Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P6

Chapter 3 Hepatocellular Cancer: Pathologic Considerations Gregory Y. Lauwers Keywords Histology · Prognostic factors · Precursor lesions While the incidence of HCCs has been rising worldwide, there has been a steady streamofnovelinformationrelatedtothehistologiccharacteristicsofHCCs,includ-ing their pattern of spread, the risk factors for recurrence, and long-term prognosis. More particularly, a focus of great interest has been the diagnosis of early HCC. Understanding by histopathologists, surgeons, hepatologists, and oncologists of the nuances of the diagnosis of early HCC, as well as the importance of detailed patho-logic analysis of surgical specimens, is crucial to developing appropriate therapeutic algorithms based on precise prognostic stratification. Macroscopic Features of Hepatocellular Carcinoma VariationsinthemorphologyofHCCarerelatedtothesizeofthetumorandwhether the surrounding liver is cirrhotic. Western series have emphasized that between 42 and 51% of HCCs arise in non-cirrhotic livers [1, 2]. However, some of the “noncirrhotic” cases may be better characterized as associated with limited fibrosis. Differences in the multiplicity of tumors, incidence of encapsulation, and rate of venous invasion have been reported in this group of tumors. Also, HCCs in noncirrhotic livers may grow faster and in general are larger than those in cirrhotic livers [3, 4]. In cirrhotic livers, small HCCs may be well demarcated and surrounded by a fibrous capsule, whereas advanced tumors are expansive multinodular masses, frequently accompanied by intrahepatic metastases [5]. In noncirrhotic livers, HCCs usually present as single large tumors that may infiltrate both lobes [2, 3]. G.Y. Lauwers ( ) Department of Pathology, Massachusetts General Hospital, Boston, MA, USA K.M. McMasters, J.-N. Vauthey (eds.), Hepatocellular Carcinoma, 35 DOI 10.1007/978-1-60327-522-4_3, C Springer Science+Business Media, LLC 2011 36 G.Y. Lauwers The risk of intrahepatic and extrahepatic spread is related to the size of the tumor [6–8]. HCCs less than 5 cm in size are less likely to develop intrahepatic metastasis, portal vein tumor thrombosis, or hematogenous metastasis [6, 8, 9]. Conversely, the incidence of portal vein thrombosis rises from 40 to 75% when HCCs grow larger than 5 cm, and the rate of intrahepatic metastasis rises dramatically (60% vs. 96%) [6, 7]. Most HCCs are soft neoplasms, often displaying hemorrhage and necrosis. Their color ranges from tan-gray to green, the difference reflecting the degree of bile pro-duction [10]. Peritumoral capsule is found in 46% of HCCs measuring less than 2 cm and 84% of tumors between 2 and 5 cm in size. A capsule is present in only 45% of HCCs measuring more than 5 cm in diameter [11]. Peritumoral capsule is associated with improved survival, lower rate of intrahepatic recurrence, and lower incidence of venous invasion [1, 12]. Macroscopic Classification of HCCs The different patterns of growth are associated with various risks of spread, both intrahepatic and extrahepatic [6]. Eggel’s classification, published in 1901, remains widely used [13]. HCCs are divided into nodular, massive, and diffuse types. The nodular type consists of well-circumscribed tumor nodules. Massive HCCs are circumscribed, huge tumor masses occupying most or all of a hepatic lobe. This type is commonly observed in patients without cirrhosis. The diffuse type is rare and characterized by innumerable indistinct small nodules studding the entire liver. Subsequently, the Liver Cancer Study Group of Japan has proposed a modification, with the nodular category being divided into three subtypes: single nodular, single nodular type with perinodular tumor growth, and the confluent multinodular subtype [10] (Fig. 3.1) HCC Is a Multicentric Disease Multicentricity is noted in 16–74% of HCCs resected in cirrhotic liver [6, 11, 14– 17]. In contrast, multifocality is reported to be only 12% in noncirrhotic liver [3]. Tumor multiplicity can be explained by either the metachronous development of tumors (i.e., multicentric carcinogenesis) or intrahepatic metastases via the por-tal system [18, 19]. Tumor nodules are considered metastatic if (a) they show a portal vein tumor thrombus or grow contiguously with a thrombus, (b) multiple small satellite nodules surround a larger main tumor, or (c) a single lesion is adja-cent to the main tumor but is significantly smaller in size and presents the same histology [18]. Intravascular and Biliary Growth Malignant thrombosis of the portal vein system plays a role in the development of intrahepatic metastases. Most patients develop recurrence within 1 year and die 3 Hepatocellular Cancer: Pathologic Considerations 37 Fig. 3.1 Macroscopic appearance of hepatocellular carcinoma (HCC). Example of large single nodular lesion involving most of a lobe. Note that the surrounding liver was not cirrhotic within 2 years after surgery [9, 20]. In some cases with thrombosis of the hepatic veins, the malignant thrombus may extend into the inferior vena cava and the right atrium [21]. Tumor extension into the hepatic duct or common bile duct or both is also rare. Patients may develop obstructive jaundice or hemobilia, at times leading to a misconstrued preoperative diagnosis of cholangiocarcinoma or choledocholithiasis [22, 23]. Microscopic Features of Hepatocellular Carcinoma Neoplastic hepatocytes exhibit various degrees of hepatocellular differentiation. They usually are polygonal with abundant eosinophilic and granular cytoplasm surrounded by distinct cell membranes. Characteristically, the nucleus is round and vesicular with a distinct nucleolus. Various intracytoplasmic inclusions can be observed. Glycogen, fat, bile, fibrinogen (pale bodies), Mallory bodies (accumula-tion of keratin and p62 stress protein) and intracellular hyaline bodies (accumula-tions of p62 stress protein), α-fetoprotein (AFP), giant lysosomes, or α1-antitrypsin have been reported [24, 25]. A trabecular arrangement mimicking normal hepatic cords is the basic architec-tural growth pattern of HCCs. The histologic appearance is variable, however. 38 G.Y. Lauwers Histologic Patterns of HCC The World Health Organization classification recognizes five major histologic subtypes [24]. Except for the fibrolamellar pattern, their significance is more of diagnostic value than indicative of prognosis [24]. The four other subtypes, fre-quently found simultaneously, are trabecular, pseudoglandular (acinar), compact, and scirrhous. The trabecular and acinar patterns are commonly observed in well to moderately differentiated HCCs. The trabeculae can vary from a few cells thick (microtrabecu-larpattern)tomorethanadozencells(macrotrabecularpattern)andareseparatedby sinusoid-like spaces lined by flat endothelial cells (Fig 3.2). In the acinar (pseudog-landular) variant, the cells are arranged in a rosette-like fashion with a central bile canaliculus (Fig 3.3). In the solid type, 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 can be seen after radiation, chemotherapy, or infarction. Various degrees of the scirrhous pattern are found without any previous treatment in approximately 4% of cases [10, 24]. Histologic Grading of Hepatocellular Carcinomas The Edmondson grading scheme is based on the degree of differentiation of the neo-plastic cells [26]. Tumors with well-differentiated neoplastic hepatocytes arranged in thin trabeculae correspond to grade I (Fig 3.4). In grade II, the larger and more atypical neoplastic cells are sometimes organized in an acinar pattern. Architectural and cytologic anaplasia are prominent in grade III, but the neoplastic cells are readily identified as hepatocytic in origin. When composed of markedly anaplas-tic neoplastic cells not readily identified as hepatocytic origin, the tumor is grade IV (Fig. 3.5) Fig. 3.2 Macrotrabecular growth pattern of hepatocellular carcinoma composed of wide anastomosing cords wrapped by endothelial cells 3 Hepatocellular Cancer: Pathologic Considerations 39 Fig. 3.3 Pseudoglandular (acinar) pattern of hepatocellular carcinoma. The neoplastic hepatocytes are moderately atypical (grade II), and bile plugs are identified in the lumen Fig. 3.4 Grade I (well-differentiated) hepatocellular carcinoma. The well-differentiated neoplastic hepatocytes show minimal cytologic and architectural atypia. Note the scattered acinar structures An alternate four-tier histologic grading scheme is advocated by the Liver Cancer Study Group of Japan [10]. In this classification, well-differentiated HCCs that com-monly measure less than 2 cm in diameter demonstrate an increased cellular density. The small neoplastic cells are organized in irregular microtrabeculae, and focal aci-nar formation can be seen. Frequent fatty macrovesicular changes can be seen as well. Cellular and nuclear atypia are distinctly absent. Moderately differentiated HCCs are composed of neoplastic hepatocytes displaying abundant eosinophilic cytoplasm with round nuclei and distinct nucleoli. Notably, the nucleus to cytoplasm ratio is equal to that of the normal hepatocytes. These hepatocytes are organized in either trabeculae or pseudoglands. Poorly differentiated HCCs usually grow in a solid sheet-like pattern. The hep-atocytes show an increased nucleus to cytoplasm ratio. Cellular pleomorphism is noticeable, with mononucleated or multinucleated giant cells, or both. ... - tailieumienphi.vn