By Rodney T. Miller, M.D.

Paget’s disease of the skin is a relatively common form of intraepidermal adenocarcinoma that is often easy to diagnose on H&E examination in florid cases. However, in certain situations, distinguishing Paget’s disease from Bowen’s disease (intraepidermal squamous carcinoma) and melanoma can be difficult, a fact well known to diagnostic surgical pathologists.

When the diagnosis of Paget’s disease requires the use of ancillary methods, immunohistochemistry (IHC) can be an indispensable tool to aid in the accurate classification of these biopsies. A number of antibodies that may be useful in this situation are discussed below.

Cytokeratin 7: Neoplastic cells of Paget’s disease express large amounts of cytokeratin 7, so immunostains for cytokeratin 7 characteristically highlight Paget’s cells very nicely. One exception to this finding is in some cases of perianal Paget’s disease associated with underlying rectal carcinoma. In these cases, the Paget’s cells may express Cytokeratin 20 and lack expression of Cytokeratin 7. Unfortunately, some cases of Bowen’s disease also express strong cytokeratin 7, so a marker of squamous differentiation is also recommended.

Cytokeratin 5/6: This is an excellent marker of squamous differentiation, so it can be very useful in identifying Bowen’s disease. Characteristically, squamous carcinomas (and normal squamous epithelium) express cytokeratin 5/6 strongly and diffusely, so it highlights the benign squamous epithelium in the background, and will stain those cases of Bowen’s disease that express cytokeratin 7, allowing distinction of Bowen’s disease from Paget’s disease. (Although a few scattered cells in Paget’s disease may show expression of cytokeratin 5/6, Paget’s disease lacks the strong and diffuse expression of cytokeratin 5/6 that is observed in cases of Bowen’s disease).

S100 Protein: S100 protein stains the vast majority of melanoma cells strongly, including intraepidermal melanoma. Therefore, this is a useful marker to employ in cases where melanoma is in the differential diagnosis. Some cases of Paget’s disease may also express S100 protein, so it is crucial to include markers of epithelial differentiation in the panel of immunostains, such as cytokeratin 7 and cytokeratin 5/6.


Some authors have noted that “Toker cells” in the nipple epidermis also express cytokeratin 7, so attention must be paid to morphologic features to make certain that there is sufficient cytologic atypia in these cases to warrant a malignant interpretation. Normal intraepidermal Merkel cells may also be cytokeratin 7 positive. Some authors have also reported the finding of cytokeratin 7 positive cells in the nipple epidermis when there is an underlying benign proliferative nipple duct lesion, but in this situation, the cells in question are cytologically bland. In some cases of perianal Paget’s disease, the addition of cytokeratin 20 is also suggested to identify cases that may be an association with an underlying rectal carcinoma. Some authors suggest including PSA and prostatic acid phosphatase stains in male patients.


In most cases, the differential diagnosis of Paget’s disease of the skin vs. melanoma vs. Bowen’s disease can be effectively addressed using immunostains to cytokeratin 7, cytokeratin 5/6, and S100 protein.


  1. Am J Surg Pathol 22(2): 170-9, 1998
  2. Mod Pathol 10(11): 1069-1074, 1997
  3. Am J Clin Pathol 108:6-12, 1997
  4. Am J Surg Pathol 23(2): 212-219, 1999
  5. Am J Clin Pathol 108:334, 1997
  6. Am J Surg Pathol 23(11): 1349-1355, 1999
  7. Arch Pathol Lab Med 124: 427-430, 2000