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Sir James Paget first described Paget's disease of nipple in 1874. Fifteen  years later Crocker described the first case of extramammary Paget's disease affecting the scrotum and penis. Dubreuith described the first case of vulvar extramammary Paget's disease in 1901.

Extramammary Paget's disease is an uncommon neoplastic condition observed mostly in areas with numerous apocrine and  or eccrine glands.

The most common site is the anogenital region followed by axilla, eyelid and external ear.

This condition can be classified into primary (of cutaneous origin)  and secondary (of extracutaneous origin).

The secondary extramammary Paget disease results from spread of an internal malignancy, most commonly of an anorectal origin or of urothelial origin (bladder, urethra).

A small number of intraepithelial Paget's disease is associated with adnexal adenocarcinoma. This is referred to as 'pagetoid spread' from the adnexal adenocarcinoma.

Clinically,  extramammary Paget's disease begins insidiously with pruritis and burning sensation.

The macroscopic appearance  ranges from flaking ,oozing and maceration to crusted plaque and tumour formation.

The histopatholoical features are similar in mammary and extramammary disease. The Paget's cells are present singly or in small clusters. These cells may form small tubular structures in the epidermis.

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Paget's cells are large with amphophilic, granular cytoplasm and prominent atypical nucleus. Small numbers of signet ring cells may be present.

The Paget's cells may infiltrate into the upper portion of the epidermis, however these are usually  located in the lower portion of the epidermis and may also be noted within the pilosebaceous unit.

Most of these cells contain  mucin and stain positively with mucicarmine and PAS. Immunohistochemical examination shows positivity with  CAM 5.2, EMA, CK7 and GCDFP-15. These findings indicate that the Paget's cells show glandular differentiation.   GCDFP- 15 is strongly expressed in cases of vulval and perianal extramammary Paget's disease without any underlying internal malignancy.

Differential Diagnosis:

The differential diagnosis includes superficial spreading malignant melanoma, Bowen's disease, the epidermal phase of neuroendocrine carcinoma , mycosis fungoides, Toker cells, clear cell papulosis and pagetoid spread of visceral carcinoma.
In superficial spreading melanoma, the tumour cells show prominent nesting along the dermoepidermal junction. Immunohistochemically,   these cells  are negative for CAM 5.2, EMA, CEA (these are positive in Paget's disease) and are positive for S100 and HMB45.

No intracellular mucin is seen and there is no  acinar formation  in melanoma .  In 25% cases S100 expression has been noted in mammary Paget's disease . In extramammary Paget's disease only occasional cells show S100 positivity.

In  pagetoid Bowen's disease no signet ring cells , intracellular mucin or  acinar structures are identified. Immunohistochemical staining will cofirm the diagnosis (CAM 5.2, EMA, CEA negativity).

In mycosis fungoides the 'cerebriform cells' with pale cytoplasm may resemble Paget's cells. However T cell markers will help in establishing the diagnosis. (CD3, UCHL-1 positive in mycosis fungoides).

In rectal carcinoma with pagetoid spread the cells show immunopositivity with CK7 and CK20 together with  CAM 5.2, EMA and CEA and negativity with GCDFP-15 .  In extramammary paget's disease  CK20 is negative  and GCDFP-15 is positive.

In pagetoid spread of prostatic carcinoma the cells show immunopositivity with PSA and CAM5.2 . The others stains are negative.

In pagetoid spread of neuroendocrine  carcinoma  paranuclear dot positivity is noted with  CAM 5.2, CK20, EMA and Synaptophysin are also positive.

Toker cells are normally found in the nipple epithelium and is characterised by clear cytoplasm and small eccentric nuclei. In clear cell papulosis the histological  features are similar to toker cell hyperplasia. Unlike Paget's cells, these cells have a bland appearance.

The treatment for noninvasive extramammary Paget's disease is wide surgical excision  (ideally with 1cm margin of normal skin).  In cases of  locally invasive extramammary Paget's disease  radical surgery  with or without adjuvant radiotherapy is advocated.
Primary extramammary Paget's disease ,confined to epidermis has a good  prognosis. 

The diagnosis of extramammary Paget's disease warrants a thorough search for associated adnexal or visceral malignancy.

In conclusion, extramammary Paget's disease is a rare entity  which may takes a progressive course, if not treated early. Histologically,  the most common differential diagnosis includes superficial spreading melanoma and Bowen's disease. A careful clinicopathological correlation  and histological assessment  with appropriate histochemical and immunohistochemical staining should allow a confident histological diagnosis of extramammary Paget's disease to be made in most cases.

Abstracts:

Vulvar Clear Cells of Toker: Precursors of Extramammary Paget's Disease. Am J Dermatopathol. 2005;27(3):185-188.

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.

p185(HER2) overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease.Mod Pathol. 2005;18(3):354-7.

Androgen receptors are frequently expressed in mammary and extramammary Paget's disease.Mod Pathol. 2005;18(10):1283-8.

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.

Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease.J Cutan Pathol. 2004;31(7):483-91

Extramammary Paget disease of the scrotum with features of Bowen disease.Arch Pathol Lab Med. 2004 Jan;128(1):84-6.

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(2): 169-73.

Zirconyl hematoxylin vs. alcian blue staining in a case of extramammary Paget's disease.J Cutan Pathol. 2003;30(6):401-4.

Keratin profile of intraepidermal cells in Paget's disease, extramammary Paget's disease, and pagetoid squamous cell carcinoma in situ. J Cutan Pathol. 2003 ;30(7):449-54.

Clear cells of Toker in accessory nipples. J Cutan Pathol 2003 ;30(4): 256-60

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

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):185-189

Extramammary Paget Disease of the Axilla Associated With Comedo-like Apocrine Carcinoma In Situ.Am J Dermatopathol 2002;24(4):351-7

Ectopic extramammary Paget's disease arising on the cheek. Dermatol Surg. 2002;28(5):430-3.

The ectopic expression of gastric mucin in extramammary and mammary Paget's disease.Am J Surg Pathol 2002 ;26(5):617-23

Uroplakin-III to distinguish primary vulvar Paget disease from Paget disease secondary to urothelial carcinoma.Hum Pathol 2002 ;33(5):545-8

Pagetoid variant of actinic keratosis with or without squamous cell carcinoma of sun-exposed skin: a lesion simulating extramammary Paget's disease.Histopathology. 2002 ;41(4):331-6.

Differential Expression of Mucin Genes in Mammary and Extramammary Paget's Disease .Am J Surg Pathol 2001;25:1469-1477

Proliferative Epidermal Lesions Associated With Anogenital Paget's Disease. Am J Surg Pathol 2000; 24:543-552

Pagetoid Dyskeratosis of the Cervix An Incidental Histologic Finding in Uterine Prolapse. Am J Surg Pathol 2000;24:1518-1523

Benign mucinous metaplasia of the penis. A lesion resembling extramammary Paget's disease.J Cutan Pathol 2000;27 (2), 76-7

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.

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.

Vulvar Paget's disease: a clinicopathologic and immunohistochemical study of 19 cases.Am J Surg Pathol. 1997;21(10):1178-87.

Vulvar disease: a clinicopathologic and immunohistochemical study of 19 cases. Am J Surg Pathol 1997;21(10):1178-87

Cytokeratin 7 staining in mammary and extramammary  Paget's disease. Mod Pathol 1997; 11:1069-74

Extramammary Paget's disease: a report of 22 cases in Chinese males. J Dermatol 1996;23: 320-324

A clinicopathologic study of  30 patients with Paget's disease of the vulva. Gynecol Oncol 1995; 56:63-70

Immunohistochemical stains in extramammary Paget's disease.Am J Dermatopathol. 1992 Oct;14(5):402-7.

Paget's disease and melanoma of the vulva. Use of a panel of monoclonal antibodies to identify cell type and and to microscopilly define adequacy of surgical margins. Gynecol Oncol 1992;46: 216-21

Expression of ras p21 in mammary and extramammary Paget's disease.Arch Pathol Lab Med. 1990 ;114(8):858-61.

The histogenesis of  mammary and extramammary Paget's  disease . Histopathology 1989;14(4): 409-416

Perianal Paget's disease. Dis Colon Rectum 1987;30:263-266

Bowen's disease Paget's disease and malignant melanoma in situ. South Med J 1986;79(4): 410-413

Extramammary Paget's disease prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985;13:1009-1014

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.

Extramammary Paget's disease. a critical reexamination. Am J Dermatopathol 1979; 1:101-132