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Extramammary Paget’s Disease

  • Nathalie C. Zeitouni
  • Jose A. Cervantes
Chapter

Abstract

Extramammary Paget’s disease (EMPD) is a rare, slow-growing intraepithelial adenocarcinoma typically localized to areas of apocrine gland distribution outside the mammary glands. EMPD typically involves the vulva, perianal area, and male genitalia, with rare sites including the thighs, buttocks, axilla, eyelids, and external ear canal. The vulva remains the most frequently involved site with 65% of EMPD located in this area. Lesions appear as erythematous, brown or white, moist plaques that are well differentiated and often accompanied by subtle subjective symptoms of pruritus and pain. Its pathogenesis has been debated, but most cases are thought to arise as a primary intraepidermal neoplasm of glandular origin. A minority of disease appears to be intraepithelial spread of an underlying dermal adnexal malignancy or a regional neoplasm with contiguous epithelium. The diagnosis of EMPD is confirmed histologically by the presence of vacuolated Paget cells in the epidermis that stain for glandular cytokeratins, epithelial membrane antigen, and carcinoembryonic antigen. Treatment options which include surgical excision, Mohs micrographic surgery, radiotherapy, photodynamic therapy, topical imiquimod 5% cream, 5-fluorouracil, and systemic chemotherapy have also been used successfully. Recurrence is common, necessitating a close follow-up.

Keywords

Extramammary Paget’s disease Genital disease Perianal disease Vulva Vulvar neoplasia Skin cancer Imiquimod Pruritic lesions Paget cells 

References

  1. 1.
    Crocker HR. Paget’s disease, affecting the scrotum and penis. Trans Path Soc Lond. 1889;40:187.Google Scholar
  2. 2.
    Love WE, Schmitt AR, Bordeaux JS. Management of unusual cutaneous malignancies: atypical fibroxanthoma, malignant fibrous histiocytoma, sebaceous carcinoma, extramammary Paget disease. Dermatol Clin. 2011;29(2):201–16. viiiPubMedCrossRefGoogle Scholar
  3. 3.
    Lloyd J, Flanagan AM. Mammary and extramammary Paget’s disease. J Clin Pathol. 2000;53(10):742–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Heymann WR. Extramammary Paget’s disease. Clin Dermatol. 1993;11(1):83–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol. 1985;13(6):1009–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Shepherd V, Davidson EJ, Davies-Humphreys J. Extramammary Paget’s disease. BJOG. 2005;112(3):273–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Wojnarowska F, Cooper S. Anogenital (non-venereal) disease. Dermatology. Edinburgh: Mosby; 2003. p. 1099–113.Google Scholar
  8. 8.
    LEE KY, Roh MR, Chung WG, Chung KY. Comparison of Mohs micrographic surgery and wide excision for extramammary Paget’s disease: Korean experience. Dermatol Surg. 2009;35(1):34–40.PubMedGoogle Scholar
  9. 9.
    Moreno-Arias G, Conill C, Sola-Casas M, Mascaro-Galy J, Grimalt R. Radiotherapy for in situ extramammary Paget disease of the vulva. J Dermatolog treat. 2003;14(2):119–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Brown R, McCormack M, Lankester K, Spittle M. Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget’s disease: response to topical 5-fluorouracil. Cutis. 2000;66(6):454–5.PubMedGoogle Scholar
  11. 11.
    Wagner G, Sachse MM. Extramammary Paget disease–clinical appearance, pathogenesis, management. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2011;9(6):448–54.PubMedGoogle Scholar
  12. 12.
    Fardal RW, Kierland RR, Clagett OT, Woolner LB. Prognosis in cutaneous Paget’s disease. Postgrad Med. 1964;36(6):584–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Kanitakis J. Mammary and extramammary Paget’s disease. J Eur Acad Dermatol Venereol. 2007;21(5):581–90.PubMedGoogle Scholar
  14. 14.
    Landay M, Satmary W, Memarzadeh S, Smith D, Barclay D. Premalignant & malignant disorders of the vulva & vagina. Current diagnosis & treatment obstetrics & gynecology. 10th ed. New York: McGraw-Hill; 2007. p. 822–7.Google Scholar
  15. 15.
    Kodama S, Kaneko T, Saito M, Yoshiya N, Honma S, Tanaka K. A clinicopathologic study of 30 patients with Paget’s disease of the vulva. Gynecol Oncol. 1995;56(1):63–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Parker LP, Parker JR, Bodurka-Bevers D, Deavers M, Bevers MW, Shen-Gunther J, et al. Paget’s disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol. 2000;77(1):183–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Sawada Y, Bito T, Kabashima R, Yoshiki R, Hino R, Nakamura M, et al. Ectopic extramammary Paget’s disease: case report and literature review. Acta Derm Venereol. 2010;90(5):502–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Urabe A, Matsukuma A, Shimizu N, Nishimura M, Wada H, Hori Y. Extramammary Paget’s disease: comparative histopathologic studies of intraductal carcinoma of the breast and apocrine adenocarcinoma. J Cutan Pathol. 1990;17(5):257–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Kuehn PG, Tennant R, Brenneman AR. Familial occurrence of extramammary Paget’s disease. Cancer. 1973;31(1):145–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Demitsu T, Gonda K, Tanita M, Takahira K, Inoue T, Okada O, et al. Extramammary Paget’s disease in two siblings. Br J Dermatol. 1999;141(5):951–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Inoue S, Aki T, Mihara M. Extramammary Paget’s disease in siblings. Dermatology. 2000;201(2):178.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang X, Jin W, Zhu H, Yu H. Extramammary Paget’s disease in two brothers. Indian J Dermatol. 2015;60(4):423.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Kang Z, Xu F, Zhu Y, Fu P, Q-a Z, Hu T, et al. Genetic analysis of mismatch repair genes alterations in extramammary Paget disease. Am J Surg Pathol. 2016;40(11):1517–25.PubMedCrossRefGoogle Scholar
  24. 24.
    Marchesa P, Fazio VW, Oliart S, Goldblum JR, Lavery IC, Milsom JW. Long-term outcome of patients with perianal Paget’s disease. Ann Surg Oncol. 1997;4(6):475–80.PubMedCrossRefGoogle Scholar
  25. 25.
    Fanning J, Lambert HL, Hale TM, Morris PC, Schuerch C. Paget’s disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget’s disease, and recurrence after surgical excision. Am J Obstet Gynecol. 1999;180(1):24–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Neuhaus I, Grekin R. Mammary and extramammary Paget disease. Fitzpatrick’s dermatology in general medicine. 7th ed. New York: McGraw-Hill; 2008. p. 1094–198.Google Scholar
  27. 27.
    Perrotto J, Abbott JJ, Ceilley RI, Ahmed I. The role of immunohistochemistry in discriminating primary from secondary extramammary Paget disease. Am J Dermatopathol. 2010;32(2):137–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Willman JH, Golitz LE, Fitzpatrick JE. Vulvar clear cells of Toker: precursors of extramammary Paget’s disease. Am J Dermatopathol. 2005;27(3):185–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Belousova IE, Kazakov DV, Michal M, Suster S. Vulvar toker cells: the long-awaited missing link: a proposal for an origin-based histogenetic classification of extramammary paget disease. Am J Dermatopathol. 2006;28(1):84–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Lam C, Funaro D. Extramammary Paget’s disease: summary of current knowledge. Dermatol Clin. 2010;28(4):807–26.PubMedCrossRefGoogle Scholar
  31. 31.
    Li YC, Lu LY, Yang YT, Chang CC, Chen LM. Extramammary Paget’s disease of the scrotum associated with hepatocellular carcinoma. J Chin Med Assoc. 2009;72(10):542–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Zollo J, Zeitouni N. The Roswell park cancer institute experience with extramammary Paget’s disease. Br J Dermatol. 2000;142(1):59–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Goldblum JR, Hart WR. Vulvar Paget’s disease: a clinicopathologic and immunohistochemical study of 19 cases. Am J Surg Pathol. 1997;21(10):1178–87.PubMedCrossRefGoogle Scholar
  34. 34.
    Siesling S, Elferink MA, van Dijck JA, Pierie JP, Blokx WA. Epidemiology and treatment of extramammary Paget disease in the Netherlands. Eur J Surg Oncol. 2007;33(8):951–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Wilkinson EJ, Brown HM. Vulvar Paget disease of urothelial origin: a report of three cases and a proposed classification of vulvar Paget disease. Hum Pathol. 2002;33(5):549–54.PubMedCrossRefGoogle Scholar
  36. 36.
    McCarter MD, Quan SH, Busam K, Paty PP, Wong D, Guillem JG. Long-term outcome of perianal Paget’s disease. Dis Colon Rectum. 2003;46(5):612–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Salamanca J, Benito A, Garcia-Penalver C, Azorin D, Ballestin C, Rodriguez-Peralto JL. Paget’s disease of the glans penis secondary to transitional cell carcinoma of the bladder: a report of two cases and review of the literature. J Cutan Pathol. 2004;31(4):341–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Lai YL, Yang WG, Tsay PK, Swei H, Chuang SS, Wen CJ. Penoscrotal extramammary Paget’s disease: a review of 33 cases in a 20-year experience. Plast Reconstr Surg. 2003;112(4):1017–23.PubMedCrossRefGoogle Scholar
  39. 39.
    Popiolek DA, Hajdu SI, Gal D. Synchronous Paget’s disease of the vulva and breast. Gynecol Oncol. 1998;71(1):137–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol. 1998;22(2):170–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Sasaki M, Terada T, Nakanuma Y, Kono N, Kasahara Y, Watanabe K. Anorectal mucinous adenocarcinoma associated with latent perianal Paget’s disease. Am J Gastroenterol. 1990;85(2):199–202.PubMedGoogle Scholar
  42. 42.
    Powell FC, Bjornsson J, Doyle JA, Cooper AJ. Genital Paget’s disease and urinary tract malignancy. J Am Acad Dermatol. 1985;13(1):84–90.PubMedCrossRefGoogle Scholar
  43. 43.
    Koga F, Gotoh S, Suzuki S. A case of invasive bladder cancer with Pagetoid skin lesion of the vulva and anogenital Paget’s disease. Nihon Hinyokika Gakkai Zasshi. 1997;88(4):503–6.PubMedGoogle Scholar
  44. 44.
    Allan S, McLaren K, Aldridge R. Paget’s disease of the scrotum: a case exhibiting positive prostate-specific antigen staining and associated prostatic adenocarcinoma. Br J Dermatol. 1998;138(4):689–91.PubMedCrossRefGoogle Scholar
  45. 45.
    Yang WJ, Kim DS, Im YJ, Cho KS, Rha KH, Cho NH, et al. Extramammary Paget’s disease of penis and scrotum. Urology. 2005;65(5):972–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Ekwueme KC, Zakhour HD, Parr NJ. Extramammary Paget’s disease of the penis: a case report and review of the literature. J Med Case Reports. 2009;3(1):4.PubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hoch WH. Adenocarcinoma of the scrotum (extramammary Paget’s disease): case report and review of the literature. J Urol. 1984;132(1):137–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Hashimoto T, Inamoto N, Nakamura K. Triple extramammary Paget’s disease. Immunohistochemical studies. Dermatologica. 1986;173(4):174–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Van Hamme C, Marot L, Dachelet C, Dumont M, Salamon E, Lachapelle JM. Paget’s extramammary disease of the axillae and perineum. Ann Dermatol Venereol. 2002;129(5 Pt 1):717–9.PubMedGoogle Scholar
  50. 50.
    Hatta N, Yamada M, Hirano T, Fujimoto A, Morita R. Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol. 2008;158(2):313–8.PubMedGoogle Scholar
  51. 51.
    Gonzalez-Castro J, Iranzo P, Palou J, Mascaro J. Extramammary Paget’s disease involving the external ear. Br J Dermatol. 1998;138(5):914–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Inada S, Kohno T, Sakai I. A case of extramammary Paget’s disease on the back. Jpn J Clin Dermatol. 1985;39:685–91.Google Scholar
  53. 53.
    Chilukuri S, Page R, Reed JA, Friedman J, Orengo I. Ectopic extramammary Paget’s disease arising on the cheek. Dermatol Surg. 2002;28(5):430–3.PubMedGoogle Scholar
  54. 54.
    Cohen MA, Hanly A, Poulos E, Goldstein GD. Extramammary Paget’s disease presenting on the face. Dermatol Surg. 2004;30(10):1361–3.PubMedGoogle Scholar
  55. 55.
    Remond B, Aractingi S, Blanc F, Verola O, Vignon D, Dubertret L. Umbilical Paget’s disease and prostatic carcinoma. Br J Dermatol. 1993;128(4):448–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Whorton CM, Patterson JB. Carcinoma of Moll’s glands with extramammary Paget’s disease of the eyelid. Cancer. 1955;8(5):1009–15.PubMedCrossRefGoogle Scholar
  57. 57.
    Matsukuma S, Aida S, Shima S, Tamai S. Paget’s disease of the esophagus. A case report with review of the literature. Am J Surg Pathol. 1995;19(8):948–55.PubMedCrossRefGoogle Scholar
  58. 58.
    Higashiyama M, Doi O, Kodama K, Tateishi R, Kurokawa E. Extramammary Paget’s disease of the bronchial epithelium. Arch Pathol Lab Med. 1991;115(2):185–8.PubMedGoogle Scholar
  59. 59.
    Changus GW, Yonan TN, Bartolome JS. Extramammary Paget’s disease of the tongue. Laryngoscope. 1971;81(10):1621–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Pierie J-PE, Choudry U, Muzikansky A, Finkelstein DM, Ott MJ. Prognosis and management of extramammary Paget’s disease and the association with secondary malignancies. J Am Coll Surg. 2003;196(1):45–50.PubMedCrossRefGoogle Scholar
  61. 61.
    Koseki S, Mitsuhashi Y, Yoshikawa K, Kondo S. A case of triple extramammary Paget’s disease. J Dermatol. 1997;24(8):535–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Hayashibara Y, Ikeda S. Extramammary Paget’s disease with internal malignancies. Gan To Kagaku Ryoho. 1988;15(4 Pt 2–3):1569–75.PubMedGoogle Scholar
  63. 63.
    Nakano S, Narita R, Tabaru A, Ogami Y, Otsuki M. Bile duct cancer associated with extramammary Paget’s disease. Am J Gastroenterol. 1995;90(3):507–8.PubMedGoogle Scholar
  64. 64.
    Balducci L, Crawford ED, Smith GF, Lambuth B, McGehee R, Hardy C. Extramammary Paget’s disease: an annotated review. Cancer Invest. 1988;6(3):293–303.PubMedCrossRefGoogle Scholar
  65. 65.
    Chen YH, Wong TW, Lee J. Depigmented genital extramammary Paget’s disease: a possible histogenetic link to Toker’s clear cells and clear cell papulosis. J Cutan Pathol. 2001;28(2):105–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Iwenofu OH, Samie FH, Ralston J, Cheney RT, Zeitouni NC. Extramammary Paget’s disease presenting as alopecia neoplastica. J Cutan Pathol. 2008;35(8):761–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Bansal D, Bowman CA. Extramammary Paget’s disease masquerading as lichen sclerosus. Int J STD AIDS. 2004;15(2):141–2.PubMedCrossRefGoogle Scholar
  68. 68.
    Murata Y, Kumano K, Tani M. Underpants-pattern erythema: a previously unrecognized cutaneous manifestation of extramammary Paget’s disease of the genitalia with advanced metastatic spread. J Am Acad Dermatol. 1999;40(6 Pt 1):949–56.PubMedCrossRefGoogle Scholar
  69. 69.
    Shaco-Levy R, Bean SM, Vollmer RT, Jewell E, Jones EL, Valdes CL, et al. Paget disease of the vulva: a study of 56 cases. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):86–91.PubMedCrossRefGoogle Scholar
  70. 70.
    Wolff K, Johnson RA. Fitzpatrick’s color atlas and synopsis of clinical dermatology. New York: McGraw Hill; 2009.Google Scholar
  71. 71.
    O’connor WJ, Lim KK, Zalla MJ, Gagnot M, Otley CC, Nguyen TH, et al. Comparison of Mohs micrographic surgery and wide excision for extramammary Paget’s disease. Dermatol Surg. 2003;29(7):723–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Bhatia P, Ahuja A, Dey P, Suri V. Vulval intraepithelial neoplasia with extra mammary pagets disease: a rare association. J Clin Pathol. 2007;60(1):110–2.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Jones RE Jr, Austin C, Ackerman AB. Extramammary Paget’s disease: a critical reexamination. Am J Dermatopathol. 1979;1(2):101–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Roth LM, Lee SC, Ehrlich CE. Paget’s disease of the vulva. A histogenetic study of five cases including ultrastructural observations and review of the literature. Am J Surg Pathol. 1977;1(3):193–206.PubMedCrossRefGoogle Scholar
  75. 75.
    Sitakalin C, Ackerman AB. Mammary and extramammary Paget’s disease. Am J Dermatopathol. 1985;7(4):335–40.PubMedCrossRefGoogle Scholar
  76. 76.
    Ishida-Yamamoto A, Sato K, Wada T, Takahashi H, Toyota N, Shibaki T, et al. Fibroepithelioma-like changes occurring in perianal Paget’s disease with rectal mucinous carcinoma: case report and review of 49 cases of extramammary Paget’s disease. J Cutan Pathol. 2002;29(3):185–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Battles OE, Page DL, Johnson JE. Cytokeratins, CEA, and mucin histochemistry in the diagnosis and characterization of extramammary Paget’s disease. Am J Clin Pathol. 1997;108(1):6–12.PubMedCrossRefGoogle Scholar
  78. 78.
    Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. 1999;23(2):212–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Kohler S, Smoller BR. Gross cystic disease fluid protein-15 reactivity in extramammary Paget’s disease with and without associated internal malignancy. Am J Dermatopathol. 1996;18(2):118–23.PubMedCrossRefGoogle Scholar
  80. 80.
    Nowak MA, Guerriere-Kovach P, Pathan A, Campbell TE. Perianal Paget’s disease: distinguishing primary and secondary lesions using immunohistochemical studies including gross cystic disease fluid protein-15 and cytokeratin 20 expression. Arch Pathol Lab Med. 1998;122(12):1077.PubMedGoogle Scholar
  81. 81.
    Mazoujian G, Pinkus GS, Haagensen DE Jr. Extramammary Paget’s disease--evidence for an apocrine origin. An immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Pathol. 1984;8(1):43–50.PubMedCrossRefGoogle Scholar
  82. 82.
    Liegl B, Leibl S, Gogg-Kamerer M, Tessaro B, Horn LC, Moinfar F. Mammary and extramammary Paget’s disease: an immunohistochemical study of 83 cases. Histopathology. 2007;50(4):439–47.PubMedCrossRefGoogle Scholar
  83. 83.
    Kuan S-F, Montag AG, Hart J, Krausz T, Recant W. Differential expression of mucin genes in mammary and extramammary Paget’s disease. Am J Surg Pathol. 2001;25(12):1469–77.PubMedCrossRefGoogle Scholar
  84. 84.
    Yoshii N, Kitajima S, Yonezawa S, Matsukita S, Setoyama M, Kanzaki T. Expression of mucin core proteins in extramammary Paget’s disease. Pathol Int. 2002;52(5–6):390–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Alo PL, Galati GM, Sebastiani V, Ricci F, Visca P, Mariani L, et al. Fatty acid synthase expression in Paget’s disease of the vulva. Int J Gynecol Pathol. 2005;24(4):404–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Mori O, Hachisuka H, Sasai Y. Immunohistochemical demonstration of epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), and keratin on mammary and extramammary Paget’s disease. Acta Histochem. 1989;85(1):93–100.PubMedCrossRefGoogle Scholar
  87. 87.
    Enjoji M, Noguchi K, Watanabe H, Yoshida Y, Kotoh K, Nakashima M, et al. A novel tumour marker RCAS1 in a case of extramammary Paget’s disease. Clin Exp Dermatol. 2003;28(2):211–3.PubMedCrossRefGoogle Scholar
  88. 88.
    Liegl B, Horn LC, Moinfar F. Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease. Mod Pathol. 2005;18(10):1283–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Diaz de Leon E, Carcangiu ML, Prieto VG, McCue PA, Burchette JL, To G, et al. Extramammary Paget disease is characterized by the consistent lack of estrogen and progesterone receptors but frequently expresses androgen receptor. Am J Clin Pathol. 2000;113(4):572–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Plaza JA, Torres-Cabala C, Ivan D, Prieto VG. HER-2/neu expression in extramammary Paget disease: a clinicopathologic and immunohistochemistry study of 47 cases with and without underlying malignancy. J Cutan Pathol. 2009;36(7):729–33.PubMedCrossRefGoogle Scholar
  91. 91.
    Ogawa T, Nagashima Y, Wada H, Akimoto K, Chiba Y, Nagatani T, et al. Extramammary Paget’s disease: analysis of growth signal pathway from the human epidermal growth factor receptor 2 protein. Hum Pathol. 2005;36(12):1273–80.PubMedGoogle Scholar
  92. 92.
    Gu M, Ghafari S, Lin F. Pap smears of patients with extramammary Paget’s disease of the vulva. Diagn Cytopathol. 2005;32(6):353–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Oji M, Furue M, Tamaki K. Serum carcinoembryonic antigen level in Paget’s disease. Br J Dermatol. 1984;110(2):211–3.PubMedCrossRefGoogle Scholar
  94. 94.
    Hammer A, Hager H, Steiniche T. Prostate-specific antigen-positive extramammary Paget’s disease––association with prostate cancer. Apmis. 2008;116(1):81–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Petković S, Jeremić K, Vidakovic S, Jeremić J, Lazović G. Paget’s disease of the vulva--a review of our experience. Eur J Gynaecol Oncol. 2005;27(6):611–2.Google Scholar
  96. 96.
    Tsutsumida A, Yamamoto Y, Minakawa H, Yoshida T, Kokubu I, Sugihara T. Indications for lymph node dissection in the treatment of extramammary Paget’s disease. Dermatol Surg. 2003;29(1):21–4.PubMedGoogle Scholar
  97. 97.
    Murata Y, Kumano K. Extramammary Paget’s disease of the genitalia with clinically clear margins can be adequately resected with 1 cm margin. Eur J Dermatol. 2005;15(3):168–70.PubMedGoogle Scholar
  98. 98.
    Hendi A, Brodland DG, Zitelli JA. Extramammary Paget’s disease: surgical treatment with Mohs micrographic surgery. J Am Acad Dermatol. 2004;51(5):767–73.PubMedCrossRefGoogle Scholar
  99. 99.
    Appert DL, Otley CC, Phillips PK, Roenigk RK. Role of multiple scouting biopsies before Mohs micrographic surgery for extramammary Paget’s disease. Dermatol Surg. 2005;31(11):1417–22.PubMedGoogle Scholar
  100. 100.
    Kato T, Fujimoto N, Fujii N, Tanaka T. Mapping biopsy with punch biopsies to determine surgical margin in extramammary Paget’s disease. J Dermatol. 2013;40(12):968–72.PubMedCrossRefGoogle Scholar
  101. 101.
    Yelamos O, Hibler BP, Cordova M, Hollmann TJ, Kose K, Marchetti MA, et al. Handheld reflectance confocal microscopy for the detection of recurrent extramammary Paget disease. JAMA Dermatol. 2017.Google Scholar
  102. 102.
    Kim SJ, Thompson AK, Zubair AS, Otley CC, Arpey CJ, Baum CL, et al. Surgical treatment and outcomes of patients with extramammary paget disease: a cohort study. Dermatol Surg. 2017.Google Scholar
  103. 103.
    Misas JE, Cold CJ, Hall FW. Vulvar Paget disease: fluorescein-aided visualization of margins. Obstet Gynecol. 1991;77(1):156–9.PubMedGoogle Scholar
  104. 104.
    Johnson TM, Headington J, Baker SR, Lowe L. Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the “square” procedure. J Am Acad Dermatol. 1997;37(5:758–64.CrossRefGoogle Scholar
  105. 105.
    Hendi A, Perdikis G, Snow JL. Unifocality of extramammary Paget disease. J Am Acad Dermatol. 2008;59(5):811–3.PubMedCrossRefGoogle Scholar
  106. 106.
    Zhu Y, Ye DW, Chen ZW, Zhang SL, Qin XJ. Frozen section-guided wide local excision in the treatment of penoscrotal extramammary Paget’s disease. BJU Int. 2007;100(6):1282–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Damavandy AA, Hendi A, Zitelli JA. Surgical treatment of cutaneous extramammary Paget’s disease. Curr Dermatol Rep. 2016;5(3):166–71.CrossRefGoogle Scholar
  108. 108.
    Fishman DA, Chambers SK, Schwartz PE, Kohorn EI, Chambers JT. Extramammary Paget’s disease of the vulva. Gynecol Oncol. 1995;56(2):266–70.PubMedCrossRefGoogle Scholar
  109. 109.
    Gunn RA, Gallager HS. Vulvar Paget’s disease. A topographic study. Cancer. 1980;46(3):590–4.PubMedCrossRefGoogle Scholar
  110. 110.
    Louis-Sylvestre C, Haddad B, Paniel BJ. Paget’s disease of the vulva: results of different conservative treatments. Eur J Obstet Gynecol Reprod Biol. 2001;99(2):253–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Stacy D, Burrell MO, Franklin EW 3rd. Extramammary Paget’s disease of the vulva and anus: use of intraoperative frozen-section margins. Am J Obstet Gynecol. 1986;155(3):519–23.PubMedCrossRefGoogle Scholar
  112. 112.
    Bae JM, Choi YY, Kim H, Oh BH, Roh MR, Nam K, et al. Mohs micrographic surgery for extramammary Paget disease: a pooled analysis of individual patient data. J Am Acad Dermatol. 2013;68(4):632–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg. 2007;33(3):333–9.PubMedGoogle Scholar
  114. 114.
    Abide JM, Nahai F, Bennett RG. The meaning of surgical margins. Plast Reconstr Surg. 1984;73(3):492–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Coldiron BM, Goldsmith BA, Robinson JK. Surgical treatment of extramammary Paget’s disease. A report of six cases and a reexamination of Mohs micrographic surgery compared with conventional surgical excision. Cancer. 1991;67(4):933–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Bergen S, DiSaia PJ, Liao SY, Berman ML. Conservative management of extramammary Paget’s disease of the vulva. Gynecol Oncol. 1989;33(2):151–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Guerrieri M, Back MF. Extramammary Paget’s disease: role of radiation therapy. Australas Radiol. 2002;46(2):204–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Burrows NP, Jones DH, Hudson PM, Pye RJ. Treatment of extramammary Paget’s disease by radiotherapy. Br J Dermatol. 1995;132(6):970–2.PubMedCrossRefGoogle Scholar
  119. 119.
    Moreno-Arias G, Conill C, Castells-Mas A, Arenas M, Grimalt R. Radiotherapy for genital extramammary Paget’s disease in situ. Dermatol Surg. 2001;27(6):587–90.PubMedGoogle Scholar
  120. 120.
    Yanagi T, Kato N, Yamane N, Osawa R. Radiotherapy for extramammary Paget’s disease: histopathological findings after radiotherapy. Clin Exp Dermatol. 2007;32(5):506–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Besa P, Rich TA, Delclos L, Edwards CL, Ota DM, Wharton JT. Extramammary Paget’s disease of the perineal skin: role of radiotherapy. Int J Radiat Oncol Biol Phys. 1992;24(1):73–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Luk N, Yu K, Yeung W, Choi C, Teo M. Extramammary Paget’s disease: outcome of radiotherapy with curative intent. Clin Exp Dermatol. 2003;28(4):360–3.PubMedCrossRefGoogle Scholar
  123. 123.
    Hata M, Koike I, Wada H, Miyagi E, Kasuya T, Kaizu H, et al. Radiation therapy for extramammary Paget’s disease: treatment outcomes and prognostic factors. Ann Oncol. 2013;25(1):291–7.  https://doi.org/10.1093/annonc/mdt478.CrossRefPubMedGoogle Scholar
  124. 124.
    Brierley J, Stockdale A. Radiotherapy: an effective treatment for extramammary Paget’s disease. Clin Oncol. 1991;3(1):3–5.CrossRefGoogle Scholar
  125. 125.
    Kwan W, Teo P, Ngar Y, Yu K, Choi P. Perineal Paget’s disease: effective treatment with fractionated high dose rate brachytherapy. Clin Oncol. 1995;7(6):400–1.CrossRefGoogle Scholar
  126. 126.
    Korbelik M, Dougherty GJ. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res. 1999;59(8):1941–6.PubMedGoogle Scholar
  127. 127.
    Henta T, Itoh Y, Kobayashi M, Ninomiya Y, Ishibashi A. Photodynamic therapy for inoperable vulval Paget’s disease using – aminolaevulinic acid: successful management of a large skin lesion. Br J Dermatol. 1999;141:347–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Shieh S, Dee A, Cheney R, Frawley N, Zeitouni N, Oseroff A. Photodynamic therapy for the treatment of extramammary Paget’s disease. Br J Dermatol. 2002;146(6):1000–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Housel JP, Izikson L, Zeitouni NC. Noninvasive extramammary Paget’s disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. Dermatol Surg. 2010;36(11):1718–24.PubMedCrossRefGoogle Scholar
  130. 130.
    Mikasa K, Watanabe D, Kondo C, Kobayashi M, Nakaseko H, Yokoo K, et al. 5-Aminolevulinic acid-based photodynamic therapy for the treatment of two patients with extramammary Paget’s disease. J Dermatol. 2005;32(2):97–101.PubMedCrossRefGoogle Scholar
  131. 131.
    Li Q, Gao T, Jiao B, Qi X, Long HA, Qiao H, et al. Long-term follow-up of in situ extramammary Paget’s disease in Asian skin types IV/V treated with photodynamic therapy. Acta Derm Venereol. 2010;90(2):159–64.PubMedCrossRefGoogle Scholar
  132. 132.
    Becker-Wegerich PM, Fritsch C, Schulte KW, Megahed M, Neuse W, Goerz G, et al. Carbon dioxide laser treatment of extramammary Paget’s disease guided by photodynamic diagnosis. Br J Dermatol. 1998;138(1):169–72.PubMedCrossRefGoogle Scholar
  133. 133.
    Ewing TL. Paget’s disease of the vulva treated by combined surgery and laser. Gynecol Oncol. 1991;43(2):137–40.PubMedCrossRefGoogle Scholar
  134. 134.
    Kurzl RG. Paget’s disease. Semin Dermatol. 1996;15(1):60–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Zampogna JC, Flowers FP, Roth WI, Hassenein AM. Treatment of primary limited cutaneous extramammary Paget’s disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol. 2002;47(4):S229–S35.PubMedCrossRefGoogle Scholar
  136. 136.
    Berman B, Spencer J, Villa A, Poochareon V, Elgart G. Successful treatment of extramammary Paget’s disease of the scrotum with imiquimod 5% cream. Clin Exp Dermatol. 2003;28(s1):36–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Cohen PR, Schulze KE, Tschen JA, Hetherington GW, Nelson BR. Treatment of extramammary Paget disease with topical imiquimod cream: case report and literature review. South Med J. 2006;99(4):396–403.PubMedCrossRefGoogle Scholar
  138. 138.
    Wang LC, Blanchard A, Judge DE, Lorincz AA, Medenica MM, Busbey S. Successful treatment of recurrent extramammary Paget’s disease of the vulva with topical imiquimod 5% cream. J Am Acad Dermatol. 2003;49(4):769–71.PubMedCrossRefGoogle Scholar
  139. 139.
    Luyten A, Sörgel P, Clad A, Gieseking F, Maass-Poppenhusen K, Lellé RJ, et al. Treatment of extramammary Paget disease of the vulva with imiquimod: a retrospective, multicenter study by the German Colposcopy Network. J Am Acad Dermatol. 2014;70(4):644–50.PubMedCrossRefGoogle Scholar
  140. 140.
    Ye JN, Rhew DC, Yip F, Edelstein L. Extramammary Paget’s disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report. Cutis. 2006;77(4):245–50.PubMedGoogle Scholar
  141. 141.
    Qian Z, Zeitoun N, Shieh S, Helm T, Oseroff A. Successful treatment of extramammary Paget’s disease with imiquimod. J Drugs Dermatol JDD. 2003;2(1):73–6.PubMedGoogle Scholar
  142. 142.
    Vereecken P, Awada A, Ghanem G, da Costa CM, Larsimont D, Simoens C, et al. A therapeutic approach to perianal extramammary Paget’s disease: topical imiquimod can be useful to prevent or defer surgery. Med Sci Monit. 2007;13(6):CS75–CS7.PubMedGoogle Scholar
  143. 143.
    Machida H, Moeini A, Roman LD, Matsuo K. Effects of imiquimod on vulvar Paget’s disease: a systematic review of literature. Gynecol Oncol. 2015;139(1):165–71.PubMedCrossRefGoogle Scholar
  144. 144.
    Eliezri YD, Silvers DN, Horan DB. Role of preoperative topical 5-fluorouracil in preparation for Mohs micrographic surgery of extramammary Paget’s disease. J Am Acad Dermatol. 1987;17(3):497–505.PubMedCrossRefGoogle Scholar
  145. 145.
    Del Castillo L, Garcia C, Schoendorff C, Garcia J, Torres L, Garcia AD. Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget’s disease: response to topical 5-fluorouracil. Cutis. 2000;65(5):331–3.PubMedGoogle Scholar
  146. 146.
    Watring WG, Roberts JA, Lagasse LD, Berman ML, Ballon SC, Moore JG, et al. Treatment of recurrent Paget’s disease of the vulva with topical bleomycin. Cancer. 1978;41(1):10–1.PubMedCrossRefGoogle Scholar
  147. 147.
    Thirlby RC, Hammer CJ, Galagan KA, Travaglini JJ, Picozzi VJ. Perianal Paget’s disease: successful treatment with combined chemoradiotherapy. Dis Colon Rectum. 1990;33(2):150–2.PubMedCrossRefGoogle Scholar
  148. 148.
    Yamazaki N. Chemotherapy for advanced adenocarcinoma of the skin: experience with combination chemotherapy and a review of the literature. Gan to kagaku ryoho Cancer & chemotherapy. 1997;24(1):30–6.Google Scholar
  149. 149.
    Watanabe Y, Hoshiai H, Ueda H, Nakai H, Obata K, Noda K. Low-dose mitomycin C, etoposide, and cisplatin for invasive vulvar Paget’s disease. Int J Gynecol Cancer. 2002;12(3):304–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Kariya K, Tsuji T, Schwartz RA. Trial of Low-dose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget’s disease. Dermatol Surg. 2004;30(s2):341–4.PubMedCrossRefGoogle Scholar
  151. 151.
    Oguchi S, Kaneko M, Uhara H, Saida T. Docetaxel induced durable response in advanced extramammary Paget’s disease: a case report. J Dermatol. 2002;29(1):33–7.PubMedCrossRefGoogle Scholar
  152. 152.
    Kao SC-H, Yap ML, Berry M, Santos L, Lin M, Goldrick A. Metastatic extramammary paget’s disease responding to cisplatin, 5-fluorouracil and radiotherapy-a case report. Asia Pac J Clin Oncol. 2009;1:3.Google Scholar
  153. 153.
    Beleznay K, Levesque M, Gill S. Response to 5-fluorouracil in metastatic extramammary Paget disease of the scrotum presenting as pancytopenia and back pain. Curr Oncol. 2009;16(5):81–3.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Fujisawa Y, Umebayashi Y, Otsuka F. Metastatic extramammary Paget’s disease successfully controlled with tumour dormancy therapy using docetaxel. Br J Dermatol. 2006;154(2):375–6.PubMedCrossRefGoogle Scholar
  155. 155.
    Mochitomi Y, Sakamoto R, Gushi A, Hashiguchi T, Mera K, Matsushita S, et al. Extramammary Paget’s disease/carcinoma successfully treated with a combination chemotherapy: report of two cases. J Dermatol. 2005;32(8):632–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Tanskanen M, Jahkola T, Asko-Seljavaara S, Jalkanen J, Isola J. HER2 oncogene amplification in extramammary Paget’s disease. Histopathology. 2003;42(6):575–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Takahagi S, Noda H, Kamegashira A, Madokoro N, Hori I, Shindo H, et al. Metastatic extramammary Paget’s disease treated with paclitaxel and trastuzumab combination chemotherapy. J Dermatol. 2009;36(8):457–61.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Dermatology, St. Joseph’s Hospital and Medical Center, Dignity HealthPhoenixUSA
  2. 2.Tucson Hospital Medical Education ProgramTucson Medical CenterTucsonUSA

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