Although histomorphological features are usually sufficient to diagnose esophageal SCC, if pathologists deem IHC to be necessary, we recommend a combination of P40/P63 (nuclear stain) with either DSG3 (membranous stain) or CK5/6 (cytoplasmic stain) to better cover all the differentiation components of esophageal SCC. Here, KRT5 is linked to esophageal squamous cell carcinoma.