3):273-9. doi: 10.1111/j.1471-0528.2004.00438.x.
Abstract/Text
PMID 15713139  BJOG. 2005 Mar;112(3):273-9. doi: 10.1111/j.1471-0528.2・・・
著者: N G Ordóñez, H Awalt, B Mackay
雑誌名: Cancer. 1987 Mar 15;59(6):1173-83.
Abstract/Text Twenty-one cases of Paget's disease have been studied using histochemical, ultrastructural, and immunohistochemical methods. Eight of the tumors involved the nipple, and 13 were extramammary (11 vulvar and two anal). The antibodies used were directed against different classes of cytokeratin proteins, epithelial membrane antigen, carcinoembryonic antigen, gross cystic disease fluid protein-15, and S-100 protein. The findings of this study provide conclusive evidence that Paget's cells, regardless of their location, are adenocarcinoma cells. Intracytoplasmic mucin is scanty in Paget's cells within the nipple, but typically plentiful in the extramammary sites where the cells are frequently signet-ring cells. The common mechanism for the evolution of Paget's disease is extension of cells from an underlying carcinoma, but the possibility that some cases, particularly in the vulva, develop from intraepithelial precursors cannot be excluded.

PMID 2434206  Cancer. 1987 Mar 15;59(6):1173-83.
著者: J R Goldblum, W R Hart
雑誌名: Am J Surg Pathol. 1998 Feb;22(2):170-9.
Abstract/Text Perianal Paget's disease is rare, and its relationship to an associated internal regional cancer has been ill defined. We analyzed the histologic and immunohistochemical features of perianal Paget's disease in 11 patients to determine the frequency and relationship of associated regional internal carcinoma and to gain insight into its histogenesis. Of five patients with documented rectal adenocarcinoma, it was discovered synchronously with the Paget's disease in four and, subsequently, in one. Paget's cells of signet ring type predominated in four cases. Intraepithelial glands with intraluminal dirty necrosis were present in four cases. The immunophenotype in four cases studied was cytokeratin (CK)7+/CK20+/gross cystic disease fluid protein- (GCDFP) in both the intraepithelial Paget's cells and the invasive rectal adenocarcinoma. Six patients did not have documented rectal carcinoma. The Paget's cells in four were CK7+/CK20-/GCDFP15+. Three of these had purely intraepithelial Paget's disease, and invasive or metastatic disease developed in none after wide local excision. Bilateral inguinal lymph node metastases developed in the fourth patient, and the patient died 8 months after diagnosis of Paget's disease. In two patients, the Paget's cells were CK7+/CK20+/GCDFP15-. Recurrent intraepithelial perianal Paget's disease developed in one patient at 7 months; the patient was alive without disease at 24 months, and the other patient had several intraepithelial recurrences of perianal Paget's disease, and, subsequently, a large perianal tumor of uncertain cell type developed at 108 months, which led to the patient's death. We conclude that there are two types of perianal Paget's disease. One type has endodermal differentiation with gastrointestinal-type glands containing intraluminal dirty necrosis, numerous signet ring cells, CK20 positivity, and GCDFP15 negativity. Such cases are especially likely to be associated with synchronous or metachronous rectal adenocarcinoma. The other type is a primary cutaneous intraepithelial neoplasm in which the Paget's cells display sweat gland differentiation, including GCDFP15 positivity; it generally lacks gastrointestinal-type glands, intraluminal dirty necrosis, and CK20 positivity. The CK7 is a sensitive, albeit nonspecific, marker for Paget's cells.

PMID 9500217  Am J Surg Pathol. 1998 Feb;22(2):170-9.
著者: J R Goldblum, W R Hart
雑誌名: Am J Surg Pathol. 1997 Oct;21(10):1178-87.
Abstract/Text Vulvar Paget's disease (VPD) is the most common type of extramammary Paget's disease; however, the frequency of dermal invasion and its clinical significance are unclear, as are the frequency and relationship of an associated regional internal cancer. Thus, we studied the clinicopathologic and immunohistochemical features of 19 patients with VPD. Patients ranged in age from 56 to 86 years (median 65). VPD was entirely intraepithelial (IE-VPD) in 13 patients. Three patients developed IE-VPD recurrence and one developed deeply invasive and metastatic VPD at 10.8 years. Five patients had invasive Paget's disease (INV-VPD) characterized by clinically occult microscopic foci of superficial dermal invasion, ranging in depth from 0.3 to 0.9 mm. All five patients were alive without disease after 12 months to 17 years (median 66 months). A regional internal cancer (CA ASSOC-VPD) occurred in one patient whose VPD was preceded by a deeply invasive grade 3 transitional cell carcinoma of the urinary bladder 9 months earlier. Immunophenotypes of 16 cases with IE-VPD or INV-VPD were CK7+/CK20-/GCDFP15+ in 14 cases and CK7+/CK20+/GCDFP15+ in two cases, with concordant immunophenotypes of the intraepithelial and invasive components in all cases studied. The patient with CA ASSOC-VPD had a CK7+/CK20+/GCDFP15- immunophenotype in the invasive TCC of the urinary bladder and the VPD. We conclude that the predominant form of VPD begins as a primary cutaneous intraepithelial neoplasm that is universally CK7+/GCDFP15+. Foci of unsuspected synchronous dermal invasion by Paget's cells can be expected in almost one third of cases. Subsequent progression into an invasive carcinoma occurs less often. Foci of "minimally invasive" carcinoma (<1 mm) probably do not adversely affect prognosis, whereas deeply invasive carcinoma behaves as a fully malignant adenocarcinoma. The rarer form of VPD appears to result from secondary intraepithelial spread from an associated regional internal carcinoma. The finding of Paget's cells that are CK20+/GCDFP15- suggests the presence of a regional internal carcinoma with a corresponding immunophenotype.

PMID 9331290  Am J Surg Pathol. 1997 Oct;21(10):1178-87.
著者: M A Nowak, P Guerriere-Kovach, A Pathan, T E Campbell, L M Deppisch
雑誌名: Arch Pathol Lab Med. 1998 Dec;122(12):1077-81.
Abstract/Text BACKGROUND: Extramammary Paget's disease most commonly occurs on the female external genitalia and rarely occurs in the perianal region and male external genitalia. We present the clinical and pathologic features of 5 cases of perianal Paget's disease and review the literature.
METHODS: Clinical and pathologic data were recorded for 5 cases of perianal Paget's disease. Cases were studied retrospectively with special stains, including periodic acid-Schiff, mucicarmine, Alcian blue, carcinoembryonic antigen, S100 protein, pan-keratin, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme, CD15 (Leu-M1), cytokeratin 7 (CK7), and cytokeratin 20 (CK20).
RESULTS: Three (60%) of 5 patients had concurrent rectal adenocarcinomas. All cases reacted positively for pankeratin, although the intensity and distribution of staining varied. Both cases not associated with an underlying carcinoma showed strong GCDFP-15 and CK7 expression and an absence of CK20 expression. The 3 cases associated with an underlying malignancy demonstrated CK7 and CK20 expression and an absence of GCDFP-15 expression. All cases were negative for lysozyme and CD15 (Leu-M1).
CONCLUSIONS: The 5 cases reported herein demonstrate that perianal Paget's disease is a heterogeneous entity. The high frequency of associated underlying malignancies and resultant poor clinical outcomes highlight the importance of an aggressive search for a second malignancy. In some cases, perianal Paget's disease merely represents a cutaneous manifestation of an underlying rectal adenocarcinoma and demonstrates a CK7+/CK20+/GCDFP-15-/lysozyme-/Leu-M1- immunophenotype and signet ring Paget's cells. Other cases represent primary adenocarcinomas of the skin, which are associated with a CK7+/CK20-/GCDFP-15+/lysozyme /Leu-M1- immunophenotype and an excellent prognosis if adequately resected. Immunohistochemical studies, particularly CK20 and GCDFP-15, are useful adjuncts in distinguishing primary and secondary perianal Paget's disease.

PMID 9870855  Arch Pathol Lab Med. 1998 Dec;122(12):1077-81.
著者: A Lopez-Beltran, R J Luque, A Moreno, E Bollito, E Carmona, R Montironi
雑誌名: Virchows Arch. 2002 Aug;441(2):148-53. doi: 10.1007/s00428-002-0627-8. Epub 2002 Apr 4.
Abstract/Text Pagetoid urothelial carcinoma in situ (CIS) is a rare variant of bladder cancer that is characterized by an intraepithelial proliferation of large cells arranged singly or in clusters and randomly distributed. These neoplasms deserve recognition and attention, chiefly because they may be overlooked or misdiagnosed as urothelial dysplasia, then causing unsuspected tumor recurrence after surgery. We report on the clinicopathological features and immunohistochemical findings of 11 (14.86%) cases of pagetoid CIS in a retrospective study of 74 cases of conventional carcinoma in situ. Most patients were male ( n=10). Their ages ranged from 31 years to 78 years. The lesion can be present with primary ( n=2) or secondary ( n=9) CIS. Pagetoid CIS is usually a focal lesion occurring in a clinical and histological setting of conventional CIS, and these patients essentially have the same progression and survival rates as patients without pagetoid changes and are treated in the same way. In cases with extensive urothelial denudation, pagetoid CIS may be focally present in otherwise normal-looking urothelium, thus alerting the pathologist to search for additional CIS elsewhere in the bladder. Given that primary extramammary Paget disease of the external genitalia and of the anal canal may extend to the bladder and, conversely, some bladder cases of pagetoid CIS may extend to the urethra, ureter, and beyond to the external genitalia, the differential diagnoses between these two entities represent an important therapeutic consideration. Our data suggest that a panel of immunostains including CK7+/CK20+/TM+ may assist in differentiating urothelial pagetoid CIS from extramammary Paget disease which is known to be CK7+/CK20-.

PMID 12189504  Virchows Arch. 2002 Aug;441(2):148-53. doi: 10.1007/s00・・・
著者: Kuniaki Ohara, Yasuhiro Fujisawa, Koji Yoshino, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Kenichi Yoshimura, Manabu Fujimoto
雑誌名: J Dermatol Sci. 2016 Sep;83(3):234-9. doi: 10.1016/j.jdermsci.2016.06.004. Epub 2016 Jun 3.
Abstract/Text BACKGROUND: Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be established.
OBJECTIVE: The aim of this study was to establish a TNM staging system for iEMPD.
METHODS: We retrospectively collected iEMPD patients treated at 12 institutes in Japan. Factors reported to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor status were evaluated using the log-rank test.
RESULTS: We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had no remote metastasis. Distant metastasis (M1) showed worse survival (P<0.00001). In the analysis of the 250 patients without distant metastasis, LN metastasis also showed worse survival (P<0.00001). Among the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN metastasis (N1, P=0.02). Lastly, in the analysis of the 187 patients without metastasis, tumor thickness of over 4mm or lymphovascular invasion showed worse survival (T2, P<0.05 and P<0.001, respectively). Patients with neither of these features were defined as T1. From these results, we propose this TNM staging system: stage I, T1N0M0; stage II, T2N0M0; stage IIIa, anyTN1M0; stage IIIb, anyTN2M0; stage IV, anyTanyNM1. Other than stages II and IIIa, each stage had a statistically distinct survival curve.
CONCLUSION: We propose a TNM staging system for EMPD using simple factors for classification that could provide important prognostic information in managing EMPD. However, accumulation of more patient data and further revision of the system are required.

Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
PMID 27329007  J Dermatol Sci. 2016 Sep;83(3):234-9. doi: 10.1016/j.jd・・・
著者: N Hatta, M Yamada, T Hirano, A Fujimoto, R Morita
雑誌名: Br J Dermatol. 2008 Feb;158(2):313-8. doi: 10.1111/j.1365-2133.2007.08314.x. Epub 2007 Nov 19.
Abstract/Text BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma usually presenting as a genital erythematous lesion in the elderly. Although most EMPD tumours are in situ, invasive EMPD has a poor prognosis.
OBJECTIVE: To evaluate the clinical and pathological features of EMPD and determine prognostic factors for survival.
METHODS: The medical records of 76 patients with EMPD were retrospectively reviewed.
RESULTS: Of the 66 patients who underwent curative surgical excision, five (8%) developed local recurrence, but surgical margin (2 cm) was not correlated with local recurrence. Thirteen of the 76 patients (17%) developed systemic metastases and 10 of these died of disease. On univariate analysis, the presence of nodules in the primary tumour, clinical lymph node swelling, elevated serum carcinoembryonic antigen (CEA) levels, tumour invasion level and lymph node metastasis were significant prognostic factors. On multivariate analysis, invasion level and elevated serum CEA were the only factors that were significantly associated with reduced survival.
CONCLUSIONS: Invasion level and lymph node metastasis are important prognostic factors in EMPD. In patients with in situ tumour, local tumour control is the major aim of treatment; however, wide surgical margins are not associated with a lower risk of local recurrence.

PMID 18028492  Br J Dermatol. 2008 Feb;158(2):313-8. doi: 10.1111/j.13・・・
著者: Y Murata, K Kumano
雑誌名: Eur J Dermatol. 2005 May-Jun;15(3):168-70.
Abstract/Text For the treatment of extramammary Paget's disease (EMPD), wide excision has been recommended because of unpredictable spread of tumor cells. EMPD lesions are often well circumscribed. Should all the lesions of EMPD be resected with a 3 cm margin? Forty-six patients with EMPD were surgically treated with a 1 cm margin. Width of tumor cell free area from the last lesional cells at the borders to the resected edge was measured with micro-oculometer. The microscopic gap between the histopathological tumor border and the clinical border scored by scalpel tract was also measured. The tumor cell free area measured 10.2 +/- 2.48 mm. The microscopic gap between the histopathological and clinical borders measured 0.334 +/- 1.183 mm. Thus, the clinically determined border of well-defined lesions of EMPD corresponded well to the histopathologic border. No local recurrence was observed in 24 to 115 months of follow-up. Well-demarcated lesions of EMPD can be adequately managed with 1 cm margin resection.

PMID 15908300  Eur J Dermatol. 2005 May-Jun;15(3):168-70.
著者: Yasuhiro Fujisawa, Koji Yoshino, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Manabu Fujimoto, Kuniaki Ohara
雑誌名: J Dermatol Sci. 2015 Jul;79(1):38-42. doi: 10.1016/j.jdermsci.2015.03.014. Epub 2015 Apr 18.
Abstract/Text BACKGROUND: Although extramammary Paget's disease (EMPD) mostly presents as intraepithelial carcinoma, we sometimes encounter patients with invasive EMPD (iEMPD) who have lymph node metastasis and may develop distant metastasis. Although sentinel lymph node biopsy (SLNB) is widely accepted for various cancers, there is no large study that has assessed its role in iEMPD.
OBJECTIVE: The main objective of this study is to assess the role of SLNB in patients with iEMPD.
MATERIALS AND METHODS: We retrospectively collected data on 151 iEMPD patients treated from 1998 to 2012 in 11 institutes in Japan. All 151 patients received curative surgery for their primary tumor and none of them had distant metastasis. SLNB was performed on the 107 patients without lymphadenopathy to determine their LN status. The 44 other patients with lymphadenopathy underwent one of the following procedures to determine their LN status: SLNB in 22 cases, immediate LN dissection in 21, and LN biopsy in 1.
RESULTS: Compared to those without lymphadenopathy, patients with lymphadenopathy had advanced primary tumors (nodule in the primary tumor, thicker tumor, deeper invasion level, and lymphovascular invasion). The rate of LN metastasis in patients with lymphadenopathy was 80%, compared to 15% in patients without lymphadenopathy who underwent SLNB. Compared to those with negative SLN, patients with positive SLN had advanced primary tumors (nodule in the primary tumor, deeper invasion level, and lymphovascular invasion). Multivariate analysis revealed that dermal invasion (odds ratio 5.8, p=0.04) and lymphovascular invasion (odds ratio 18.0, p=0.0023) were independent factors associated with SLN positivity. Notably, there was no difference in survival between patients with or without SLN metastasis (p=0.71). On the other hand, patients with lymphadenopathy showed worse survival than those with positive SLN (p=0.045).
CONCLUSION: Clinical lymphadenopathy was strongly correlated with pathological LN metastasis and also associated with worse survival than absence of lymphadenopathy. The rate of occult LN metastasis detected by SLNB was 15%. Survival was not affected by SLN status even when an advanced primary tumor was present in patients with positive SLN. Our results raise the possibility that SLNB and subsequent LN dissection improved the survival of patients with early stage lymphatic spread. Our study indicates that SLNB should be considered for iEMPD if lymphadenopathy is not apparent.

Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
PMID 25944505  J Dermatol Sci. 2015 Jul;79(1):38-42. doi: 10.1016/j.jd・・・
著者: Koji Yoshino, Yasuhiro Fujisawa, Yoshio Kiyohara, Takafumi Kadono, Yozo Murata, Hisashi Uhara, Naohito Hatta, Hiroshi Uchi, Shigeto Matsushita, Tatsuya Takenouchi, Toshihiko Hayashi, Kuniaki Ohara
雑誌名: J Dermatol. 2015 Nov 25;. doi: 10.1111/1346-8138.13200. Epub 2015 Nov 25.
Abstract/Text In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first-line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1-year overall survival rate determined by the Kaplan-Meier method was 75.0%. All adverse effects were manageable and no treatment-related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first-line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.

© 2015 Japanese Dermatological Association.
PMID 26603144  J Dermatol. 2015 Nov 25;. doi: 10.1111/1346-8138.13200.・・・
著者: Yasutaka Tokuda, Fuyuko Arakura, Hisashi Uhara
雑誌名: Int J Clin Oncol. 2015 Feb;20(1):194-7. doi: 10.1007/s10147-014-0686-2. Epub 2014 Apr 2.
Abstract/Text BACKGROUND: Extramammary Paget's disease (EPD) is a cutaneous adenocarcinoma. It is usually curable by wide local excision. However, the prognosis for EPD patients with metastases is extremely poor because effective chemotherapy for advanced EPD has not been established.
METHODS: We retrospectively analyzed the efficacy of combination chemotherapy consisting of infusions of 5-fluorouracil (5-FU, 600 mg/m(2)/body, 5 days/week) and cisplatin (5-10 mg/body, 5-7 days/week) administered intravenously for 8-24 h (low-dose FP).
RESULTS: The patients were 15 males and 7 females and the ages ranged from 54 to 91 years old (median 71). The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia. Seventeen patients were treated with low-dose FP only, and the clinical results included 10 partial responses (PR), 4 stable disease (SD), and 3 progressive disease (PD). The overall survival ranges (medians) were 5-51 months (12) in all 22 patients, 6-51 months (13) in the 13 patients showing complete response or PR, and 5-12 months (11) in the 6 SD patients. The reported palliative effects of low-dose FP include control of pain and improvement of lymphedema.
CONCLUSION: Although the number of cases is limited and there is a bias because cases without clinical effects are less likely to be reported, this regimen might be considered a relatively effective option for advanced EPD.

PMID 24687531  Int J Clin Oncol. 2015 Feb;20(1):194-7. doi: 10.1007/s1・・・
著者: M Kato, K Yoshino, T Maeda, K Nagai, S Oaku, A Hiura, Y Fujisawa
雑誌名: Br J Dermatol. 2019 Oct;181(4):831-832. doi: 10.1111/bjd.17922. Epub 2019 Jul 15.
Abstract/Text
PMID 30920650  Br J Dermatol. 2019 Oct;181(4):831-832. doi: 10.1111/bj・・・
著者: P Besa, T A Rich, L Delclos, C L Edwards, D M Ota, J T Wharton
雑誌名: Int J Radiat Oncol Biol Phys. 1992;24(1):73-8.
Abstract/Text We have reviewed our treatment results in 65 patients with extramammary Paget's disease arising in the vulva, perianal area, or scrotum. In 30 patients with primary disease, positive surgical margins were found in 53%, and there was an actuarial local recurrence rate of 40% within 5 years. The median follow-up period for primary extramammary Paget's disease patients treated with surgery alone was 198 months, and none died of this disease. Three patients treated with definitive radiotherapy were without recurrence at 12, 21, and 60 months after 56 Gy of supervoltage x-rays. In 22 patients with extramammary Paget's disease and associated adnexal or rectal adenocarcinoma, nine treated with surgery alone had a 75% local control rate. Three patients treated with surgery and adjuvant radiotherapy all had local control; of two patients treated with radiotherapy alone, one had persistent adenocarcinoma. The median survival for all patients with extramammary Paget's disease and adenocarcinoma was 22 months. We conclude that patients with extramammary Paget's disease have excellent survival but that local recurrence and morbidity from surgery, especially in the elderly, can be high. Radiotherapy greater than 50 Gy as primary treatment for extramammary Paget's disease in those medically unfit for surgery, or as an alternative to further surgery for recurrence after surgery and for anyone wishing to avoid mutilating surgery, is indicated. For those with adenocarcinoma and extramammary Paget's disease, the use of adjuvant postoperative radiotherapy in doses greater than 55 Gy is indicated because of the high risk of local recurrence after surgery alone.

PMID 1324902  Int J Radiat Oncol Biol Phys. 1992;24(1):73-8.
著者: Seok-Hyun Son, Jung-Seok Lee, Yeon-Sil Kim, Mi-Ryeong Ryu, Su-Mi Chung, Sung-Eun Namkoong, Gu-Taek Han, Hee-Jeong Lee, Sei-Chul Yoon
雑誌名: Cancer Res Treat. 2005 Dec;37(6):365-9. doi: 10.4143/crt.2005.37.6.365. Epub 2005 Dec 31.
Abstract/Text We have experienced three cases of extramammary Paget's disease (EMPD) of the vulva that received radiation therapy (RT). Here, we analyze the efficacy of RT and include a literature survey.Three patients with EMPD of the vulva were treated with curative RT between 1993 and 1998. One of the patients had associated underlying adenocarcinoma of the vulva. The total doses of radiation administered were 54~78 Gy/6~8 weeks. Radiation fields encompassed 2 to 3 cm outer margins free from all visible disease including or not including the inguinal area using a 9 MeV electron or a 6 MV photon beam. Follow-up durations after radiotherapy were 0.6~11 years. Complete response was obtained in all three patients. Marginal failure occurred in one patient, and another patient with underlying adenocarcinoma treated by vulvectomy with bilateral inguinal lymph node dissection followed by external RT showed no relapse. Radiation induced side effects were transient acute confluent wet desquamation in the treated area resulting in mild late atrophic skin changes.Although surgery is currently considered the preferred primary treatment for EMPD, it has a high relapse rate due to the multifocal nature of the disease. We conclude that RT is of benefit in some selected cases of EMPD.

PMID 19956374  Cancer Res Treat. 2005 Dec;37(6):365-9. doi: 10.4143/cr・・・
著者: Y Zhu, D W Ye, X D Yao, S L Zhang, B Dai, H L Zhang, Y J Shen, H R Mao
雑誌名: Br J Dermatol. 2009 Sep;161(3):577-82. doi: 10.1111/j.1365-2133.2009.09203.x. Epub 2009 Apr 29.
Abstract/Text BACKGROUND: Metastatic penoscrotal extramammary Paget's disease (EMPD) has seldom been reported in the literature.
OBJECTIVES: To improve the knowledge of the clinicopathological characteristics, management and outcome in patients with this disease.
METHODS: The medical records and pathological slides of 10 patients with metastatic EMPD and 33 patients with nonmetastatic disease were reviewed. Immunohistochemical staining for epithelial cadherin (E-cadherin) was performed in the primary skin disease. All the 10 patients received 5-fluorouracil- or docetaxel-based chemotherapy.
RESULTS: The most common sites of metastases were lymph nodes followed by bone. Patients with metastatic EMPD were more likely to be young and had elevated carcinoembryonic antigen (CEA) levels. Dermal or deeper invasion, lymphovascular embolization and negative expression of E-cadherin were important pathological predictors of metastatic potential. In invasive EMPD, lymphovascular embolization but not expression of E-cadherin was significantly associated with the risk of metastases. In three patients, (18)F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography (CT) scans revealed occult lymph node metastases which were overlooked at conventional CT examinations. Two patients had complete response to the chemotherapy, three had partial response and five had progressive disease. The 2-year overall survival rate was 48% in patients with metastatic EMPD. In those patients with significantly elevated CEA level, the value of CEA paralleled the disease course.
CONCLUSIONS: Metastatic EMPD tended to have dermal invasion and lymphovascular embolization. PET-CT scans were helpful in detecting distant metastases. 5-Fluorouracil- or docetaxel based-chemotherapy was effective in some patients. Serum CEA level can be a useful biomarker for monitoring disease course.

PMID 19438449  Br J Dermatol. 2009 Sep;161(3):577-82. doi: 10.1111/j.1・・・

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