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