Background: Tumor cells of malignant melanoma, the "great imitator," may mo
rphologically mimic almost any cell, including histiocytes. Immunohistochem
ical stains for histiocytes are often used to distinguish histiocytic lesio
ns that resemble melanomas, but we have noted and others have reported that
these markers may be immunoreactive in melanomas. Methods: We evaluated 43
primary and metastatic melanomas with traditional markers for melanomas (S
100, HMB45, and NKI-C3) and common markers used for histiocytes (alpha-1-an
titrypsin or AAT, CD68/KP1, HAM56, Mac387, and Muramidase). The extent (< 5
%, 5 to 30%, 30 to 60%, 60 to 90%, >90%) and intensity (1+ to 4+) of staini
ng were recorded semi-quantitatively. Results: Melanoma immunoreactivity (>
5% of tumor cells) was as follows: S100, 100%; HMB45, 91%; NKI, 91%; AAT, 9
5%; CD68, 86%; HAM56, 26%; Mac387, 7%; and Muramidase, 30%. Among the histi
ocytic markers, staining by AAT and CD68 was typically diffuse but weak. St
aining by HAM56, Mac387, and Muramidase was usually focal. In contrast, the
traditional melanoma markers showed diffuse and strong staining. Interpret
ation of the histiocytic markers was complicated by scattered atypical hist
iocytes and pigmented tumor cells. Conclusion: Melanomas are commonly immun
oreactive for histiocytic markers. AAT and CD68 immunostains are diffusely
positive almost as frequently as traditional melanoma markers, although wit
h weaker intensity. HAM56, Mac387, and Muramidase are less commonly positiv
e and exhibit focal staining. Therefore, depending on the context, histiocy
tic markers may not be helpful in differentiating histiocytes and histiocyt
ic tumors from melanomas.