Patología Hepática

Enfermedades no neoplásicas Malformaciones Inflamatorias: hepatitis Alteraciones de la vía biliar intrahepática Hepatopatías por fármacos y tóxicos Cirrosis (vía final común) Errores innatos del metabolismo Trastornos circulatorios Alteraciones 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 Linfocitos Plasmocitos Eosinófilos Actividad necroinfla matoria Hepatitis de interfase Necrosis lobulillar Infiltrado lobulillar Grado Tipo Localización Sinusoidal Con necrosis Linfoplasmocit. Ductos biliares Daño ductal Pérdida ductal Proliferación Hialina de Mallory Cobre Granulomas Vidrio esmerilado  

Tipos de virus y cambios histológicos - + Fibrosis + - Degeneración de los ductos biliares Proliferación ductular NL LP PLEN Tipos 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 E D C B A

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

Característica histológica Trombos biliares canaliculares 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 Localización de los cambios Centrolobular Periportal/ Periseptal Portal Característica auxiliar Daño hepatocelular; inflamación lobular Acumulación de cobre; Cuerpos de Mallory Colestasis Canalicular; Cambios portales obstructivos 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

  Disease Característica CBP CEP Wilson Medicamentos Cambios portales Difusos En parches - ++ + Tipo de infiltrado portal Linfocitos Plasmocitos Eosinófilos Actividad necroinflamatoria Hepatitis de interfase Necrosis lobulillar Infiltrado lobulillar Grado Tipo Localización Sinusoidal Ductos biliares Daño ductal Pérdida ductal Proliferación Hialina de Mallory Tardía Cobre Granulomas Vidrio esmerilado  

Scheuer system for PBC (56) Ludwig (Mayo) system for PBC/PSC (54) 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: Es la cirrosis de tipo biliar 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 Colestasis compuesta CRÓNICA Obstrucción biliar crónica Colangitis esclerosante Primaria Cirrosis biliar Primaria 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 1 Steatosis (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 2 Steatosis 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 3 Panacinar 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 Inflammation 1—Mild 22 1-2 Minimal 1-2 acinar; 0-1 portal 2—Moderate 23 2-3 Present-zone 3 2 acinar; 1-2 portal 3—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 Inflammation 0 No foci Acidophil bodies are not included in this 1 2 foci/200x assessment, nor is portal inflammation 2 2-4 foci/200x 3 >4 foci/200x Hepatocyte Ballooning 0 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) 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 Benign Malignant Epithelial 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 Benign Malignant Epithelial 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 Benign Malignant Mesenchymal 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 Benign Malignant Mesenchymal Fatty tumors Angiomyolipoma (and related tumors) Liposarcoma Pseudolipoma   Focal (hepatocellular) fatty change

Table 1. Classification of primary hepatic neoplasms and nonneoplastic masses Benign Malignant Mesenchymal Other Solitary (localized) fibrous tumor Undifferentiated (embryonal) sarcoma Inflammatory myofibroblastic tumor pseudotumor) Rhabdomyosarcoma Leiomyoma Fibrosarcoma, malignant fibrous histiocytoma   Leiomyosarcoma Osteosarcoma Mixed epithelial and mesenchymal Mesenchymal hamartoma Mixed hepatoblastoma Sarcomatoid carcinoma (carcinosarcoma)

Hepatocellular carcinoma 82 19–20 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 7–9 Other malignant tumors < 1

Infantile hemangioendotelioma — 18 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 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 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 Benign Malignant Epithelial 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 Benign Malignant Epithelial 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 Benign Malignant Mesenchymal 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.