Squamous cell carcinoma (SCC) is a common and important primary cutaneous malignancy. On skin biopsies, SCC is characterized by significant squamous cell atypia, abnormal keratinization, and invasive features. Diagnostic challenges may occasionally arise, especially in the setting of small punch biopsies or superficial shave biopsies, where only part of the lesion may be assessable by the pathologist. Benign mimics of SCC include pseudoepitheliomatous hyperplasia, eccrine squamous syringometaplasia, inverted follicular keratosis, and keratoacanthoma, while malignant mimics of SCC include basal cell carcinoma, melanoma, and metastatic carcinoma. The careful application of time-honored diagnostic criteria, close clinicopathological correlation and a selective request for a further, deeper, or wider biopsy remain the most useful strategies to clinch the correct diagnosis. This review aims to present the key differential diagnoses of SCC, to discuss common diagnostic pitfalls, and to recommend ways to deal with diagnostically challenging cases. 1. Introduction Squamous cell carcinoma (SCC) is amongst the top 3 common skin cancers, ranking behind basal cell carcinoma (BCC) and ahead of melanoma [1]. It is a tumor that is locally invasive and which has the capacity to metastasize. Prognostically, it also occupies an intermediate position between BCC and melanoma, with BCC being locally invasive but typically nonmetastasizing, while melanoma having the well-known capability to metastasize. Histopathologically, most cases of SCC are readily diagnosable. However, diagnostic challenges are occasionally encountered and contributed mainly by the myriad of histopathologic mimics of SCC and small biopsies that sample only part of the lesion [2]. For the simulators of SCC, on the one hand, there are benign squamous lesions that appear to be infiltrative histopathologically. On the other hand, there are other malignant skin tumors that may display squamous differentiation or which elicit squamous proliferation that mimic SCC. Misdiagnosis of benign lesions as SCC would result in unnecessarily extensive surgery, while delayed diagnosis of SCC could lead to local tissue destruction by tumor, sometimes metastatic disease, and even death. Some malignant differential diagnostic entities, for example, melanoma and Merkel cell carcinoma (MCC), have worse prognosis or require different surgical strategies and differ in the need for adjuvant treatment [3, 4]. This review will present all the salient benign and malignant differential diagnoses of SCC, highlight diagnostic
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