Keratin pearls (marked **A**) are a characteristic histologic hallmark of squamous cell carcinoma of the lung. They represent concentric layers of keratin produced by malignant squamous cells and are classically associated with smoking-related central lung lesions. The presence of keratin pearls, along with intercellular bridges and atypical squamous cells, confirms squamous differentiation rather than adenocarcinoma or small cell carcinoma. Squamous cell carcinoma is strongly linked to smoking history and typically arises in a central/hilar location. Importantly, EGFR and ALK mutations are very rare in squamous cell carcinoma (unlike adenocarcinoma), making targeted therapy generally not applicable. While squamous cell carcinoma can present with paraneoplastic hypercalcemia from PTHrP production, this is not a universal feature and does not negate the diagnostic significance of keratin pearls. The presence of keratin pearls mandates staging by TNM classification and consideration of surgical resection for early-stage disease (IA-II) or chemoradiation for locally advanced disease (Robbins 10e Ch 15; Harrison 21e Ch 78).
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