乳房外Paget病发病机制研究进展

doi:10.35541/cjd.20220588

Abstract

Abstract: 【Abstract】 Extramammary Paget′s disease （EMPD） usually occurs in the apocrine gland-bearing areas, in which Paget cells are scattered in the middle and lower epidermis, arranged singly or in clusters, and spread to all skin layers. The pathogenesis of EMPD is still unclear, and the origin of Paget cells remains controversial. This review discusses the pathogenesis of EMPD from 4 aspects, i.e., histogenesis, driver genes, signal transduction pathways and immune environment, and focuses on relevant research progress.

Key words: Paget disease, extramammary, Pathogenesis, Histogenesis, Driver genes, Signal transduction pathways, Immune environment

Ding Meilin, Li Hongyang, Zhang Wei, Zeng Xuesi. Pathogenesis of extramammary Paget′s disease[J]. Chinese Journal of Dermatology,2023,e20220588. doi:10.35541/cjd.20220588

References ［49］

［1］	Siesling S, Elferink MA, van Dijck JA, et al. Epidemiology and treatment of extramammary Paget disease in the Netherlands［J］. Eur J Surg Oncol, 2007,33（8）:951⁃955. doi: 10.1016/j.ejso.2006. 11.028.
［2］	Wigley C, Zargaran D, Nikkhah D, et al. Ectopic extramammary Paget′s disease of the abdominal wall with abdominoplasty reconstruction［J］. BMJ Case Rep, 2022,15（3）:e243322. doi: 10.1136/bcr⁃2021⁃243322.
［3］	Tan L, Huang J, Zhang Y, et al. Evaluation of in vivo reflectance confocal microscopy in the diagnosis of extramammary Paget′s disease［J］. Microsc Res Tech, 2022,85（1）:283⁃289. doi: 10. 1002/jemt.23903.
［4］	Scarbrough CA, Vrable A, Carr DR. Definition, association with malignancy, biologic behavior, and treatment of ectopic extramammary Paget′s disease: a review of the literature［J］. J Clin Aesthet Dermatol, 2019,12（8）:40⁃44.
［5］	Fusumae T, Fukuda K, Hirai I, et al. Management and outcomes of hydronephrosis in patients with metastatic extramammary Paget′s disease: a retrospective analysis［J］. J Dermatol, 2022,49（8）:787⁃791. doi: 10.1111/1346⁃8138.16407.
［6］	Shah VI, Bergin L, Rowlands GL, et al. Unusual manifestations of vulval Paget disease［J］. Int J Gynecol Pathol, 2022,41（5）:476⁃483. doi: 10.1097/PGP.0000000000000824.
［7］	Simonds RM, Segal RJ, Sharma A. Extramammary Paget′s disease: a review of the literature［J］. Int J Dermatol, 2019,58（8）:871⁃879. doi: 10.1111/ijd.14328.
［8］	张韡, 曾学思, 孙建方. 乳房外 Paget 病的病理学研究进展［J］. 中华皮肤科杂志, 2015,48（12）:897⁃898. doi: 10.3760/cma.j.issn.0412⁃4030.2015.12.023.
［9］	Karpathiou G, Mobarki M, Papoudou⁃Bai A, et al. Autophagic factors in Paget disease［J］. Pathol Res Pract, 2022,236:154001. doi: 10.1016/j.prp.2022.154001.
［10］	Chang YW, Ma H, Liao WC. Survival analysis of extramammary Paget′s disease （EMPD） in a tertiary hospital in Taiwan［J］. World J Surg Oncol, 2021,19（1）:110. doi: 10.1186/s12957⁃021⁃02228⁃z.
［11］	Lam C, Funaro D. Extramammary Paget′s disease: summary of current knowledge［J］. Dermatol Clin, 2010,28（4）:807⁃826. doi: 10.1016/j.det.2010.08.002.
［12］	Marucci G, Betts CM, Golouh R, et al. Toker cells are probably precursors of Paget cell carcinoma: a morphological and ultrastructural description［J］. Virchows Arch, 2002,441（2）:117⁃123. doi: 10.1007/s00428⁃001⁃0581⁃x.
［13］	Smith AA. Pre⁃Paget cells express a Paget cell marker before losing a keratinocyte marker［J］. Intractable Rare Dis Res, 2021,10（1）:58⁃59. doi: 10.5582/irdr.2020.03086.
［14］	Belousova IE, Kazakov DV, Michal M, et al. Vulvar toker cells: the long⁃awaited missing link: a proposal for an origin⁃based histogenetic classification of extramammary paget disease［J］. Am J Dermatopathol, 2006,28（1）:84⁃86. doi: 10.1097/01.dad. 0000194052.65695.f1.
［15］	Hutchings D, Windon A, Assarzadegan N, et al. Perianal Paget′s disease as spread from non⁃invasive colorectal adenomas［J］. Histopathology, 2021,78（2）:276⁃280. doi: 10.1111/his.14218.
［16］	Nowak MA, Guerriere⁃Kovach P, Pathan A, et al. Perianal Paget′s disease: distinguishing primary and secondary lesions using immunohistochemical studies including gross cystic disease fluid protein⁃15 and cytokeratin 20 expression［J］. Arch Pathol Lab Med, 1998,122（12）:1077⁃1081.
［17］	Liao X, Liu X, Fan X, et al. Perianal Paget′s disease: a clinicopathological and immunohistochemical study of 13 cases［J］. Diagn Pathol, 2020,15（1）:29. doi: 10.1186/s13000⁃020⁃00952⁃w.
［18］	Tekin B, Kundert P, Yang HH, et al. CDX2 expression in primary skin tumors⁃case series and review of the literature［J］. Hum Pathol, 2022,129:1⁃10. doi: 10.1016/j.humpath.2022.07. 013.
［19］	Zhang G, Zhou S, Zhong W, et al. Whole⁃exome sequencing reveals frequent mutations in chromatin remodeling genes in mammary and extramammary Paget′s diseases［J］. J Invest Dermatol, 2019,139（4）:789⁃795. doi: 10.1016/j.jid.2018.08.030.
［20］	Kiniwa Y, Yasuda J, Saito S, et al. Identification of genetic alterations in extramammary Paget disease using whole exome analysis［J］. J Dermatol Sci, 2019,94（1）:229⁃235. doi: 10.1016/j.jdermsci.2019.03.006.
［21］	Kang Z, Xu F, Zhang QA, et al. Oncogenic mutations in extramammary Paget′s disease and their clinical relevance［J］. Int J Cancer, 2013,132（4）:824⁃831. doi: 10.1002/ijc.27738.
［22］	Kusaba Y, Kajihara I, Myangat TM, et al. Intertumor and intratumor heterogeneity of PIK3CA mutations in extramammary Paget′s disease［J］. J Dermatol, 2022,49（5）:508⁃514. doi: 10. 1111/1346⁃8138.16343.
［23］	Ishida Y, Kakiuchi N, Yoshida K, et al. Unbiased detection of driver mutations in extramammary Paget disease［J］. Clin Cancer Res, 2021,27（6）:1756⁃1765. doi: 10.1158/1078⁃0432.CCR⁃20⁃3205.
［24］	Takeichi T, Okuno Y, Matsumoto T, et al. Frequent FOXA1⁃activating mutations in extramammary Paget′s disease［J］. Cancers （Basel）, 2020,12（4）:820. doi: 10.3390/cancers12040820.
［25］	Zhang Y, Zhang D, Li Q, et al. Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering［J］. Nat Genet, 2016,48（9）:1003⁃1013. doi: 10.1038/ng.3635.
［26］	Sawamura S, Mijiddorj Myangat T, Kajihara I, et al. Genomic landscape of circulating tumour DNA in metastatic extramammary Paget′s disease［J］. Exp Dermatol, 2022,31（3）:341⁃348. doi: 10.1111/exd.14476.
［27］	Tanaka R, Sasajima Y, Tsuda H, et al. Concordance of the HER2 protein and gene status between primary and corresponding lymph node metastatic sites of extramammary Paget disease［J］. Clin Exp Metastasis, 2016,33（7）:687⁃697. doi: 10.1007/s10585⁃016⁃9804⁃z.
［28］	Maeda T, Kitamura S, Nishihara H, et al. Extramammary Paget′s disease patient⁃derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2⁃targeted therapies［J］. Oncogene, 2020,39（36）:5867⁃5875. doi: 10.1038/s41388⁃020⁃01404⁃x.
［29］	Bartoletti M, Mazzeo R, De Scordilli M, et al. Human epidermal growth factor receptor⁃2 （HER2） is a potential therapeutic target in extramammary Paget′s disease of the vulva［J］. Int J Gynecol Cancer, 2020,30（11）:1672⁃1677. doi: 10.1136/ijgc⁃2020⁃001771.
［30］	Tokuchi K, Maeda T, Kitamura S, et al. HER2⁃targeted antibody⁃drug conjugates display potent antitumor activities in preclinical extramammary Paget′s disease models: in vivo and immuno⁃histochemical analyses［J］. Cancers （Basel）, 2022,14（14）:3519. doi: 10.3390/cancers14143519.
［31］	Liegl B, Horn LC, Moinfar F. Androgen receptors are frequently expressed in mammary and extramammary Paget′s disease［J］. Mod Pathol, 2005,18（10）:1283⁃1288. doi: 10.1038/modpathol. 3800437.
［32］	Azmahani A, Nakamura Y, Ozawa Y, et al. Androgen receptor, androgen⁃producing enzymes and their transcription factors in extramammary Paget disease［J］. Hum Pathol, 2015,46（11）:1662⁃1669. doi: 10.1016/j.humpath.2015.07.007.
［33］	Angelico G, Santoro A, Inzani F, et al. Hormonal environment and HER2 status in extra⁃mammary paget′s disease （eMPD）: a systematic literature review and meta⁃analysis with clinical considerations［J］. Diagnostics （Basel）, 2020,10（12）:1040. doi: 10.3390/diagnostics10121040.
［34］	Chang K, Li GX, Kong YY, et al. Chemokine receptors CXCR4 and CXCR7 are associated with tumor aggressiveness and prognosis in extramammary paget disease［J］. J Cancer, 2017,8（13）:2471⁃2477. doi: 10.7150/jca.19127.
［35］	Urata K, Kajihara I, Myangat TM, et al. Overexpression of cyclin⁃dependent kinase 4 protein in extramammary Paget′s disease［J］. J Dermatol, 2019,46（5）:444⁃448. doi: 10.1111/1346⁃8138. 14858.
［36］	Kitamura S, Yanagi T, Maeda T, et al. Cyclin⁃dependent kinase 4/6 inhibitors suppress tumor growth in extramammary Paget′s disease［J］. Cancer Sci, 2022,113（2）:802⁃807. doi: 10.1111/cas.15234.
［37］	Urano⁃Takaoka M, Sumida H, Miyagawa T, et al. Serum cytokeratin 18 as a metastatic and therapeutic marker for extramammary Paget′s disease［J］. Acta Derm Venereol, 2022,102:adv00636. doi: 10.2340/actadv.v101.866.
［38］	Chen S, Nakahara T, Uchi H, et al. Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget′s disease［J］. Br J Dermatol, 2009,161（2）:357⁃363. doi: 10.1111/j.1365⁃2133.2009.09179.x.
［39］	van der Linden M, van Esch E, Bulten J, et al. The immune cell infiltrate in the microenvironment of vulvar Paget disease［J］. Gynecol Oncol, 2018,151（3）:453⁃459. doi: 10.1016/j.ygyno.2018. 09.026.
［40］	Press JZ, Allison KH, Garcia R, et al. FOXP3+ regulatory T⁃cells are abundant in vulvar Paget′s disease and are associated with recurrence［J］. Gynecol Oncol, 2011,120（2）:296⁃299. doi: 10.1016/j.ygyno.2010.10.019.
［41］	González⁃Suárez E, Sanz⁃Moreno A. RANK as a therapeutic target in cancer［J］. FEBS J, 2016,283（11）:2018⁃2033. doi: 10.1111/febs.13645.
［42］	Kambayashi Y, Fujimura T, Furudate S, et al. The possible interaction between receptor activator of nuclear factor kappa⁃B ligand expressed by extramammary Paget cells and its ligand on dermal macrophages［J］. J Invest Dermatol, 2015,135（10）:2547⁃2550. doi: 10.1038/jid.2015.199.
［43］	Fujimura T, Kambayashi Y, Furudate S, et al. Receptor activator of NF⁃κB ligand promotes the production of CCL17 from RANK+ M2 macrophages［J］. J Invest Dermatol, 2015,135（11）:2884⁃2887. doi: 10.1038/jid.2015.209.
［44］	Karpathiou G, Chauleur C, Hathroubi S, et al. Expression of CD3, PD⁃L1 and CTLA⁃4 in mammary and extra⁃mammary Paget disease［J］. Cancer Immunol Immunother, 2018,67（8）:1297⁃1303. doi: 10.1007/s00262⁃018⁃2189⁃x.
［45］	Maeda T, Uehara J, Toyoshima R, et al. Neutrophil⁃to⁃lymphocyte ratio is a potential prognostic biomarker for extramammary Paget disease: a retrospective study［J］. J Dermatol, 2022,49（11）:1188⁃1192. doi: 10.1111/1346⁃8138.16533.
［46］	Kawaguchi A, Akiba J, Kondo R, et al. Programmed death⁃ligand 1 and programmed death⁃ligand 2 expression can affect prognosis in extramammary Paget′s disease［J］. Anticancer Res, 2021,41（1）:219⁃226. doi: 10.21873/anticanres.14768.
［47］	Chuang KC, Chang CR, Chang SH, et al. Imiquimod⁃induced ROS production disrupts the balance of mitochondrial dynamics and increases mitophagy in skin cancer cells［J］. J Dermatol Sci, 2020,98（3）:152⁃162. doi: 10.1016/j.jdermsci.2020.03.009.
［48］	Borella F, Preti M, Vieira⁃Baptista P, et al. Vulvar Paget′s disease: outcomes of 51 patients treated with imiquimod cream［J］. Maturitas, 2022,163:23⁃27. doi: 10.1016/j.maturitas.2022. 05.010.
［49］	van der Linden M, van Hees CL, van Beurden M, et al. The Paget Trial: topical 5% imiquimod cream for noninvasive vulvar Paget disease［J］. Am J Obstet Gynecol, 2022,227（2）:250.e1⁃250.e8. doi: 10.1016/j.ajog.2022.04.012.

[1]	Yan Rufan, Liao Jieyue, Guo Ziyu, Yao Nan, Zhou Wenyu, Luo Shuaihantian, Zhang Guiying, Zhao Ming. Pathogenesis and targeted therapy of pemphigus [J]. Chinese Journal of Dermatology, 2024, 57(4): 374-378.
[2]	Ju Qiang, Li Jiaqi. Acne vulgaris revisited: from pathogenesis to treatment strategies [J]. Chinese Journal of Dermatology, 2024, 57(4): 289-294.
[3]	Zong Yangyongyi, Ma Chujun, Su Zhonglan. Eczematization following the treatment of psoriasis with biological agents: pathogenesis and management [J]. Chinese Journal of Dermatology, 2024, 0(3): 20220578-e20220578.
[4]	Liu Tingwei, Meng Xiaoqi, Gu Duoduo, Pan Ruoxin, Zhang Yue, Xu Yang. Advances in the pathogenesis of rosacea [J]. Chinese Journal of Dermatology, 2024, 57(2): 186-190.
[5]	Song Zhiqiang, Chen Qiquan, Ge Lan. Insights into the progress in targeted therapy of atopic dermatitis from the perspective of its pathogenesis [J]. Chinese Journal of Dermatology, 2023, 56(8): 718-723.
[6]	Liang Yunsheng, Li Zhanhong, Wu Yibei. Progress in the treatment of chronic spontaneous urticaria: insights from the changes in the understanding of its pathogenesis [J]. Chinese Journal of Dermatology, 2023, 56(6): 552-558.
[7]	Jiang Jiayi, Wang Daguang. Pathogenesis of nail damages secondary to systemic diseases [J]. Chinese Journal of Dermatology, 2023, 0(2): 20220078-e20220078.
[8]	Chen Qitao, Li Yuqian, Shao Guanghui, Zhu Jing, Zhu Qilin, Li Zhongming, Du Xufeng, Fan Weixin. Erosive pustular dermatosis of the scalp [J]. Chinese Journal of Dermatology, 2023, 0(2): 20210803-e20210803.
[9]	Wang Li, Wang Qianqiu, Zhang Ruili. Research progress in latent syphilis [J]. Chinese Journal of Dermatology, 2023, 0(2): 20220283-e20220283.
[10]	Xie Deqiong, Yang Kaiying, Yang Yang, Chen Siyuan, Ji Yi. Long non-coding RNAs in infantile hemangioma [J]. Chinese Journal of Dermatology, 2023, 56(12): 1173-1176.
[11]	Li Rong, Chen Kun, Zhang Jiaan. Mechanism of action of long non-coding RNA in cutaneous squamous cell carcinoma [J]. Chinese Journal of Dermatology, 2023, 56(10): 985-988.
[12]	Liu Jin, Shen Zhengyu. Epigenetic regulation in psoriasis [J]. Chinese Journal of Dermatology, 2022, 55(9): 825-829.
[13]	Feng Mengdi, Wang Wenqing. Regulatory roles of transcription factors and receptors in the pathogenesis of acne [J]. Chinese Journal of Dermatology, 2022, 0(1): 20210457-e20210457.
[14]	Tian Cuicui, Chen Hao. Pathogenesis of cutaneous T-cell lymphoma-related pruritus [J]. Chinese Journal of Dermatology, 2022, 0(1): 20210941-e20210941.
[15]	Qiu Yueqi, Fu Siqi, Luo Shuaihantian, Li Yaping, Zhang Guiying. Research advance in androgenetic alopecia in 2020 [J]. Chinese Journal of Dermatology, 2021, 54(9): 835-838.

Pathogenesis of extramammary Paget′s disease

PDF

PDF (Mobile)

Knowledge

Abstract

Cite this article

share this article

References ［49］

Related Articles 15

Metrics

Comments

Recommended 10