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Hepatocellular Carcinoma
Epidemiologybull 5th most common cancer in men and the eighth most
common cancer in women worldwide bull Incidence rate equals death rate bull It is common in Asian persons due to childhood
infections with hepatitis B bull It occurs more commonly in men than in women
ndash US = 74 occur in menndash In high risk countries = male-to-female ratios 81
Risk FactorsMajor Minor
Chronic Hepatitis B VirusChronic Hepatitis C Virus
CirrhosisDietary exposure to Aflatoxin B1
Oral contraceptive steroidCigarette Smoking
Dietary iron overload in persons of black African ancestry
Hereditary hemochromatosis Wilson disease
α1-Antitrypsin deficiency Type 1 hereditary tyrosinemia
Type 1 and type 2 glycogen storage disease
Hypercitrullinemia Ataxia-telangiectasia
Membranous obstruction of the inferior vena cava
Clinical Features
bull Pruritusbull Jaundicebull Splenomegaly-most common signbull Variceal bleedingbull Cachexiabull Increasing abdominal girthbull Hepatic encephalopathybull Right upper quadrant pain
Clinical Features (cont)
bull Jaundicebull Ascitesbull Hepatomegalybull Alcoholic stigmata (Dupuytren contracture
spider angiomata)bull Asterixisbull Pedal edemabull Periumbilical collateral veinsbull Enlarged hemorrhoidal veins
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Epidemiologybull 5th most common cancer in men and the eighth most
common cancer in women worldwide bull Incidence rate equals death rate bull It is common in Asian persons due to childhood
infections with hepatitis B bull It occurs more commonly in men than in women
ndash US = 74 occur in menndash In high risk countries = male-to-female ratios 81
Risk FactorsMajor Minor
Chronic Hepatitis B VirusChronic Hepatitis C Virus
CirrhosisDietary exposure to Aflatoxin B1
Oral contraceptive steroidCigarette Smoking
Dietary iron overload in persons of black African ancestry
Hereditary hemochromatosis Wilson disease
α1-Antitrypsin deficiency Type 1 hereditary tyrosinemia
Type 1 and type 2 glycogen storage disease
Hypercitrullinemia Ataxia-telangiectasia
Membranous obstruction of the inferior vena cava
Clinical Features
bull Pruritusbull Jaundicebull Splenomegaly-most common signbull Variceal bleedingbull Cachexiabull Increasing abdominal girthbull Hepatic encephalopathybull Right upper quadrant pain
Clinical Features (cont)
bull Jaundicebull Ascitesbull Hepatomegalybull Alcoholic stigmata (Dupuytren contracture
spider angiomata)bull Asterixisbull Pedal edemabull Periumbilical collateral veinsbull Enlarged hemorrhoidal veins
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Risk FactorsMajor Minor
Chronic Hepatitis B VirusChronic Hepatitis C Virus
CirrhosisDietary exposure to Aflatoxin B1
Oral contraceptive steroidCigarette Smoking
Dietary iron overload in persons of black African ancestry
Hereditary hemochromatosis Wilson disease
α1-Antitrypsin deficiency Type 1 hereditary tyrosinemia
Type 1 and type 2 glycogen storage disease
Hypercitrullinemia Ataxia-telangiectasia
Membranous obstruction of the inferior vena cava
Clinical Features
bull Pruritusbull Jaundicebull Splenomegaly-most common signbull Variceal bleedingbull Cachexiabull Increasing abdominal girthbull Hepatic encephalopathybull Right upper quadrant pain
Clinical Features (cont)
bull Jaundicebull Ascitesbull Hepatomegalybull Alcoholic stigmata (Dupuytren contracture
spider angiomata)bull Asterixisbull Pedal edemabull Periumbilical collateral veinsbull Enlarged hemorrhoidal veins
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Clinical Features
bull Pruritusbull Jaundicebull Splenomegaly-most common signbull Variceal bleedingbull Cachexiabull Increasing abdominal girthbull Hepatic encephalopathybull Right upper quadrant pain
Clinical Features (cont)
bull Jaundicebull Ascitesbull Hepatomegalybull Alcoholic stigmata (Dupuytren contracture
spider angiomata)bull Asterixisbull Pedal edemabull Periumbilical collateral veinsbull Enlarged hemorrhoidal veins
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Clinical Features (cont)
bull Jaundicebull Ascitesbull Hepatomegalybull Alcoholic stigmata (Dupuytren contracture
spider angiomata)bull Asterixisbull Pedal edemabull Periumbilical collateral veinsbull Enlarged hemorrhoidal veins
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Signs and SymptomsSymptom Frequency Sign Frequency
Abdominal pain 59-95 Hepatomegaly 54-98
Weight loss 34-71 Hepatic bruit 6-25
Weakness 22-53 Ascites 35-61
Abdominal swelling 28-43 Splenomegaly 27-42
Jaundice 4-35
Nonspecific gastrointestinal
symptoms
25-28 Wasting 25-41
Fever 11-54
Jaundice 5-26
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Pathogenesis
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Hepatitis B Virus Direct Carcinogenic Effect
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Hepatitis B Virus Indirect Carcinogenic Effect
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
bull Hepatitis C Virus - genome does not integrate into host DNA the virus would have to exert its direct carcinogenic effect from an extrachromosomal position
bull Cirrhosis ndash potent tumor promoter
bull Aflatoxin B1 - Aspergillus flavus and Aspergillus parasiticusndash inactivating mutation of the third base of codon 249
of the p53 tumor suppressor gene
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull Total bilirubinbull Aspartate aminotransferase (AST)bull Alkaline phosphatasebull Albuminbull Prothrombin timebull AFPbull DCP(Des-gamma carboxyprothrombin)
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Chest Radiograph
bull Pulmonary metastases bull They almost always are multiple and may
enlarge rapidly bull The right hemidiaphragm or rarely the left
hemidiaphragm may be raisedbull Skeletal metastases are seen occasionally
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Ultrasoundbull Detects a majority of
hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver
bull 23 of symptomatic hepatocellular carcinomas - hyperechoic
bull 13 - partly hyperechoic and partly hypoechoic
bull Small tumors are uniformly hypoechoic
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Ultrasoundbull Ultrasonography with Doppler technology -
patency of the inferior vena cava portal vein and its larger branches hepatic veins and biliary tree
bull Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO2 microbubbles and intravenous enhanced color Doppler ultrasonography - characterizing hepatic arterial and portal venous flow in tumorous nodulesndash facilitate the diagnosis of malignant
and benign hepatic nodules
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
CT-scanbull Multiphase helical CT and CT during arterial portography are the
imaging techniques of choice in the diagnosis of hepatocellular carcinoma
bull Tumor - hypervascular during the hepatic arterial phase and hypodense in the delayed phases
bull Defining the extent of the tumor within and beyond the liver bull Showing the course caliber and patency of blood vessels
bull Iodized poppy seed oil (Lipiodol) - concentrated and retained in hepatocellular carcinoma tissuendash can be used in conjunction with CTndash Detect very small tumors
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
MRI
bull Provides another way of distinguishing hepatocellular carcinoma from normal liver tissue
bull Using contrast increases the accuracy of MRI especially in detecting small hepatocellular carcinomas in cirrhotic livers and in distinguishing small hepatocellular carcinomas from hemangiomas
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Diagnosis
bull CHEST XRAYbull UTZbull CT SCANbull MRIbull ANGIOGRAPHYbull PET SCAN
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Hepatic Angiography
bull Helpful in recognizing small hypervascular hepatocellular carcinomas
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Serum Tumor Markers
Marker Sensitivity Specificity CommentsAlpha-fetoprotein High-incidence
populations 80-90
Low-incidence populations 50-
70
90 Relatively quick and easy to measure most extensively
studiedRelatively expensive
Des-γ-carboxyprothrombin
58-91 84 Quick and easy to measure
Much more expensive than a-
fetoprotein
α-L-Fucosidase 75 70-90 Quick and easy to measure relatively
inexpensive
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Hematologic Changes
bull Anemiabull Leukocytosis
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Stagingbull TNM staging criteria for hepatocellular carcinoma
ndash T1 - Solitary tumor without vascular invasionndash T2 - Solitary tumor with vascular invasion or multiple
tumors none more than 5 cmndash T3 - Multiple tumors more than 5 cm or tumor involving a
major branch of the portal or hepatic vein(s)ndash T4 - Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral peritoneum
ndash N0 - Indicates no nodal involvementndash N1 - Indicates regional nodal involvementndash M0 - Indicates no distant metastasisndash M1 - Indicates metastasis presence beyond the liver
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Stage grouping
ndash Stage I = T1 + N0 + M0ndash Stage II = T2 + N0 + M0ndash Stage IIIA = T3 + N0 + M0ndash Stage IIIB = T4 + N0 + M0ndash Stage IIIC = TX + N1 + M0ndash Stage IVB = TX + NX + M1
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Childrsquos Pugh Stage
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
CLIP scoring systembull Score of 0-2 is assigned for each of the 4 features listed below cumulative score
ranging from 0-6 is the CLIP scorendash Child-Pugh stage
bull Stage A = 0bull Stage B = 1bull Stage C = 2
ndash Tumor morphologybull Uninodular and extension less than 50 = 0bull Multinodular and extension less than 50 = 1bull Massive and extension greater than 50 = 2
ndash Alpha-fetoproteinbull Less than 400 = 0bull Greater than 400 = 1
ndash Portal vein thrombosisbull Absent = 0bull Present = 1
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Pathology
bull Gross Appearance
Nodular Massive Diffuse75-Numerous-round or irregular-nodules of various sizes scattered throughout the liver-some of which are confluent
- large circumscribed mass often with small satellite nodules -prone to rupture and - more common in younger patients with a noncirrhotic liver
- infiltrated homogeneously by indistinct minute tumor nodules
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Microscopic
bull Well Differentiatedbull Moderately Differentiatedbull Undifferentiated
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Well Differentiated ( Trabecular and Acinar)
Trabecular malignant hepatocytes grow in irregular anastomosing plates separated by often inconspicuous sinusoids lined by flat cells resembling Kupffer cells
bull Resemble those of normal adult liver but often are thicker and may be composed of several layers of cells
bull Scanty collagen fibers may be seen adjacent to the sinusoid wallsbull The malignant hepatocytes are polygonal with abundant slightly
granular cytoplasm that is less eosinophilic than that of normal hepatocytes
bull The nuclei are large and hyperchromatic with prominent nucleolibull Bile production is the hallmark of hepatocellular carcinoma regardless
of the pattern
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Acinar
bull Malignant hepatocytes surrounding the lumen of a bile canaliculus which may contain inspissated bile
bull A tubular or pseudopapillary appearance may be produced by degeneration and loss of cells or cystic spaces may form in otherwise solid trabeculae
bull The individual cells may be more elongated and cylindrical than in the trabecular variety
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Moderately Differentiatedbull Solid - cells usually are small although they vary considerably in shape
ndash Pleomorphic multinucleated giant cells occasionally are present ndash The tumor grows in solid masses or cell nests ndash Evidence of bile secretion is rare and connective tissue is inconspicuous
Central ischemic necrosis is common in larger tumors
bull Scirrhous - malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma Duct-like structures occasionally are present In most tumors the cells resemble hepatocytes
bull Clear cells - appearance of these cells results from a high glycogen or in some cases fat content
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Undifferentiated
bull Pleomorphic varying greatly in size and shape bull Nuclei also are extremely variable bull Large numbers of bizarre-looking giant cells are present bull The cells may be spindle-shaped resembling those of
sarcomas bull Globular hyaline structures may be seen in all types of
hepatocellular carcinomandash These reflect the presence of alpha-fetoprotein α1-
antitrypsin or other proteinsndash Mallorys hyaline occasionally is present
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Hepatocellular carcinoma poorly differentiated
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Extra Slides
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma
Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma
N Engl J Med 1984 May 31310(22)1427-31Liebman HA Furie BC Tong MJ Blanchard RA Lo KJ Lee SD Coleman MS
Furie Bbull Detected des-gamma-carboxy prothrombin(DCP) an abnormal prothrombin
in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter)
bull In contrast levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean 10 ng per milliliter) or metastatic carcinoma involving the liver (mean 42 ng per milliliter) and undetectable in normal subjects In five patients treated with vitamin K there was no reduction in abnormal prothrombin indicating that its presence was not due to vitamin K deficiency Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations which later increased with recurrence of disease Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels Together the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent) Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma