Recently, an East-West consensus on the histopathologic criteria for the diagnosis of high-grade dysplastic nodules (HGDN) versus early hepatocellular carcinoma (HCC) was reached. Next to classical morphologic criteria such as nucleocytoplasmic ratio, thickness of cell plates, mitotic index, and architectural disturbance like acinar structures, one of the most relevant criteria to diagnose early HCC is stromal invasion. Because a structured basement membrane is lacking along the hepatocytes in the liver, invasion cannot be defined as tumor growth through the basement membrane as in other tissues. However, the number of portal tracts that are present in a nodule gradually decrease because the tumoral hepatocytes start to show a destructive invading growth pattern in the mesenchyma/stroma of these portal tracts. This feature of stromal invasion is however sometimes difficult to recognize in needle biopsies because included portal tracts can be absent. Therefore, other diagnostic criteria are necessary. Based on molecular profiling, several additional markers for early malignant HCC have been found recently. Glypican-3, heat shock protein 70, and glutamine synthetase have been already validated and can be used as a panel of stains to confirm the pathologist's histopathologic diagnosis and to solve difficult cases.