Tumours of the Liver and Intrahepatic Bile Ducts .CHAPTER 8 Tumours of the Liver and Intrahepatic

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Transcript of Tumours of the Liver and Intrahepatic Bile Ducts .CHAPTER 8 Tumours of the Liver and Intrahepatic


Tumours of the Liver and Intrahepatic Bile Ducts

The most frequent and important hepatic neoplasm is the pri-mary hepatocellular carcinoma (HCC). In many parts of theworld, in particular Africa and Asia, it poses a significant dis-ease burden. In these high incidence regions, chronic infec-tion with hepatitis B virus (HBV) is the principal underlyingcause, with the exception of Japan which has a high preva-lence of hepatitis C infection. HBV vaccination has become apowerful tool in reducing cirrhosis and HCC, but implementa-tion is still suboptimal in several high risk regions. In Westerncountries, chronic alcohol abuse is a major aetiological factor.

Hepatic cholangiocarcinoma has a different geographical dis-tribution, with peak incidences in Northern Thailand. Here, it iscaused by chronic infection with the liver fluke, OpisthorchisViverrini, which is ingested through infected raw fish.

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WHO histological classification of tumours of the liver and intrahepatic bile ducts

TNM classification1, 2, 3

T Primary TumourTX Primary tumour cannot be assessedT0 No evidence of primary tumour

T1 Solitary tumour 2 cm or less in greatest dimension without vas-cular invasion

T2 Solitary tumour 2 cm or less in greatest dimension with vascularinvasion; or multiple tumours limited to one lobe, none more than2 cm in greatest dimension without vascular invasion; or solitarytumour more than 2 cm in greatest dimension without vascular invasion.

T3 Solitary tumour more than 2 cm in greatest dimension with vas-cular invasion; or multiple tumours limited to one lobe, none morethan 2 cm in greatest dimension with vascular invasion; or multi-ple tumours limited to one lobe, any more than 2 cm in greatestdimension with or without vascular invasion.

T4 Multiple tumours in more than one lobe; or tumour(s) involve(s) amajor branch of the portal or hepatic vein(s); or tumour(s) withdirect invasion of adjacent organs other than gallbladder; ortumour(s) with perforation of visceral peritoneum.

N Regional Lymph NodesNX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

M Distant MetastasisMX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage GroupingStage I T1 N0 M0Stage II T2 N0 M0Stage IIIA T3 N0 M0Stage IIIB T1 N1 M0

T2 N1 M0T3 N1 M0

Stage IVA T4 Any N M0Stage IVB Any T Any N M1

TNM classification of tumours of the liver and intrahepatic bile ducts

158 Tumours of the liver and intrahepatic bile ducts

Epithelial tumours

BenignHepatocellular adenoma (liver cell adenoma) 8170/01

Focal nodular hyperplasiaIntrahepatic bile duct adenoma 8160/0Intrahepatic bile duct cystadenoma 8161/0Biliary papillomatosis 8264/0


Hepatocellular carcinoma (liver cell carcinoma) 8170/3Intrahepatic cholangiocarcinoma 8160/3

(peripheral bile duct carcinoma)Bile duct cystadenocarcinoma 8161/3Combined hepatocellular and cholangiocarcinoma 8180/3Hepatoblastoma 8970/3Undifferentiated carcinoma 8020/3

Non-epithelial tumours


Angiomyolipoma 8860/0Lymphangioma and lymphangiomatosis 9170/0Haemangioma 9120/0Infantile haemangioendothelioma 9130/0


Epithelioid haemangioendothelioma 9133/1Angiosarcoma 9120/3Embryonal sarcoma (undifferentiated sarcoma) 8991/3Rhabdomyosarcoma 8900/3

OthersMiscellaneous Tumours

Solitary fibrous tumour 8815/0Teratoma 9080/1Yolk sac tumour (endodermal sinus tumour) 9071/3Carcinosarcoma 8980/3Kaposi sarcoma 9140/3Rhabdoid tumour 8963/3Others

Haemopoietic and lymphoid tumours

Secondary tumours

Epithelial abnormalities

Liver cell dysplasia (liver cell change)Large cell type (large cell change)Small cell type (small cell change)

Dysplastic nodules (adenomatous hyperplasia)Low-gradeHigh-grade (atypical adenomatous hyperplasia)

Bile duct abnormalitiesHyperplasia (bile duct epithelium and peribiliary glands)Dysplasia (bile duct epithelium and peribiliary glands)Intraepithelial carcinoma (carcinoma in situ) 8500/211

Miscellaneous lesions

Mesenchymal hamartomaNodular transformation

(nodular regenerative hyperplasia)Inflammatory pseudotumour

_________1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded

/0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for in situ carcinomas and grade III intraepithelial neoplasia and /3 for malignant tumours.

_________1 {1, 66}. This classification applies only to primary hepatocellular and cholangio-(intrahepatic bile duct) carcinomas of the liver.2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.3 For classification, the plane projecting between the bed of the gallbladder and the inferior vena cava divides the liver in two lobes.

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159Hepatocellular carcinoma

Hepatocellular carcinoma S. Hirohashi H.E. BlumK.G. Ishak Y. DeugnierM. Kojiro P. Laurent PuigI.R. Wanless H.P. FischerN.D. Theise M. SakamotoH. Tsukuma

Fig. 8.01 Worldwide annual incidence (per 100,000) of liver cancer in males(1995). Numbers on the map indicate regional average values.

DefinitionA malignant tumour derived from hepato-cytes. Most common aetiological factorsare viral infections (HBV, HCV), dietaryaflatoxin B1 ingestion and chronic alco-hol abuse.

EpidemiologyPrimary liver cancer (PLC) is a majorpublic health problem worldwide. In1990, the global number of new caseswas estimated at 316,300 for males and121,100 for females, accounting for 7.4%(males) and 3.2% (females) of all malig-nancies, excluding skin cancer {1469}.Hepatocellular carcinoma (HCC) is themost common histological type of PLC.Population-based cancer registries showthat HCC as a percentage of histologi-cally specified PLCs varies considerably{1471} but in over half of the registries,the fraction is above 70%. Regions with percentages less than 40%are exceptional, e.g., Khon Kaen (Thai-land), where intrahepatic cholangiocarci-noma is predominant, due to endemicinfection with liver flukes (Opisthorchisviverrini) {1470}. Owing to the limitedavailability of histological data, the follow-ing epidemiological survey is based onPLC but it can be assumed that it largelyreflects HCC incidence and mortality.

Geographical distributionThe estimated PLC incidence in 1990 for23 areas of the world is shown in Figure8.01 {1469}. High-risk areas with an age-standardized incidence rate (ASIR, stan-dardized to world population) of morethan 20.1 per 100,000 for males are Sub-Saharan and South Africa, East Asia,and Melanesia. Low-risk areas with anASR < 3.2 are North and South America,South-Central Asia, Northern Europe,Australia and New Zealand. Thus, devel-oping countries carry the greatest dis-ease burden, with more than 80% ofaccounted global cases. The geograph-ical distribution of PLC is similar formales and females, although males havea considerably higher risk of developingPLC. Geographical variations in PLC riskare present even in relatively homoge-nous populations and environments{1471, 176}. Geographical variations in HCC inci-dence and mortality can be ascribed todifferent levels of exposure to HCC riskfactors: chronic infections with hepa-titis B virus (HBV) and aflatoxin expo-sure in developing countries, and smok-ing and alcohol abuse in developedcountries {1545, 1482, 1417}. In Japan,local differences in the age-standardizedmortality rate (ASMR, standardized to

world population) reflect the sero-preva-lence of anti-hepatitis C virus (anti-HCV)antibodies among blood donors {1973,1893, 1471, 67}.

Time trendsIn most countries, the incidence ratesstayed largely constant or have de-creased over the past two decades.However, they have increased in Japanand Italy, especially for males {982,1522}. A changing prevalence of risk fac-tors among populations as well aschanges in diagnostic techniques and inclassification of the disease and appre-ciably affected the disease incidence.

Fig. 8.02 Geographic distribution of the prevalence of chronic HBV infection,based on HBs Ag serology.

Fig. 8.03 Age-specific incidence rates of liver can-cer in males for selected populations 1992. From: M. Parkin et al. {1471}.

> 8% = high2-7% = intermediate< 2% = low


6.6 35.8



< 3.6 < 5.4 < 10.8 < 20.9 < 48.9

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160 Tumours of the liver and intrahepatic bile ducts

Age and sex distributionRegional age-specific incidence ratesdiffer significantly (Fig. 8.03). Qidongand Hong Kong (China) are high-riskpopulations for HBV-related HCC.Characteristics of their curves are asteep increase in the ages 20-34 years;in Qidong the curve levels off already atthe age of 40. Osaka (Japan) is a high-risk area, but Varese (Italy) is a low tointermediate risk area; approximately70% of HCC in these populations is relat-ed to chronic HCV infection {1417}. Theirrates increase at older ages and showrelatively high rates over age 55-59. Thecurve for whites in the USA (SEER data)is representative of both low-risk popula-tions. Males are always more frequentlyaffected than females but high male tofemale ratios of > 3 in the age-specificrates occur particularly in populationswith a high incidence of HCC {1534, 402,1906, 391, 452}.

AetiologyChronic infection with HBV, HCV or bothis the most common cause of HCCworldwide {889}. Among Western popu-lations, alcohol-induced liver injury is alead