Fig.16.37 ),eventuallyovergrowingtheseprecursorlesions.Intrahepaticmetastasesbyeithervascularinvasionordirectextensionbecomemorelikelyoncetumorsreach3cminsize.Thesemetastasesareusuallysmall,satellitetumornodulesaroundalargerprimarymass.Vascularinvasionisalsothemostlikelyrouteforextrahepaticmetastasis,especiallybythehepaticvenoussystem,usuallyonlyinadvancedcases.Occasionally,long,snakelikemassesoftumorinvadetheportalvein(causingportalhypertension)orinferiorvenacava;inthelatterinstance,thetumormayextendallthewayupintotherightventricle.Lymphnodemetastasesarelesscommon.
HCCsrangefromwelldifferentiatedtohighlyanaplasticlesions.Well-differentiatedHCCsarecomposedofcellsthatlooklikenormalhepatocytesandgrowasthicktrabeculae(recapitulatinglivercellplates)orinpseudoglandularpatternsthatrecapitulatepoorlyformed,ectaticbilecanaliculi(see
Fig.16.37
The clinical manifestations of HCC are varied and in Western populations are often masked by symptoms related to underlying cirrhosis or chronic hepatitis. In areas of high incidence, such as tropical Africa where aflatoxin exposure is common, patients usually have no clinical history of liver disease (although cirrhosis may be detected at autopsy). In both populations, most patients have ill-defined upper-abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness. Jaundice, fever, and gastrointestinal or esophageal variceal bleeding are inconstant findings.
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Fig. 16.37 Hepatocellularcarcinoma.(A)Liverremovedatautopsyshowingaunifocal,massiveneoplasmreplacingmostoftherighthepaticlobeinanoncirrhoticliver.(B)Malignanthepatocytesgrowingindistortedversionsofnormalarchitecture:largepseudoacinarspaces,essentiallymalformed,dilatedbilecanaliculi,andthickenedhepatocytetrabeculae.
Laboratory studies may provide clues but are rarely conclusive. Elevated serum levels of α-fetoprotein are found in 50% of individuals with advanced HCC, but this is neither a sensitive nor specific marker for premalignant or early well-differentiated cancers. Better tests for detection of small tumors are imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging. Increasing arterialization during the development and progression of HCC can be identified by imaging and is so characteristic that its detection can be diagnostic, precluding the need for tissue biopsy.
The natural history of HCC involves the progressive enlargement of the primary mass until it disturbs hepatic function or metastasizes, most commonly to the lungs. Death usually occurs from (1) cachexia, (2) gastrointestinal or esophageal variceal bleeding, (3) liver failure with hepatic coma, or rarely (4) rupture of the tumor with fatal hemorrhage. The 5-year survival of large tumors is dismal, and the majority of patients die within 2 years of diagnosis.
With implementation of screening procedures and advances in imaging, the detection of HCCs less than 2 cm in diameter has increased in countries where such facilities are available. These small tumors can be removed surgically or ablated (e.g., through embolization, microwave radiation, or freezing) with good outcomes. If relatively small HCCs arise in the setting of advanced stage (cirrhotic) chronic liver disease, liver transplantation is a better option and may be curative. Radiofrequency ablation and chemoembolization are used for local control of unresectable tumors. The kinase inhibitor sorafenib can prolong the life of individuals with advanced-stage HCC.