Differentiating hypertrophic lichen planus (LP) from well-differentiated squamous cell carcinoma (SCC) is a histological challenge given the numerous histopathologic similarities between SCC and pseudoepitheliomatous hyperplasia (PEH) arising in the setting of hypertrophic LP. Multiple reports have shown that SCC can arise from hypertrophic LP not infrequently, but that the LP-to-SCC sequence is poorly understood, and many cases defy diagnosis due to histologic similarities. However, there are several clinical clues and histopathologic details that have shown to have some value when trying to ascertain the correct diagnosis. To the contrary, immunohistochemical tests have shown little promise in differentiating hypertrophic LP from SCC. Although multiplex PCR has shown some potential in differentiating PEH from SCC, this has only been in the setting of patients diagnosed with prurigo and lichen simplex chronicus, but not necessarily in the case hypertrophic LP.