Melanoma In Situ Versus Paget’s Disease

  • Jon A. ReedEmail author
  • Christopher R. Shea
  • Victor G. Prieto


Malignant melanoma in situ (MIS) is characterized by an intraepidermal proliferation of cytologically atypical melanocytes, often disposed as single cells in a haphazard pattern. This “pagetoid” scatter of atypical melanocytes closely resembles Paget’s disease itself. In addition, several other epithelial neoplasms (benign and malignant) are characterized by prominent pagetoid scatter of cells within the epidermis. Histological features that help to distinguish these neoplasms will be discussed.


Atypical Cell Seborrheic Keratosis Inflammatory Dermatosis Clinical Differential Diagnosis Keratohyaline Granule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Clark WHJ, Mihm MCJ. Lentigo maligna and lentigo-maligna melanoma. Am J Pathol. 1969;55:39–67.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Clark WHJ. Malignant melanoma in situ. Hum Pathol. 1990;21:1197–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Costello MJ, Fisher SB, Defeo CP. Melanotic freckle, lentigo maligna. Arch Dermatol. 1959;80:753–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Klauder JV, Beerman H. Melanotic freckle (Hutchinson), melanose circonscrite precancereuse (Dubreuilh). AMA Arch Derm. 1955;71:2–10.PubMedCrossRefGoogle Scholar
  5. 5.
    McGovern VJ, Shaw HM, Milton GW, Farago GA.Is malignant melanoma arising in a Hutchinson’s melanotic freckle a separate disease entity? Histopathology. 1980;4:235–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Mishima Y. Melanosis circumscripta praecancerosa (Dubreuilh), a non-nevoid premelanoma distinct from junction nevus. J Invest Dermatol. 1960;34:361–75.PubMedGoogle Scholar
  7. 7.
    Rahbari H, Nabai H, Mehregan AH, Mehregan DA, Mehregan DR, Lipinski J. Amelanotic lentigo maligna melanoma: a diagnostic conundrum—presentation of four new cases. Cancer. 1996;77: 2052–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Su WP, Bradley RR. Amelanotic lentigo maligna. Arch Dermatol. 1980;116:82–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Borkovic SP, Schwartz RA. Amelanotic lentigo maligna melanoma manifesting as a dermatitislike plaque. Arch Dermatol. 1983;119:423–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Kelly RI, Cook MG, Mortimer PS. Aggressive amelanotic lentigo maligna. Br J Dermatol. 1994;131: 562–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Pichler E, Fritsch P. Macular amelanotic melanoma in situ. Dermatologica. 1988;177:313–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Prieto VG, McNutt NS, Prioleau PG, Shea CR. Scaly erythematous lesion in a patient with extensive solar damage. Malignant melanoma in situ, amelanotic type. Arch Dermatol. 1996;132:1239, 1242.PubMedCrossRefGoogle Scholar
  13. 13.
    Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163:1765–70.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Gerami P, Mafee M, Lurtsbarapa T, Guitart J, Haghighat Z, Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol. 2010;146:273–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Grammatico P, Modesti A, Steindl K, et al. Lentigo maligna. Cytogenetic, ultrastructural, and phenotypic characterization of a primary cell culture. Cancer Genet Cytogenet. 1992;60:141–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Stevens G, Cockerell CJ. Avoiding sampling error in the biopsy of pigmented lesions. Arch Dermatol. 1996;132:1380–2.PubMedCrossRefGoogle Scholar
  17. 17.
    Katz SK, Guitart J. Starburst giant cells in benign nevomelanocytic lesions. J Am Acad Dermatol. 1998; 38:283.PubMedCrossRefGoogle Scholar
  18. 18.
    Gruber SB, Barnhill RL, Stenn KS, Roush GC. Nevomelanocytic proliferations in association with cutaneous malignant melanoma: a multivariate analysis. J Am Acad Dermatol. 1989;21:773–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Helm K, Findeis-Hosey J. Immunohistochemistry of pigmented actinic keratoses, actinic keratoses, melanomas in situ and solar lentigines with Melan-A. J Cutan Pathol. 2008;35:931–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Prieto VG, Argenyi ZB, Barnhill RL, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003; 120:203–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Lane H, O’Loughlin S, Powell F, Magee H, Dervan PA. A quantitative immunohistochemical evaluation of lentigo maligna and pigmented solar keratosis. Am J Clin Pathol. 1993;100:681–5.PubMedGoogle Scholar
  22. 22.
    Bhawan J. Mel-5: a novel antibody for differential diagnosis of epidermal pigmented lesions of the skin in paraffin-embedded sections. Melanoma Res. 1997;7:43–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Kohler S, Rouse RV, Smoller BR. The differential diagnosis of pagetoid cells in the epidermis. Mod Pathol. 1998;11:79–92.PubMedGoogle Scholar
  24. 24.
    Reed JA, Shea CR. Lentigo maligna: melanoma in situ on chronically sun-damaged skin. Arch Pathol Lab Med. 2011;135:838–41.PubMedGoogle Scholar
  25. 25.
    Shah KD, Tabibzadeh SS, Gerber MA. Immunohistochemical distinction of Paget’s disease from Bowen’s disease and superficial spreading melanoma with the use of monoclonal cytokeratin antibodies. Am J Clin Pathol. 1987;88:689–95.PubMedGoogle Scholar
  26. 26.
    Kelley LC, Starkus L. Immunohistochemical staining of lentigo maligna during Mohs micrographic surgery using MART-1. J Am Acad Dermatol. 2002;46: 78–84.PubMedCrossRefGoogle Scholar
  27. 27.
    Menaker GM, Chiang JK, Tabila B, Moy RL. Rapid HMB-45 staining in Mohs micrographic surgery for melanoma in situ and invasive melanoma. J Am Acad Dermatol. 2001;44:833–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Demartini CS, Dalton MS, Ferringer T, Elston DM. Melan-A/MART-1 positive “pseudonests” in lichenoid inflammatory lesions: an uncommon phenomenon. Am J Dermatopathol. 2005;27:370–1.PubMedCrossRefGoogle Scholar
  29. 29.
    Buonaccorsi JN, Prieto VG, Torres-Cabala C, Suster S, Plaza JA. Diagnostic utility and comparative immunohistochemical analysis of MITF-1 and SOX10 to distinguish melanoma in situ and actinic keratosis: a clinicopathological and immunohistochemical study of 70 cases. Am J Dermatopathol. 2014;36:124–30.PubMedCrossRefGoogle Scholar
  30. 30.
    King R, Weilbaecher KN, McGill G, Cooley E, Mihm M, Fisher DE. Microphthalmia transcription factor. A sensitive and specific melanocyte marker for melanoma diagnosis. Am J Pathol. 1999;155:731–8.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    King R, Page RN, Googe PB, Mihm MCJ. Lentiginous melanoma: a histologic pattern of melanoma to be distinguished from lentiginous nevus. Mod Pathol. 2005;18:1397–401.PubMedCrossRefGoogle Scholar
  32. 32.
    Mohamed A, Gonzalez RS, Lawson D, Wang J, Cohen C. SOX10 expression in malignant melanoma, carcinoma, and normal tissues. Appl Immunohistochem Mol Morphol. 2013;21:506–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Ramos-Herberth FI, Karamchandani J, Kim J, Dadras SS. SOX10 immunostaining distinguishes desmoplastic melanoma from excision scar. J Cutan Pathol. 2010;37:944–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Shin J, Vincent JG, Cuda JD, et al. Sox10 is expressed in primary melanocytic neoplasms of various histologies but not in fibrohistiocytic proliferations and histiocytoses. J Am Acad Dermatol. 2012;67:717–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Glasgow BJ, Wen DR, Al-Jitawi S, Cochran AJ. Antibody to S-100 protein aids the separation of pagetoid melanoma from mammary and extramammary Paget’s disease. J Cutan Pathol. 1987;14:223–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Rosen L, Amazon K, Frank B. Bowen’s disease, Paget’s disease, and malignant melanoma in situ. South Med J. 1986;79:410–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Guldhammer B, Norgaard T. The differential diagnosis of intraepidermal malignant lesions using immunohistochemistry. Am J Dermatopathol. 1986;8: 295–301.PubMedCrossRefGoogle Scholar
  38. 38.
    Reed W, Oppedal BR, Eeg LT. Immunohistology is valuable in distinguishing between Paget’s disease, Bowen’s disease and superficial spreading malignant melanoma. Histopathology. 1990;16:583–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Seetharam S, Fentiman IS. Paget’s disease of the nipple. Womens Health (Lond Engl). 2009;5:397–402.CrossRefGoogle Scholar
  40. 40.
    Vergati M, Filingeri V, Palmieri G, Roselli M. Perianal Paget’s disease: a case report and literature review. Anticancer Res. 2012;32:4461–5.PubMedGoogle Scholar
  41. 41.
    Chilukuri S, Page R, Reed JA, Friedman J, Orengo I. Ectopic extramammary Paget’s disease arising on the cheek. Dermatol Surg. 2002;28:430–3.PubMedGoogle Scholar
  42. 42.
    Cohen MA, Hanly A, Poulos E, Goldstein GD. Extramammary Paget’s disease presenting on the face. Dermatol Surg. 2004;30:1361–3.PubMedGoogle Scholar
  43. 43.
    de Blois GG, Patterson JW, Hunter SB. Extramammary Paget’s disease. Arising in knee region in association with sweat gland carcinoma. Arch Pathol Lab Med. 1984;108:713–6.PubMedGoogle Scholar
  44. 44.
    Hilliard NJ, Huang C, Andea A. Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature. J Cutan Pathol. 2009;36:995–1000.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Sawada Y, Bito T, Kabashima R, et al. Ectopic extramammary Paget’s disease: case report and literature review. Acta Derm Venereol. 2010;90:502–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Hastrup N, Andersen ES. Adenocarcinoma of Bartholin’s gland associated with extramammary Paget’s disease of the vulva. Acta Obstet Gynecol Scand. 1988;67:375–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Inose T, Asao T, Nakamura J, Ide M, Fukuchi M, Kuwano H. Double anal canal cancers associated with a long history of perianal Paget’s disease: report of a case. Surg Today. 2012;42:697–702.PubMedCrossRefGoogle Scholar
  48. 48.
    Sleater JP, Ford MJ, Beers BB. Extramammary Paget’s disease associated with prostate adenocarcinoma. Hum Pathol. 1994;25:615–7.PubMedCrossRefGoogle Scholar
  49. 49.
    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;33:549–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Lanzafame S, Broggi B. Extramammary Paget’s disease. Immunocytochemical study and histogenetic considerations. Pathologica. 1989;81:661–9.PubMedGoogle Scholar
  51. 51.
    Pizzichetta MA, Canzonieri V, Massarut S, et al. Pigmented mammary Paget’s disease mimicking melanoma. Melanoma Res. 2004;14:S13–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Petersson F, Ivan D, Kazakov DV, Michal M, Prieto VG. Pigmented Paget disease—a diagnostic pitfall mimicking melanoma. Am J Dermatopathol. 2009;31: 223–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Bayer-Garner IB, Reed JA. Immunolabeling pattern of syndecan-1 expression may distinguish pagetoid Bowen’s disease, extramammary Paget’s disease, and pagetoid malignant melanoma in situ. J Cutan Pathol. 2004;31:169–73.PubMedCrossRefGoogle Scholar
  54. 54.
    Sellheyer K, Krahl D. Ber-EP4 enhances the differential diagnostic accuracy of cytokeratin 7 in pagetoid cutaneous neoplasms. J Cutan Pathol. 2008;35:366–72.PubMedCrossRefGoogle Scholar
  55. 55.
    Bhawan J. Squamous cell carcinoma in situ in skin: what does it mean? J Cutan Pathol. 2007;34:953–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004;77:574–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Yu HS, Liao WT, Chai CY. Arsenic carcinogenesis in the skin. J Biomed Sci. 2006;13:657–66.PubMedCrossRefGoogle Scholar
  58. 58.
    Cicale L, Dalle S, Thomas L. Pigmented Bowen’s disease. Ann Dermatol Venereol. 2008;135:334–6.PubMedCrossRefGoogle Scholar
  59. 59.
    De Vries K, Lelie B, Habets WJ, De Bruijckere L, Prens EP. Pigmented Bowen’s disease: a report of two cases. Dermatol Surg. 2011;37:1061–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Gahalaut P, Rastogi MK, Mishra N, Chauhan S. Multiple pigmented Bowen’s disease: a diagnostic and therapeutic dilemma. Case Rep Oncol Med. 2012;2012:342030.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Krishnan R, Lewis A, Orengo IF, Rosen T. Pigmented Bowen’s disease (squamous cell carcinoma in situ): a mimic of malignant melanoma. Dermatol Surg. 2001;27:673–4.PubMedGoogle Scholar
  62. 62.
    Lee JW, Hur J, Yeo KY, Yu HJ, Kim JS. A case of pigmented Bowen’s disease. Ann Dermatol. 2009;21: 197–9.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Marschall SF, Ronan SG, Massa MC. Pigmented Bowen’s disease arising from pigmented seborrheic keratoses. J Am Acad Dermatol. 1990;23:440–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Papageorgiou PP, Koumarianou AA, Chu AC. Pigmented Bowen’s disease. Br J Dermatol. 1998; 138:515–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Chang J, Prieto VG, Sangueza M, Plaza JA. Diagnostic utility of p63 expression in the differential diagnosis of pagetoid squamous cell carcinoma in situ and extramammary Paget disease: a histopathologic study of 70 cases. Am J Dermatopathol. 2014;36:49–53.PubMedCrossRefGoogle Scholar
  66. 66.
    Raju RR, Goldblum JR, Hart WR. Pagetoid squamous cell carcinoma in situ (pagetoid Bowen’s disease) of the external genitalia. Int J Gynecol Pathol. 2003; 22:127–35.PubMedCrossRefGoogle Scholar
  67. 67.
    Sakiz D, Turkmenoglu TT, Kabukcuoglu F. The expression of p63 and p53 in keratoacanthoma and intraepidermal and invasive neoplasms of the skin. Pathol Res Pract. 2009;205:589–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Clarke LE, Conway AB, Warner NM, Barnwell PN, Sceppa J, Helm KF. Expression of CK7, Cam 5.2 and Ber-Ep4 in cutaneous squamous cell carcinoma. J Cutan Pathol. 2013;40:646–50.PubMedCrossRefGoogle Scholar
  69. 69.
    Wang EC, Kwah YC, Tan WP, Lee JS, Tan SH. Extramammary Paget disease: immunohistochemistry is critical to distinguish potential mimickers. Dermatol Online J. 2012;18:4.PubMedGoogle Scholar
  70. 70.
    Longo C, Zalaudek I, Moscarella E, et al. Clonal seborrheic keratosis: dermoscopic and confocal microscopy characterization. J Eur Acad Dermatol Venereol. 2013. Epub ahead of print. doi:  10.1111/jdv.12261
  71. 71.
    Boer-Auer A, Jones M, Lyasnichaya OV. Cytokeratin 10-negative nested pattern enables sure distinction of clonal seborrheic keratosis from pagetoid Bowen’s disease. J Cutan Pathol. 2012;39:225–33.PubMedCrossRefGoogle Scholar
  72. 72.
    Cashmore RW, Perry HO. Differentiating seborrheic keratosis from skin neoplasm. Geriatrics. 1985;40(69–71): 74–5.Google Scholar
  73. 73.
    Cheng AG, Deubner H, Whipple ME. Melanoacanthoma of the external auditory canal: a case report and review of the literature. Am J Otolaryngol. 2007;28:433–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Jain S, Barman KD, Garg VK, Sharma S, Dewan S, Mahajan N. Multifocal cutaneous melanoacanthoma with ulceration: a case report with review of literature. Indian J Dermatol Venereol Leprol. 2011;77: 699–702.PubMedCrossRefGoogle Scholar
  75. 75.
    Lambert WC, Lambert MW, Mesa ML, et al. Melanoacanthoma and related disorders. Simulants of acral-lentiginous (P-P-S-M) melanoma. Int J Dermatol. 1987;26:508–10.PubMedCrossRefGoogle Scholar
  76. 76.
    Matsuoka LY, Barsky S, Glasser S. Melanoacanthoma of the lip. Arch Dermatol. 1982;118:290.PubMedCrossRefGoogle Scholar
  77. 77.
    Rossiello L, Zalaudek I, Ferrara G, Docimo G, Giorgio CM, Argenziano G. Melanoacanthoma simulating pigmented spitz nevus: an unusual dermoscopy pitfall. Dermatol Surg. 2006;32:735–7.PubMedGoogle Scholar
  78. 78.
    Shankar V, Nandi J, Ghosh K, Ghosh S. Giant melanoacanthoma mimicking malignant melanoma. Indian J Dermatol. 2011;56:79–81.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Spott DA, Heaton CL, Wood MG. Melanoacanthoma of the eyelid. Arch Dermatol. 1972;105:898–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Prince C, Mehregan AH, Hashimoto K, Plotnick H. Large melanoacanthomas: a report of five cases. J Cutan Pathol. 1984;11:309–17.PubMedCrossRefGoogle Scholar
  81. 81.
    Schlappner OL, Rowden G, Philips TM, Rahim Z. Melanoacanthoma. Ultrastructural and immunological studies. J Cutan Pathol. 1978;5:127–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jon A. Reed
    • 1
    • 2
    Email author
  • Christopher R. Shea
    • 3
  • Victor G. Prieto
    • 4
  1. 1.Baylor College of MedicineHoustonUSA
  2. 2.CellNetix Pathology & LaboratoriesSeattleUSA
  3. 3.University of Chicago MedicineChicagoUSA
  4. 4.MD Anderson Cancer CenterUniversity of HoustonHoustonUSA

Personalised recommendations