Background: Syphilis is often misdiagnosed clinically, and biopsies might be required. Objective: To determine histopathologic features that distinguish secondary syphilis from pityriasis lichenoides (PL), pityriasis rosea (PR), and early mycosis fungoides (MF). Methods: Histopathologic features of 100 cases of syphilis, 110 cases of PL, 72 cases of PR, and 101 cases of MF were compared. Results: Elongated rete ridges and interstitial inflammation favor syphilis over PL (likelihood ratios 3.44 and 2.72, respectively), but no feature reliably distinguishes between them. Secondary syphilis and PR can be distinguished by neutrophils in the stratum corneum, plasma cells, interface dermatitis with lymphocytes and vacuoles, and lymphocytes with ample cytoplasm. Plasma cells and lymphocytes with ample cytoplasm are rare in early MF and can be used as distinguishing features. Conclusions: Histopathologic features characteristic of syphilis can be seen in PL, PR, and early MF. Distinguishing syphilis from PL can be difficult histologically, and a high index of suspicion is required. Although elongation of rete and interstitial inflammation favor syphilis, plasma cells (historically considered a significant feature of syphilis) are often encountered in PL. Vacuolar interface dermatitis with a lymphocyte in every vacuole is considered characteristic of PL, but this feature appears to be more common in syphilis.
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