The growth pattern of HCCs has some importance because the different types are associated with various risks of intrahepatic and extrahepatic spread (9). The classification of Eggel, published a century ago and based on autopsy cases, is still widely used (17). In this scheme, HCCs are divided into three categories: nodular, massive, and diffuse types. The nodular type is composed of tumor nodules scattered within the cirrhotic parenchyma. The massive type consists of a circumscribed, huge tumor mass occupying most or all of a hepatic lobe. This type, commonly observed in patients without cirrhosis, arises frequently in the right lobe and can be surrounded by satellite nodules. The relatively rare diffuse type is characterized by innumerable indistinct small tumor nodules. However, nowadays, the smaller resected HCCs, do not readily fit into Eggel’s classification. This has led to the development of new classifications, none of them widely accepted (1,18). The most notable change is the one proposed by the Liver Cancer Study Group of Japan, by which the nodular type is divided into three categories: the single nodular type, the single nodular type with perinodular tumor growth, and the confluent multinodular type (13) (Fig. 31.1). Other classification schemes have included subtypes such as the small HCC (<2 cm) and the rare pedunculated HCC (19).

The World Health Organization classification recognizes five major histologic patterns. Except for the fibrolamellar pattern, their significance is more of diagnostic value than indicative of prognosis (29). The four other subtypes, frequently found simultaneously, are trabecular, pseudoglandular (acinar), compact, and scirrhous.

The trabecular and pseudoglandular architectural patterns are commonly encountered in well to moderately differentiated HCCs. The trabeculae, which can vary widely in thickness from a few cells thick (microtrabecular) to more than a dozen cells (macrotrabecular), are separated by sinusoidlike spaces lined by flat endothelial cells (Fig. 31.2). In the acinar (or pseudoglandular) variant, the cells are arranged in a rosettelike fashion with a central bile canaliculus (Fig. 31.3). In the solid type, a variant of macrotrabecular architecture, the sinusoids are compressed and obscured by the broad and compact trabeculae. Finally, the scirrhous pattern is characterized by abundant fibrous stroma separating cords of tumor cells. This pattern is often seen as a secondary change after radiation, chemotherapy, or infarction. Various degrees of the scirrhous pattern are found without any previous treatment in approximately 4% of cases (13,29).

The most commonly used grading scheme, developed by Edmondson and Steiner in 1954, is a four-tier system based on the degree of differentiation of the neoplastic cells (31). Grade I is composed of well-differentiated neoplastic hepatocytes arranged in thin trabeculae. In such cases, distinguishing HCC from small cell dysplasia is frequently difficult, particularly in needle biopsy specimens (Fig. 31.4). In grade II, the cells are larger and more atypical, sometimes organized in an acinar pattern. In grade III, architectural and cytologic anaplasia is prominent, but the tumor is still readily identified as hepatocytic in origin (Fig. 31.4). In grade IV, the neoplastic cells are markedly anaplastic and not easily identified as hepatocytic origin.

An alternate four-tier histologic grading scheme is advocated by the Liver Cancer Study Group of Japan (13). In this system, well-differentiated HCCs, most measuring <2 cm in diameter, are characterized by increased cellular density with irregular microtrabeculae, focal acinar formation, and frequent fatty change (Fig. 31.4). Cellular and nuclear atypia are distinctly absent. This carcinoma would correspond to the grade I carcinoma of the Edmondson-Steiner classification. In moderately differentiated HCCs, atypical hepatocytes have a trabecular arrangement, but a pseudoglandular pattern can also be observed (Fig. 31.3). Cytologically, the neoplastic hepatocytes have abundant eosinophilic cytoplasm with round nuclei and distinct nucleoli. The nucleus-to-cytoplasm ratio is equal to that of the normal hepatocytes. This type corresponds to grade II and III carcinoma of the Edmondson-Steiner scheme and is common among advanced HCCs.

A solid growth pattern characterizes the poorly differentiated HCCs. The neoplastic hepatocytes have an increased
nucleus-to-cytoplasm ratio and show pleomorphism, including mononucleated or multinucleated giant cells, or both. This category corresponds to Edmondson-Steiner grades III to IV.

In undifferentiated HCCs, the cells are characterized by scant cytoplasm with short spindle-shaped or round nuclei and grow in a solid or medullary pattern. These correspond to grade IV carcinoma of the Edmondson-Steiner classification.

Although they are widely used, the prognostic value of these systems is debated. Some series report better prognosis for low-grade HCC, whereas others deny a correlation between poor prognosis and high histologic grade (4,32). Also, Edmondson-Steiner grading was not found to be a predictor of intrahepatic recurrence by some, whereas a high histologic grade has been estimated by others to be a strong predictor of portal vein invasion (15,33). Whether the presence of cirrhosis influences the histologic grade is also debated. According to one series, the odds of having a high-grade HCC is almost double for patients with a cirrhotic liver compared to that of patients without cirrhosis (4).