Pathological Aspects of Hepatocellular Tumors 77 4 Pathological Aspects of Hepatocellular Tumors

Pathological Aspects of Hepatocellular Tumors 77 4 Pathological Aspects of Hepatocellular Tumors Hale Kirimlioglu, MD, Anthony J. Demetris, MD, and Michael A. Nalesnik, MD CONTENTS HEPATOCELLULAR ADENOMA HEPATOCELLULAR CARCINOMA FIBROLAMELLAR HCC CLEAR CELL HCC SCLEROSING HCC COMBINED HCC AND CHOLANGIOCELLULAR CARCINOMA SARCOMATOID HCC HEPATOBLASTOMA REFERENCES 1. HEPATOCELLULAR ADENOMA Hepatocellular adenoma (HA) is an uncommon and benign tumor of the liver, seen most often in young women of childbearing age with a history of oral contraceptive use (Table 1) (1). The longer the duration of intake of oral contraceptives, the higher the risk of developing hepatic adenoma (2). Anabolic steroid use also is associated with HA, and an example of this lesion arising in conjunc- tion with growth hormone therapy for Turner’s syndrome has been reported (3). An association of liver cell adenoma and various genetic metabolic disorders (such as glycogen storage diseases types I, III, or IV, galactosemia, tyrosinemia, and, rarely, diabetes mellitus or familial adenomatous polyposis) also has been reported (4–9). From: Current Clinical Oncology: Hepatocellular Cancer: Diagnosis and Treatment Edited by: B. I. Carr © Humana Press Inc., Totowa, NJ 77 78 Kirimlioglu et al. Table 1 Neoplastic Hepatocellular Lesions: Selected Features Clinical features Pathological features HA Usually single, rarely Clonal growth of normal multiple; associated appearing hepatocytes with birth control pills; with arterial vasculature may bleed and otherwise bland trabecular architecture HCC, usual Most commonly arises Single, multiple, or diffuse in cirrhotic liver tumors; cytologically abnormal hepatocytes with arterial vasculature and trabecular to solid architecture HCC Variants Most often in young adults Large, aberrant hepatocytes Fibrolamellar without cirrhosis; with large nucleoli; HCC surgical resection may be abundant cytoplasm more efficacious than in variably fibrotic stroma in case of usual HCC Clear cell HCC Similar to HCC Cytoplasmic clearing of hepatocytes because of lipid or glycogen may cause confu- sion with similarly appearing tumors arising in other organs Sclerosing HCC Reported association with Malignant cells in densely hypercalcemia fibrous stroma may cause c onfusion with other forms of adenocarcinoma; large cells of fibrolamellar type not seen Combined HCC/ Similar to HCC Cells resemble a mixture of cholangio- malignant hepatocytes and carcinoma bile duct epithelial cells likely representing diver- gent differentiation from precursor cell Sarcomatoid HCC Rare, similar to HCC Sarcomatous element derives from malignant hepatocellular element (Continued) Pathological Aspects of Hepatocellular Tumors 79 Table 1 (Continued) Neoplastic Hepatocellular Lesions: Selected Features Clinical features Pathological features Hepatoblastoma Most common primary Epithelial, mixed epithelial tumor of infancy and mesenchymal patterns and childhood; association with several congenital abnormalities Fig. 1. Two mass lesions arising in a noncirrhotic liver. The large one proved to be a HA, and the smaller one was a focal nodular hyperplasia. The characteristic fibrous scar of the latter is not evident in this photograph (see Fig. 3). The tumor may present as a palpable mass with or without abdominal pain. Bleeding into the tumor may occur, and hemoperitoneum resulting from tumor rupture with free hemorrhage into the peritoneal space is a surgical emergency. Serum α-fetoprotein (AFP) levels are within normal limits. 1.1. Macroscopic Pathology HA characteristically appears as a well-circumscribed, nonlobulated lesion arising within a noncirrhotic liver (Fig. 1). Adenomas can range from 1 to more than 30 cm, but most are between 5 and 15 cm in diameter. Adenomas typically occur in subcapsular locations and in the right lobe. The tumor may be pedun- 80 Kirimlioglu et al. culated (10). It usually is solitary; however, multiple lesions are seen rarely, particularly in glycogen storage disease type I and in the condition referred to as liver adenomatosis (4,5,11,12). The color varies from yellow to tan and can be variegated because of a combination of intratumoral hemorrhage, infarction, and fatty changes (4,13). Adenomas usually are unencapsulated. 1.2. Microscopic Pathology HAs contain normal-appearing hepatocytes arranged in a trabecular architecture between one and three cells thick (Fig. 2A,B). There are no portal tracts and, therefore, the normal hepatic microanatomical relationships are lacking. The hepatocyte nuclei are small, round, and uniform. Nucleoli are inconspicuous. Mitoses are absent or few. Cytoplasm is pale or eosinophilic. In some adenomas, clear changes of the cytoplasm may be prominent because of increased storage of glycogen, fat, or both. Cholestasis is not uncommon. The normal reticulin pattern is well-preserved, and Kupffer’s cells exist in their usual locations. Small venous and arterial branches are seen throughout the tumor (Fig. 2C). Occasional larger vessels are seen and also may appear as feeding vessels adjacent to the tumor (Fig. 2D). Occasionally, the tumoral hepatocytes may contain periodic acid–Schiff (PAS)-positive, diastase-resistant hyaline globules (14,15), Mallory’s hyaline (16), or degenerate-appearing hyperchromatic nuclei (17). The distinction of HA from well-differentiated hepatocellular carcinoma (HCC) may be difficult or impossible by conventional light microscopy. The clinical context is important in this regard, and the diagnosis of hepatic adenoma outside of the setting of a young woman taking oral contraceptives should be viewed with suspicion. Immunohistochemical markers occasionally may be helpful in distinguishing HA from a well-differentiated HCC. Investigations should focus on suspicious-looking areas that are characterized by a clonal appearance (referring to a focus of cells that has a distinctly different look from the surrounding adenoma). This may be the result of cytological to architectural differences such as solid growth or formation of pseudoacini. Dem- onstration of AFP positivity is strong evidence in support of HCC over adenoma. In our experience, foci of carcinoma within an adenoma usually show increased cytological atypia and cell cycle activity, highlighted by the marker Ki-67, in comparison with adjacent adenoma and surrounding liver. Such changes must be interpreted in the context of the overall lesion, that is, the pathologist must make the interpretation as to whether he or she believes that carcinoma, if found, involves the entire lesion or only a portion of the tumor. Other immunostains do not add appreciably to the diagnostic information. Estrogen, progesterone, and androgenic steroid receptors have been detected in 26–73% of adenomas in different series (18,19) and also may be seen in HCC. Hepatic progenitor cells are identifiable by immunohistochemical means in a considerable proportion of HAs and support the hypothesis that oval hepatic progenitor cells play a role in Pathological Aspects of Hepatocellular Tumors 81 Fig. 2. (A) Interface of HA and normal liver. The adenoma comprises most of the photomicrograph and has numerous white areas at this low magnification because of increased intracellular fat. The normal liver (lower right hand portion) has a more solid appearance. The interface is smooth and no capsule is seen (stain, hematoxylin–eosin; original magnification, ×4). (B) High-power view of HA. The bland appearance and trabecular (continued on pages 76 and 77) 82 Kirimlioglu et al. Fig. 2. (continued from page 75) arrangement of tumor cells is apparent. Large and small fat vesicles are seen within cell cytoplasm (stain, hematoxylin–eosin; original magnification, ×40). (C) Vasculature within HA. Immunostain high- lights the dispersed arterial vasculature supplying the adenoma cells (stain, anti- CD31 immunoperoxidase; original magnification, ×20). (D) Cell proliferation Pathological Aspects of Hepatocellular Tumors 83 the development of hepatic tumors (20). However, their identification does not distinguish benign from malignant tumors. Comparative genomic hybridization has been suggested as a useful ancillary technique for the distinction of adenoma and carcinoma. Gains and losses of chromosome sites on 1q, 4q, 8p, 8q, 16p, and 17p were found to be the six most frequent alterations in HCC by this approach, and detection of one or more of these has been proposed as evidence in support of the diagnosis of carcinoma (21). These authors have updated this technique by using fluorescent in situ hybridization to detect quantitative anomalies of chromosomes 1, 6, 7, and 8, thereby distinguishing HCCs from adenomas and other benign lesions in paraf- fin-embedded material (22). The distinction between HA and focal nodular hyperplasia (FNH) has clinical significance, because FNH is a benign condition that does not undergo malignant transformation and rarely ruptures, allowing in some cases for a more conserva- tive approach to management (23). Magnetic resonance imaging, enhanced CT, scintigraphic findings, and angiography show large peripheral vessels with cen- tripetal flow and are diagnostically useful, but the best method for the differentiation of HA and FNH is surgical biopsy (1,24,25). Histopathologically, both FNH and HA contain benign-appearing hepatocytes. The presence of fibrous bands with artery branches and peripheral ductular hepatocytes in the absence of true bile ducts is characteristic of FNH (Fig. 3). Small vessels are also seen in the lobular portion

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