Patología Hepática
Enfermedades no neoplásicasEnfermedades no neoplásicas
• MalformacionesMalformaciones• Inflamatorias: hepatitisInflamatorias: hepatitis• Alteraciones de la vía biliar intrahepática Alteraciones de la vía biliar intrahepática • Hepatopatías por fármacos y tóxicosHepatopatías por fármacos y tóxicos• Cirrosis (vía final común)Cirrosis (vía final común)• Errores innatos del metabolismoErrores innatos del metabolismo• Trastornos circulatoriosTrastornos circulatorios• Alteraciones vinculadas al transplanteAlteraciones vinculadas al transplante
Hepatitis aguda• El grado de afectación varía de caso a caso• Todos presentan:
• Desorganización de los acinos• Infiltrado inflamatorio portal• Balonamiento de los hepatocitos• Cuerpos apoptóticos dispersos• Necrosis periportal• Hiperplasia de células de Kupffer
Hepatitis crónica
• Causas– Virus hepatotropos
– Otros agentes infecciosos
– Autoinmune
– Fármacos
– Metabólicas
Hepatitis crónica
• ELEMENTOS DE ACTIVIDAD NECROINFLAMATORIA
• Exudado linfocitario portal• Hepatitis de interfase• Inflamación y Necrosis en puente• Inflamación y necrosis lobulillar
Cambios arquitecturales (fibrosis) evolutivos 0 Ausencia de fibrosis 1 Expansión fibrosa de algunos tractos portales (con o sin
septos fibrosos) 2 Expansión fibrosa de la mayoría de los tractos portales
(con o sin septos fibrosos) 3 Expansión fibrosa de la mayoría de los tractos portales
con ocasionales puentes fibrosos porto portales 4 Expansión fibrosa de la mayoría de los tractos portales
con abundantes puentes fibrosos porto portales y ocasionales puentes porto centrales
5 Abundantes puentes (P-P y/o P-C) con ocasionales nódulos (cirrosis incompleta)
6 Cirrosis, probable o definitiva
Disease
Característica Hepatitis B Hepatitis C Hepatitis AI Esteatohepatitis
Cambios portales
Difusos En parches
++
-++
++-
-+
Tipo de infiltrado portal
LinfocitosPlasmocitosEosinófilos
+++-
++--
+++++
+++-
Actividad necroinflamatoria
Hepatitis de interfase
+ + ++ -
Necrosis lobulillar - - + +
Infiltrado lobulillar
GradoTipoLocalización
-
+LinfocitosSinusoidal
+PlasmocitosCon necrosis
+Linfoplasmocit.
En parches
Ductos biliares Daño ductalPérdida ductalProliferación
+--
+--
+--
--+
Hialina de Mallory
- - - +
Cobre - - - -
Granulomas - - - -
Vidrio esmerilado + - - -
Tipos de virus y cambios histológicos
---+-Fibrosis
-+ ----Degeneración de los ductos biliares
+ -+ -+ -+ -+ -Proliferación ductular
NLLPLPLPPLENTipos de células inflamatorias
+++++Inflamación portal
+---+ - Hipertrofia de c.de Kupffer y acumulación de bilis
-++++Hipertrofia de c.de Kupffer y/o hierro y/o lipofucsina
+---+ -Colestasis
+ --+++ - Esteatosis
?++++Necrosis masiva
---+-Balonamiento panacinar
----+Balonamiento en zona 1
-+ -++ --Balonamiento en zona 3
+++-+Necrosis focal
EDCBA
Hepatitis fulminante
• Produce insuficiencia hepatocítica con encefalopatía en 2 a 3 semanas
• Puede producirse como coinfección, siendo uno de los virus el B
• Puede producirse por fármacos (paracetamol, alfa metil dopa, isoniazida, antidepresivos) o tóxicos
Hepatitis fulminante
• Puede afectar áreas o todo el hígado• Macroscópicamente el hígado se ve
gelatinoso • Microscopicamente: gran necrosis con
destrucción de la trama• Escaso exudado inflamatorio• Si el paciente sobrevive, se ve regeneración
de los hepatocitos
Sistemas actuales de clasificación de las hepatitis crónicas
• Los sistemas posteriores incorporaron la visión respecto de la inflamación y la necrosis como parámetro de la actividad evolutiva de la enfermedad, siendo el parámetro potencialmente respondedor a la terapia. Esto fue referido como “GRADO”
• Las lesiones de fibrosis y remodelación parenquimatosa o vascular indicó la progresión de la enfermedad a largo plazo (pronóstico) y fue referido como el “ESTADIO”
• El grado puede fluctuar con la actividad necroinflamatoria o la intervención terapéutica. En cambio el estadio se considera relativamente constante.
Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991;13:372-374.
Patología Hepática
Colestasis
Características histológicas de los cuadros de colestasis
• Colestasis activa– Hepatocelular primaria y/o secundaria
• Colestasis crónica– Enfermedades colestásicas crónicas
• Colestasis ductal– Obstrucción de grandes ductos y variantes
• Colestasis ductular– Sepsis
COLESTASIS ACTIVA
COLESTASIS CRÓNICA
COLESTASIS DUCTAL
COLESTASIS DUCTULAR
Característica histológica
Trombos biliares canaliculares
Cambios en los hepatocitos Periportales
Pigmento en ductos biliares interlobulares
Pigmento en ductulos biliares proliferados
Se ve pigmento
biliar?
SI Ocasional SI SI
Localización de los
cambios
Centrolobular Periportal/Periseptal
Portal Portal
Característica auxiliar
Daño hepatocelular; inflamación lobular
Acumulación de cobre;
Cuerpos de Mallory
Colestasis Canalicular;
Cambios portales obstructivos
Colestasis Canalicular;
Neutrófilos portales
Cuadro clínico Condiciones colestáticas activas
Condiciones colestáticas crónicas
Obstrucción biliar
Sepsis
Colestasis activa
• Trombos biliares hepatocanaliculares
• Bilirrubinostasis
• Daño hepatocelular asociado
• Inflamación lobular
• Condiciones asociadas– Drogas, hepatitis viral, etc
Colestasis Crónica
• Cambios en ductos biliares portales– Proliferación ductular atípica
• Cambios periportales / periseptales:– Degeneración plumosa– Acumulación de cobre– Cuerpos de Mallory
• Condiciones asociadas– Cirrosis biliar primaria– Colangitis esclerosante primaria
Enfermedades colestásicas
• Cirrosis biliar primaria – Granulomas periductales– Daño epitelial ductal– Evolución a la cirrosis
• Colangitis esclerosante primaria– Colangitis fibroobliterativa– Evolución a la cirrosis
Disease
Característica CBP CEP Wilson Medicamentos
Cambios portales
Difusos En parches
-++
++-
++-
++
Tipo de infiltrado portal
LinfocitosPlasmocitosEosinófilos
+++++
++++
++--
++++
Actividad necroinflamatoria
Hepatitis de interfase
+ - - +
Necrosis lobulillar - - - +
Infiltrado lobulillar
GradoTipoLocalización
+LinfocitosSinusoidal
-
-
+
Ductos biliares Daño ductalPérdida ductalProliferación
++++++
++
++
---
+++
Hialina de Mallory
+Tardía
+Tardía
+Tardía
+
Cobre + + + -
Granulomas + - - +
Vidrio esmerilado - - - +
Table 22. Staging of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
Stage Scheuer system for PBC (56) Ludwig (Mayo) system for PBC/PSC (54)
1 Florid duct lesion: portal inflammation with damage to septal or interlobular bile ducts
Portal stage: inflammation without expansion of portal tracts or piecemeal necrosis
2 Ductular proliferation: expansion of portal tracts with piecemeal necrosis and ductular proliferation
Periportal stage: piecemeal necrosis or fibrosis without bridging
3 Scarring: decreased inflammation with fibrous septum formation
Septal stage: bridging necrosis or fibrosis
4 Cirrosis Cirrhosis
Colestasis Ductal
• Cambios en ductos biliares interlobulares
• Cambios portales:– Edema– Trombos biliares ductales– Proliferación ductular típica
• Condiciones asociadas– Obstrucción de grandes ductos
Evolución
• El estadio final de:– Obstrucción biliar crónica– Enfermedades colestásicas crónicas
• Cirrosis biliar primaria
• Colangitis esclerosante primaria
Es la cirrosis de tipo biliar
Colestasis Ductular
• Cambios en ductos biliares proliferados• Cambios portales:
– Edema– Colangitis y / o pericolangitis– Proliferación ductular con pigmento biliar
intraluminal
• Condiciones asociadas– Sepsis
CLASIFICACIÓN DE ENFERMEDADES COLESTÁSICAS
GRANDES DUCTOS
PEQUEÑOS DUCTOS
HEPATOCELULAR
AGUDA
Obstrucción biliar aguda
Colangitis aguda
Injuria por drogas
Colestasis pura
Injuria por drogas
Colestasis compuesta
CRÓNICA
Obstrucción biliar crónica
Colangitis esclerosante Primaria
Cirrosis biliar Primaria
Colangitis esclerosante Primaria
Injuria por drogas
Colestasis familiar progresiva
Hepatopatía crónica con esteatosis
• 3 cuadros:
• Esteatosis
• Esteatohepatitis (alcoholica o No alcoholica)
• Cirrosis
• Los dos primeros son reversibles
Esteatosis: micro y macrovacuolar
Se inicia en el centro del lobulillo, puede llegar hasta el EP
Hepatomegalia amarilla y frágil
Esteatohepatitis: tumefacción y necrosis hepatocítica
cuerpos de Mallory
infiltración por PMN en el lobulillo
infiltración por linfocitos y macrófagos portales
fibrosis perisinusoidal y perivenular
Cirrosis
Esteatohepatitis no alcoholica
Evolución de la graduación y estadio
Table 1. Necroinflammatory Grading System for Steatohepatitis Mild, grade 1Steatosis (predominantly macrovesicular) involving up to 66% of biopsy; may see occasional ballooned zone 3 hepatocytes; scattered rate intra-acinar pmn's ± intra-acinar lymphocytes; no or mild portal chronic inflammation. Moderate, grade 2Steatosis of any degree; ballooning of hepatocytes (predominantly zone 3) obvious; intra-acinar pmn's noted, may be associated with zone 3 pericellular fibrosis; portal and intra-acinar chronic inflammation noted, mild to moderate.Severe, grade 3Panacinar steatosis; ballooning and disarray obvious, predominantly in zone 3; intra-acinar inflammation noted as scattered pmn's, pms's associated with ballooned hepatocytes ± mild chronic inflammation; portal chronic inflammation mild or moderate, not marked. Grade (n) Steatosis* Ballooning Inflammation1—Mild 22 1-2 Minimal 1-2 acinar; 0-1 portal2—Moderate 23 2-3 Present-zone 3 2 acinar; 1-2 portal3—Severe 6 3 Marked-zone 3 3 acinar; 1-2 portal
Staging
Stage 1.: Zone 3 perisinusoidal/pericellular fibrosis; focally or extensively present.Stage 2.: Zone 3 perisinusoidal/pericellular fibrosis with focal or extensive periportal fibrosis.Stage 3.: Zone 3 perisinusoidal/pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis.Stage 4.: Cirrhosis.
NAS scores of 0-2 are not diagnostic of NASH, scores of 3-4 not diagnostic, borderline, or positive for NASH. Scores of 5-8 are diagnostic of NASH
Item Score Extent Definition and Comment
Steatosis 0 <5% Refers to amount of surface area involved 1 5-33% by steatosis as evaluated on low to medium
2 >33-66% power examination; minimal steatosis 3 >66% (<5%) receives a score of 0 to avoid giving
excess weight to biopsies with very little fatty change
Lobular Inflammation0 No foci Acidophil bodies are not included in this 1 2 foci/200x assessment, nor is portal inflammation2 2-4 foci/200x 3 >4 foci/200x Hepatocyte Ballooning0 None The term "few" means rare but definite 1 Few balloon cells ballooned hepatocytes as well as cases that 2 Many cells/prominent ballooning are diagnostically borderline
Most cases with prominent ballooning also had Mallory's hyalin, but Mallory's hyaline is not scored separately for the NAS
Fibrosis Stage (Evaluated separately from NAS)Fibrosis
0 None 1 Perisinusoidal or periportal 1A Mild, zone 3, perisinusoidal "delicate" fibrosis
1B Moderate, zone 3, perisinusoidal "dense" fibrosis
1C Portal/periportal This category is included to accommodate cases with portal
and/or peri portal fibrosis without accompanying pericellular/perisinusoidal
fibrosis
2 Perisinusoidal and portal/periportal 3 Bridging fibrosis 4 Cirrhosis
• Total NAS score represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8.
• Diagnosis of NASH (or, alternatively, fatty liver not diagnostic of NASH) should be made first, then NAS is used to grade activity.
• In the reference study, NAS scores of 0-2 occurred in cases largely considered not diagnostic of NASH,
• scores of 3-4 were evenly divided among those considered not diagnostic, borderline, or positive for NASH.
• Scores of 5-8 occurred in cases that were largely considered diagnostic of NASH
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Epithelial Epithelial
Hepatocellular Hepatocellular
Hepatocellular adenoma Hepatocellular carcinoma (HCC)a
Focal nodular hyperplasia HCC, fibrolamellar variant
Nodular regenerative hyperplasia Combined HCC-cholangiocacarcinoma
Macroregenerative nodule Hepatoblastoma, epithelial type
Borderline (dysplastic) nodule
Compensatory lobar hyperplasia
Accessory lobe
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Epithelial Epithelial
Cholangiocellular Cholangiocellular
Bile duct hamartoma (von Meyenburg complex)
Cholangiocarcinoma (CC)a
Bile duct adenoma Intraductal variant (“biliary papillomatosis”)
Biliary cysts (nonneoplastic) Cholangiocellular carcinoma
Solitary Adenosquamous carcinoma
Polycystic disease (noncommunicating) Mucoepidermoid carcinoma
Caroli’s disease Squamous cell carcinoma
Multiple hilar cysts Combined CC-neuroendocrine tumor
Biliary cystadenoma Biliary cystadenocarcinoma
Mucinous (+/-mesenchymal stroma)
Serous
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Mesenchymal Mesenchymal
Vascular Vascular
Hemangioma Angiosarcoma
Infantile hemangioendothelioma Epithelioid hemangioendothelioma
Hemangiomatosis Kaposi’s sarcoma
Lymphangioma (-tosis)
Hereditary hemorrhagic telangiectasia
Peliosis hepatis
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Mesenchymal Mesenchymal
Fatty tumors Fatty tumors
Angiomyolipoma (and related tumors) Liposarcoma
Pseudolipoma
Focal (hepatocellular) fatty change
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Mesenchymal Mesenchymal
Other Other
Solitary (localized) fibrous tumor Undifferentiated (embryonal) sarcoma
Inflammatory myofibroblastic tumor pseudotumor)
Rhabdomyosarcoma
Leiomyoma Fibrosarcoma, malignant fibrous histiocytoma
Leiomyosarcoma
Osteosarcoma
Mixed epithelial and mesenchymal Mixed epithelial and mesenchymal
Mesenchymal hamartoma Mixed hepatoblastoma
Sarcomatoid carcinoma (carcinosarcoma)
Table 2. The relative prevalence rates of primary hepatic tumors in the general and pediatric populations in the United States
General population Pediatric population
(%) (%)
Malignant (total) (94) (55–68)
Hepatocellular carcinoma 82 19–20
Hepatoblastoma 1 26–36
Cholangiocarcinoma 10 —
Angiosarcoma <1 < 2
Undifferentiated sarcoma <1 7–9
Other malignant tumors <1 < 1
Table 2. The relative prevalence rates of primary hepatic tumors in the general and pediatric populations in the United States
General population Pediatric population
(%) (%)
Benign (total) (6) (32–45)
Infantile hemangioendotelioma
— 18
Hepatocellular adenoma 1 2–4
Focal nodular hyperplasia 3 3–10
Nodular regenerative hyperplasia
— 0–5
Mesenchymal hamartoma — 8
Other benign tumors 2 —
Table 3. Cystic masses of the liver
Classification Diagnostic findings
Abcesses
Amebic Cavities filled with oderless necrotic hepatic tissue(“anchovy sauce”);
neutrophils rare or absent; trophozoites at periphery, don’t mistake
for histiocytes; reactive hepatocytes may be present; PAS and iron
hematoxylin stains may be helpful
Pyogenic Cavities filled with foul-smelling necrotic hepatic tissue containing many
neutrophils; often polymicrobial; E. coli most common; anaerobes
frequently isolated
Parasitic (echinococcal) cysts Echinococcus granulosus-unilocular cysts (three layers) often with
daughter cysts; brood capsules; protoscolices with attached or
detached acid-fast, birefringent hooklets
Nonparasitic (nonneoplastic) cysts Typically, cuboidal flattened, biliary type epithelial lining; rarely
Solitary (unilocular) squamous; thin fibrous wall; found in<1% of routinely performed autopsies
Polycystic liver disease
Adult polycystic disease; (ADPKD; Typically multiple cysts with autosomal dominant inheritance; prevalence
non communicating ductal cysts) of 0.15% at autopsy; associated with adult polycystic kidney disease
in 71% to 93% of cases; rarely, liver is massively enlarged; histologically
similar to solitary type
Communicating ductal cysts Typically autosomal recessive inheritance
Caroli's disease Ectatic intrahepatic bile ducts, inspisatted bile ± hepatolithiasis, cholangitis
Caroli's syndrome Caroli's disease plus congenital hepatic fibrosis
Congenital hepatic fibrosis/ARPKD Angulated bile ducts often with inspissated bile in fibrotic portal tracts with
portal-portal bridging fibrosis; only rarely macroscopic hepatic cysts
Multiple hilar cysts Noncommunicating cysts arising from dilatation of peribiliary glands
typically in hilum; often associated with cirrhosis, portal vein
thrombosis. Common in patients with ADPKD
Mesenchymal hamartoma Solid and cystic mass, 75% 1 yr of age; admixture of nonneoplastic tissue types
(myxoid stroma, hepatocytes, bile ducts, blood vessels); association with translocation involving
chromosome 19q; rare association with undifferentiated sarcoma
Alimentary tract-related cysts Intrahepatic ileal and duodenal duplications and ciliated
foregut cyst described
Pseudocysts (trauma, ischemia, pancreatic origin) Fibrous lining; may contain blood (hematoma), bile (biloma)
Neoplastic cysts
Biliary cystadenoma/cystadenocarcinoma
Mucinous type Most common type of multilocular cyst, but only 5% of all solitary cysts; 95% occur in women; lined columnar-cuboidal mucin containing epithelium; spindle-cell stroma (85%) only in women; search carefully for dysplasia (borderline lesion),
cystadenocarcinoma; rule out metastasis from other primary site(pancreas, ovary, appendix)
Serous (microcystic, glycogen rich) type Very rare; multilocular; bland, flattened to cuboidal cell lining; clear,
glycogen-rich, mucin-negative cytoplasm; no spindle-cell stroma;
rule out metastasis from pancreas
Teratoma Derivatives from three germ layers; problem of “teratoid hepatoblastoma”
Other Cystic degeneration of various neoplasms
ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; PAS, periodic acid-Schiff.
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Epithelial Epithelial
Hepatocellular Hepatocellular
Hepatocellular adenoma Hepatocellular carcinoma (HCC)a
Focal nodular hyperplasia HCC, fibrolamellar variant
Nodular regenerative hyperplasia Combined HCC-cholangiocacarcinoma
Macroregenerative nodule Hepatoblastoma, epithelial type
Borderline (dysplastic) nodule
Compensatory lobar hyperplasia
Accessory lobe
Features HCA
Clinical
Peak age(decade) 3rd–4th
M/F 1:15
Usual presentation Acute abdominal pain
Associated conditions OCS use (85–90%),
androgens,
metabolic disorders
Serum AFP Normal Range
Macroscopic
Number of nodules 70–80% single
Nodule diameter 75% 10cm
Cut surface often Tan-white, often hemorrhagic
Fibrous septa/scar Rare
Microscopic
Portal tracts Absent
Hepatocyte plate thickness 1–2 cells (sheet like)
Nuclear atypia, macronucleoli Rare
Mitoses Absent or rare
Septa (arteries, bile ductules Absent
inflammation; few portal
veins bile ducts)
Nontriadal (intranodular) arteries Common
Hepatocytes inside and outside Absent
nodule very in size, plate
arrangement
Table 5. Nodular regenerative hyperplasia: associated conditions
Immunologic disorders Connective tissue diseases Glomerulonephritis
Systemic lupus erythematosis
Progressive systemic sclerosis
Raynaud’s phenomenon
Rheumatoid arthritis ± Felty’s syndrome
Common variable immunodeficiency
Hepatic venous outflow obstruction
Cryoglobulinemia Myasthenia gravis Hyper-/hypothyroidism
Idiopathic thrombocytopenic purpura
Primary and secondary hepatic carcinomas
Extrahepatic portal vein thrombosis
Neoplastic disorders Myeloproliferative disorders Lymphoproliferative disorders
Drugs and toxins Chemotherapeutic agents Azathioprine
Toxic oil syndrome Arsenic Vinyl chloride
Obliterative portal venopathy
Corticosteroids Anabolic steroids
Vascular disorders Contraceptive steroids Arteritis
Table 7. Histologic features useful in differential diagnosis of benign, borderline (dysplastic), and malignant hepatocellular nodules typically arising in the cirrhotic livera
Borderline nodule
Histologic feature MRN LGD HGD WD-HCC MD-HCC
Primary diagnostic utility
Mitoses, at least moderate (>5/10 HPF) – – – – +
Hepatocellular plates >3 cells thick – – – – +
Reticulin uniformly < normal – – – – +
Positive endothelial markers (endothelium) – – ? +/– +
Uniformly prominent nucleoli – – – – +
Nuclear density >2 normal – – – + +
Irregular nuclear contour, ³ moderate – – – + +
Nuclear hyperchromasia – – + + +
Intranodular (nontriadal) arteries – + + + +
Subpopulations (“clonelike”) – + + + +
Table 8. Factors implicated in the pathogenesis of hepatocellular carcinoma (HCC)
Chronic hepatic injury (60–90%) Hereditary hemochromatosis
Cirrhosis (most common) Hereditary tyrosinemia
High rate of associated HCC (>15%)Chronic hepatitis only (far less common)
Membranous obstruction of the inferior vena cava
Porphyria cutanea tarda Hypercitrullinemia
Intermediate rate associated HCC (~5–15%) Alcohol
Alpha1-antitrypsin deficiency Glycogen storage disease (types 1 and 3)
Autoimmune hepatitis
Low rate presence of associated HCC (<5%) Primary biliary cirrhosis
Primary sclerosing cholangitis Hereditary fructose intolerance
Paucity of intrahepatic bile ducts Progressive intrahepatic cholestasis
Congenital hepatic fibrosis Biliary atresia
Wilson’s disease Oral contraceptive steroids
Anabolic-androgenic steroids Exposure to various chemicals/toxins
Table 9. pTMN staging of primary hepatic epithelial malignanciesa
T—Primary tumor
T1—Solitary mass, 2cm, without vascular invasion
T2—Solitary mass, 2cm, with vascular invasion, or multiple
masses, one lobe, all 2cm, without vascular invasion, or
solitary mass, >2 cm, without vascular invasion
T3—Solitary mass, >2 cm with vascular invasion, or multiple
masses, one lobe, 2 cm, with vascular invasion, or multiple
masses, one lobe, >2 cm, with or without vascular invasion
T4—Multiple masses in more than one lobe, or invasion of
major branch of portal or hepatic vein, or invasion of adjacent
organs other than gallbladder
N—Regional lymph nodes
N0—Negative regional lymph nodes
N1—Positive regional lymph nodes
M—Distant metastases
MX—Cannot be assessed
M0—No distant metastases
M1—Distant metastases present
Stage groupings
Stage I—T1N0M0
Stage II—T2N0M0
Stage IIIA—T3N0M0
Stage IIIB—T1N1M0, T2N1M0, T3N1M0
Stage IVA—T4 any N M0
Stage IVB—any T any N M1
Modified from ref. 176. Vascular invasion includes either macroscopic or microscopic involvement of vessels.
Table 10. Histologic grading of hepatocellular carcinomaa
Well differentiated (Grades I/II of Edmondson and Steiner)
Thin plates, three or fewer hepatocytes thick, that are typically smaller than
normal, demonstrate minimal nuclear atypia, and have a nuclear density greater
than twice that of the nonneoplastic liver. Fatty change and pseudoglandular
architecture are common. Clear-cut histologic distinction from hepatocellular more
poorly adenoma may not be possible in some cases without finding other,
differentiated foci and knowing the status of the nonneoplastic liver. This pattern is
typical of small (<2 cm) HCC.
Moderately differentiated (Grades II/III of Edmondson and Steiner)
Typically characterized by a trabecular pattern in which tumor cells are arranged
in plates more than three cells thick. Tumor cells are larger and have more
abundant eosinophilic cytoplasm and distinct nucleoli, compared with
well-differentiated tumors. Pseudoglandular structures and bile are usually seen,
and tumor giant cells may be present This is the most common type of
differentiation seen in advanced (>2 cm) HCC.
Poorly differentiated (Grades III/IV of Edmondson and Steiner)
Tumor cells have larger and more hyperchromatic nuclei and are typically
arranged in a compact (solid) growth pattern with rare or no trabeculae or bile.
Pleomorphism may be prominent and spindle-cell or small-cell areas may be seen.
May be difficult to recognize as hepatocellular in origin.
aModified from refs. 2, 4, 120, 172. More than one pattern is frequently seen in tumors larger than 1.5 cm diameter.
Table 15. Fibrolamellar hepatocellular carcinoma (FL-HCC): distinguishing clinicopathologic features from the usual HCC
FL-HCC Usual HCC
Clinical features
% HCC 1–5% 95–99%
Epidemiologic factors
Age Peak, 3rd 6th–7th
decade decade
Sex (male/female) 1:1 3–6:1
Serum markers
(% elevated)
AFP 10–15% 60–80%
DCP 100% 60–90%
NT, B12 UB12BC Often increased Rarely increased
Imaging studies
Calcification 40–80% 5% (no RX)
Central scar 50–70% Rare
Resectability 48–75% 10–20%
Macroscopic features
% Solitary 75%; left > Uncommon
right lobe
Fibrous septa, scar 10–63% Absent
Necrosis, hemorrhage Occasional Common
(larger
tumors)
Associated cirrhosis <10% 60–90%
Microscopic features
Cell size, shape Larger Smaller
Cytoplasm
Abundance More Less
Granularity More Less
Pale bodies 50% 10%
Hyaline globules 50% 10–15%
Stroma Prominent lamellar bands Scant
EM (mitochondria) Numerous Less common
Survival (5 yr)
Overall 25–30% 0–7%
Resected 56–75% 20–30%
AFP, alpha-fetoprotein; DCP, des-Y-carboxy prothrombin; NT, neurotensin; UB12BC, unsaturated B12 binding capacity; RX, treatment.
Table 18. Staging of hepatoblastoma according to the children’s cancer study group
Stage I—Complete resection
Stage II—Microscopic residual disease only
Stage III—Gross residual disease or positive lymph nodes or
spilled tumor
Stage IV—Metastases
aModified from ref.236.
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Epithelial Epithelial
Cholangiocellular Cholangiocellular
Bile duct hamartoma (von Meyenburg complex)
Cholangiocarcinoma (CC)a
Bile duct adenoma Intraductal variant (“biliary papillomatosis”)
Biliary cysts (nonneoplastic) Cholangiocellular carcinoma
Solitary Adenosquamous carcinoma
Polycystic disease (noncommunicating) Mucoepidermoid carcinoma
Caroli’s disease Squamous cell carcinoma
Multiple hilar cysts Combined CC-neuroendocrine tumor
Biliary cystadenoma Biliary cystadenocarcinoma
Mucinous (+/-mesenchymal stroma)
Serous
Table 20. Intrahepatic cholangiocarcinoma: predisposing and premalignant conditions
No predisposing conditions (80–90%)
Predisposing conditions (10–20%)
Chronic cholangitis (by far most common)
Clonorchis sinensis (Hong Kong, Canton)
Hepatolithiasis (Far East, including Japan)
Hepatic cysts Ductal plate malformation PSC/CUC (Western countries)
Opisthorchis viverrini (Thailand)
Congenital dilatation of the intrahepatic bile ducts
Congenital hepatic fibrosis
Bile duct hamartomas Caroli’s disease Anabolic steroids
Toxins/drugs Hereditary hemochromatosis Thorotrast
Nonbiliary cirrhosis (<5%) Premalignant conditions: Dysplasia
Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses
BenignBenign MalignantMalignant
Mesenchymal Mesenchymal
Vascular Vascular
Hemangioma Angiosarcoma
Infantile hemangioendothelioma Epithelioid hemangioendothelioma
Hemangiomatosis Kaposi’s sarcoma
Lymphangioma (-tosis)
Hereditary hemorrhagic telangiectasia
Peliosis hepatis
Table 22. Hepatic angiosarcoma: associated etiologic agents/conditionsa
Idiopathic (58–75%)
Associated agents/conditions (25–42%)
Thorotrastb
Vinyl chlorideb
Inorganic arsenicb
Androgenic steroidsb
Copper sulfate
Estrogenic steroids
Phenelzine
Radiotherapy
Chemotherapeutic agents
Hereditary hemochromatosis (cirrhotic stage)
aData from references 282, 302, 303. Cases potentially arising from preexisting benign vascular tumors, such as infantile hemangioendothelioma and a unique case of cavemous hemangioma, are excluded.
bBy far the most commonly associated agents.
Table 23. Clinicopathologic features of angiosarcoma and epithelioid hemangioendothelioma
Feature Epithelioid hemangioendothelioma Angiosarcoma
Clinical features
Sex (male/female) 1:1.6 3–4:1
Mean age (range), yrs 47 (3–86) 53 (<1, > 80)
Etiologic factors None well documented 25–42%; Thorotrast, VC, arsenic,
androgens, etc.
Symptoms and signs
Abdominal pain, mass Most common Most common
Intraabdominal bleeding Rare 30%
Asymptomatic 50% Virtually never
Thrombocytopenia No 50%
Radiographic features
Abdominal films, calcification 20% Virtually never; Thorotrast causes
radiodensity
Angiography Typically avascular Typically vascular
Pathologic features
Macroscopic
Multiple nodules 80% 70%
Nodule size (cm) <1–12 cm; rarely cirrhotomimetic <1–5
Nodule appearance White-gray, tan, firm, infiltrative borders Blood cysts, spongy, occasionally white,
firm
Microscopic
Zonation Present Absent
Tumor cellularity Scanty in fibrotic areas Abundant
Spindle and epithelioid cells Present Present
Intracytoplasmic lumina Prominent Inconspicuous
Marked nuclear pleomorphism Absent Present
Sinusoidal/venous invasion Extensive Extensive
Stroma Myxoid/dense sclerosis, Scant, focally fibrotic, no calcification
Extramedullary hematopoiesis Absent Often present
Tumor cell immunohistochemistry
Endothelial markers Positive Positive
Cytokeratin Occasionally positive Occasionally positive
Adjacent liver Usually normal, Fibrosis, cirrhosis common with known
etiologic factors
Outcome Unpredictable, 19% 5 yrs Dismal, 3% alive at 2 yrs
NRH, nodular regenerative hyperplasia; VC, vinyl chloride.