Paget disease of the vulva can be mimicked by several disease entities 
histopathologically, but most of these entities can be clinically distinguished 
from vulvar Paget disease. However, vulvar Paget disease is in itself a 
heterogeneous group of epithelial neoplasms that can be similar both clinically 
and histopathologically. The subtypes of vulvar Paget disease include primary 
Paget disease arising from a pluripotent stem cell within the epithelium of the 
vulva, and secondary Paget disease of the vulva. Secondary vulvar Paget disease 
results from spread of an internal malignancy, most commonly from an anorectal 
adenocarcinoma or urothelial carcinoma of the bladder or urethra, to the vulvar 
epithelium. We have recently proposed that these lesions be classified as 
primary (of cutaneous origin) or secondary (of extracutaneous origin). These 
subtypes can present similarly as eczematoid skin lesions and may appear similar 
on routine hematoxylin and eosin-stained slides. Immunohistochemical studies can 
help differentiate between them. Our current study includes 17 patients with a 
pathologic diagnosis of vulvar Paget disease. We performed a panel of 
immunohistochemical stains, including cytokeratin (CK) 7 and 20, 
carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 
(GCDFP-15), and uroplakin-III (UP-III). Of these 17 patients, 14 (80%) had 
primary intraepithelial cutaneous Paget disease, 13 without invasion and 1 with 
associated invasion. Three patients had urothelial carcinoma with spread to the 
vulva, manifesting as secondary vulvar Paget disease. Immunohistochemically, 
primary vulvar Paget disease is immunoreactive for CK 7 and GCDFP-15, but 
uncommonly for CK 20. Vulvar Paget disease secondary to anorectal carcinoma 
demonstrates CK 20 immunoreactivity but is usually nonreactive for CK 7 and 
consistently nonimmunoreactive for GCDFP-15. Vulvar Paget disease secondary to 
urothelial carcinoma is immunoreactive for CK 7 and CK 20 but nonimmunoreactive 
for GCDFP-15. In addition, we propose the use of a new, commercially available 
antibody, UP-III, which is specific for urothelium and, in our experience, is 
immunoreactive in secondary vulvar Paget disease of urothelial origin. The 
distinction between these 3 types of Paget and Paget-like lesions is essential 
in that the specific diagnosis has a significant influence on current treatment. 
The difference in surgical approach to the subtypes of vulvar Paget disease 
justifies classifying them into distinct lesions, which may be aided by the use 
of immunohistochemistry, including UP-III.