Liver surgical pathology

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Liver surgical pathology

  1. 1. LIVER PATHOLOGY BERNADETTE R. ESPIRITU, M.D. FPSP Anatomic & Clinical Pathologist
  2. 2. LIVER  1.4–1.6 kg (3.1–3.5 lb)  reddish brown soft organ with four lobes of unequal size and shape  It is both the largest internal organ (the skin being the largest organ overall) and the largest gland in the human body
  3. 3. -Located in the RUQ of the abd cavity, resting just below the diaphragm. The liver lies to the right of the stomach and overlies the GB. -The Rt lobe is larger. -The falciform ligament is the dividing line between the two lobes. NORMAL LIVER: GROSS
  4. 4. BLOOD SUPPLY  Two large BV, one called the HEPATIC ARTERY and one called the PORTAL VEIN.  The HA carries blood from the aorta whereas the PV carries blood containing digested nutrients from the Small intestine and the descending colon.  These blood vessels subdivide into capillaries which then lead to a lobule.  Each lobule is made up of millions of hepatic cells which are the basic metabolic cells.
  5. 5. It is one of only two organs to have two blood supplies, receiving blood from the hepatic arteries [20%] and the portal vein [80%] (carrying blood from the intestines).
  6. 6. The Rt. lobe is the larger, measuring 6 to 7 inches in length. The left lobe is 3 inches in length.
  7. 7. - brown - smooth - soft EXTERNAL SURFACE OF A NORMAL LIVER
  8. 8.  Near the hilum - the portal vein carrying blood to the liver, which branches with accompanying hepatic artery and bile ducts.  lower right - is a branch of hepatic vein draining blood from the liver to the inferior vena cava. GROSS: NORMAL LIVER C/S
  9. 9. NORMAL LIVER ZONES 1 2 3 PT – Bile ducts, Hepatic artery & PV CV Periportal – receives blood with highest oxygen conc Midzonal – encompasses the central portion of the liver lobule Centrilobular
  10. 10. Histologically Divided into LOBULES Center of the lobule - CV Periphery of the lobule - PT Functionally, Divided into : 3 ZONES, based upon oxygen supply Zone 1- Encircles the PT where the oxygenated blood from hepatic arteries enters. Zone 3 is located around CV, where oxygenation is poor. Zone 2 is located in between. NORMAL LIVER: STRUCTURE CV PT
  11. 11. STEATOSIS 
  12. 12. FATTY CHANGE Clinical:  Incidental finding at autopsy  Most common cause in developed nations is Alcoholism  In developing nations - Kwashiorkor in children  DM, obesity, & severe GI malabsorption  Unknown cause; may be due to focal tissue hypoxia or local effects of insulin  Stable or regresses if underlying condition improves
  13. 13.  This liver is slightly enlarged and is pale yellow seen both on the capsule and cut surface FATTY CHANGE: GROSS
  14. 14. C/S - subcapsular - yellow-white foci - often multiple - up to 10 cm
  15. 15. Lipid accumulates in the hepatocytes as vacuoles FATTY CHANGE: MICRO
  16. 16. -The lipid accumulates when lipoprotein transport is disrupted and/or when fatty acids accumulate. -Alcohol, the most common cause, is a hepatotoxin that interferes with mitochondrial and microsomal function in hepatocytes, leading to accumulation of lipid. FATTY METAMORPHOSIS
  17. 17. FATTY CHANGE: MICRO  diffuse or focal steatosis
  18. 18. DIFFERENTIAL DIAGNOSIS: FC ● Angiomyolipoma ● Coelomic fat ectopia ● Diffuse steatosis ● Focal nodular hyperplasia - nodular, but not a fatty tumor; has hepatocyte nodules surrounded by fibrous septa with large malformed arterial branches ● Hepatic adenoma - neoplastic hepatocytes ● Lipoma - no trapped hepatocytes ● Myelolipoma ● Hepatocellular carcinoma may have fatty change
  19. 19. MYELOLIPOMA Greasy, yellow tumor with reddish- brown areas at the periphery corresponding to hematopoieti c elements Intimately admixed adipose tissue and hematopoietic elements. Note the large multilobate megakaryocyte. Inset : A few bony spicules present amidst the mature adipocytes
  20. 20. CIRRHOSIS
  21. 21. CIRRHOSIS  Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis.  nodular, firm liver  Nodules - larger than 3 mm ("macronodular“ cirrhosis)
  22. 22. MACRONODULAR CIRRHOSIS CAUSES: Viral hepatitis (B or C) - most common cause Wilson's disease Alpha-1-antitrypsin deficiency
  23. 23. MICRONODULAR CIRRHOSIS The regenerative nodules - quite small, averaging < 3 mm in size CAUSES: Chronic Alcoholism – Most Common Wilson's disease Primary biliary cirrhosis Hemochromatosis.
  24. 24. MICRONODULAR CIRRHOSIS Liver - yellowish hue, indicating that fatty change (also caused by alcoholism) is present.
  25. 25. MICRONODULAR CIRRHOSIS Micronodular cirrhosis with fatty change demonstrates the small, yellow nodules. .
  26. 26. CIRRHOSIS: micro Regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes as well as a proliferation of bile ducts.
  27. 27. MICRONODULAR CIRRHOSIS - Seen along with moderate fatty change - Note the regenerative nodule surrounded by fibrous connective tissue extending between portal regions
  28. 28. MALLORY'S HYALINE - HPO: seen are globular red hyaline material within hepatocytes - also known as "alcoholic" hyaline - chronic alcoholism - The globules are aggregates of intermediate filaments in the cytoplasm resulting from hepatocyte injury.
  29. 29. ALCOHOLIC HEPATITIS - Mallory's hyaline, neutrophils, necrosis of hepatocytes, collagen deposition, and fatty change
  30. 30. CAPUT MEDUSAE : CIRRHOSIS - Results from the abnormal blood flow pattern in liver -The increased pressure is transmitted to collateral venous channels. Sometimes these venous collaterals are dilated. - Dilated veins seen on the abdomen
  31. 31. ESOPHAGEAL VARICES - Produced by Portal HPN - results when submucosal veins in the esophagus become dilated. -Varices are seen here in the lower esophagus as linear blue dilated veins. There is hemorrhage around one of them. -Such varices are easily eroded, leading to massive gastrointestinal hemorrhage.
  32. 32. PORTAL HYPERTENSION: SPLENOMEGALY One of the most common findings in CIRRHOSIS SPLEEN- Is enlarged (normal 300 grams or less) 500 - 1000 gm. - irregular pale tan plaques of collagen over the purple capsule known as "sugar icing" or "hyaline perisplenitis" which follows the splenomegaly and/or multiple episodes of peritonitis that are a common accompaniment to cirrhosis of the liver
  33. 33. PIGMENTARY DISORDERS OF THE LIVER
  34. 34. HEMOSIDEROSIS The hepatocytes and Kupffer cells here are full of granular brown deposits of hemosiderin from accumulation of excess iron in the liver. The term "hemosiderosis" is used to denote a relatively benign accumulation of iron. The term "hemochromatosis" is used when organ dysfunction occurs. The iron accumulation may lead to a micronodular cirrhosis (so called "pigment" cirrhosis).
  35. 35.  Kupffer cells, also known as Browicz-Kupffer cells, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system (RES) (aka: mononuclear phagocyte system)
  36. 36. HEMOSIDEROSIS A Prussian blue iron stain demonstrates the blue granules of hemosiderin in hepatocytes and Kupffer cells. Hemochromatosis can be primary (the cause is probably an autosomal recessive genetic disease) or secondary (excess iron intake or absorption, liver disease, or numerous transfusions). Hemochromatosis leads to bronze pigmentation of skin, DM (from pancreatic involvement), and cardiac arrhythmias (from myocardial involvement).
  37. 37. HEREDITARY HEMOCHROMATOSIS (HHC): GROSS - Dark brown - liver, the pancreas and lymph nodes -due to extensive iron deposition - HHC results from a mutation involving the hemochromatosis gene (HFE) that leads to increased iron absorption from the gut. - Prevalence - 1:200 & 1:500 persons in the U.S.
  38. 38. HEREDITARY HEMOCHROMATOSIS (HH). CIRRHOSIS Prussian blue iron: reveals extensive hepatic hemosiderin deposition Excessive iron deposition in persons with HH can affect many organs, but the MOST SEVERELY AFFECTED: Heart (congestive failure) Pancreas (diabetes mellitus) Liver (cirrhosis and hepatic failure) Joints (arthritis)
  39. 39. LIPOFUSCIN PIGMENT -Pale golden brown finely granular pigment in nearly all hepatocytes is lipochrome (lipofuscin). -This is a "wear and tear" pigment from the accumulation of autophagolysosomes over time. - This pigment is of no real pathologic importance
  40. 40. CHOLESTASIS: MICRO - accumulations of pigment - bile - often this is due to extrahepatic biliary tract obstruction - Bile may also accumulate in liver (called cholestasis) when there is hepatocyte injury.
  41. 41. INTRAHEPATIC LITHIASIS - Small stone in an intrahepatic bile duct - Produce a localized cholestasis, but the serum bilirubin is NOT increased, because there is plenty of non-obstructed liver to clear the bilirubin from the blood - Serum Alkaline Phos is increased with biliary tract obstruction at any level
  42. 42. TUMORS OF THE LIVER & INTRAHEPATIC DUCTS  BENIGN EPITHELIAL TUMORS  MALIGNANT EPITHELIAL TUMORS  BENIGN MESENCHYMAL TUMORS  MALIGNANT MESENCHYMAL TUMORS  HEMATOPOIETIC NEOPLASM  TUMOR-LIKE LESIONS
  43. 43. BENIGN EPITHELIAL TUMORS
  44. 44. LIVER CELL ADENOMA  Arises in normal or nearly normal liver in patients with abnormal hormonal or metabolic condition  95% women, usually child-bearing age (very rare in children), history of 5+ years of oral contraceptives in 85% (occasionally regress after discontinuation)  Associated with anabolic steroids (in men), anti- estrogens, Klinefelter’s syndrome or other abnormal secretion of sex steroids
  45. 45. LIVER CELL ADENOMA  Associated with glycogen storage disease types Ia and III, Fanconi’s anemia, familial adenomatous polyposis, familial diabetes mellitus, Hurler’s disease or tyrosinemia  Spontaneous  2-4% of hepatic tumors in children
  46. 46. LIVER CELL ADENOMA  Subcapsular tumors may rupture, particularly during pregnancy  Benign, but may contain hepatocellular carcinoma or cause severe hemorrhage  10% or lower risk of hepatocellular carcinoma if not resected; definite risk in young men with glycogen storage disease type Ia  Must sample generously to rule out coexisting hepatocellular carcinoma  May contain hepatic progenitor cells
  47. 47. LIVER CELL ADENOMA  Laboratory: normal liver function tests, may have elevated alpha fetoprotein  Hepatocellular adenomatosis: 10+ tumors  Treatment: excision
  48. 48. LIVER CELL ADENOMA CLINICAL PRESENTATION:  RUQ pain & discomfort  Severe abdominal pain  Hemorrhages  Shock  Overall Mortality : 20%  Surgical resection  No excess α-fetoprotein
  49. 49. GROSS: LIVER CELL ADENOMA  Solitary (70%, anabolic steroid related more often multiple), pale, yellow-tan (different from surrounding liver), frequently bile-stained nodules, often subcapsular, 10-30 cm, sharply demarcated or encapsulated  Usually right lobe, may be pedunculated (10%)  May have hemorrhagic, necrotic or infarcted foci  Usually no fibrous septa or central scar  Adjacent liver is noncirrhotic
  50. 50. LIVER CELL ADENOMA At the upper right is a well-circumscribed neoplasm that is arising in liver.
  51. 51. LIVER CELL ADENOMA C /S - Well circumscribed -The remaining liver is a pale yellow brown because of fatty change from chronic alcoholism.
  52. 52. LIVER CELL ADENOMA: MICRO  Sheets and cords 1-3 cells thick of normal appearing hepatocytes with variable glycogen  No/rare mitotic figures  No portal tracts, no central veins or connection with biliary system but see prominent “free floating” arterial vessels and draining veins throughout the tumor  Intact reticulin framework  Pseudoglands may be present
  53. 53. LIVER CELL ADENOMA: MICRO  May have cytoplasmic globules (PAS+, diastase resistant, alpha-1-antitrypsin+, AFP-)  10% have multinucleation, but no atypia  No prominent nucleoli  No intranuclear vacuoles  No/rare mitotic figures  No angiolymphatic invasion  No/rare extramedullary hematopoiesis  No epithelioid granulomas  No decreased reticulin framework
  54. 54. LIVER CELL ADENOMA: MICRO  Degenerative changes include:  Dilated sinusoids  Blood filled (pelioid) spaces  Myxoid stroma  Focal necrosis  Infarction  Hematoma  Rarely contains abundant fat, oncocytic changes, Mallory’s hyaline, granulomatous inflammation
  55. 55. LIVER CELL ADENOMA Composed of cells that closely resemble normal hepatocytes, but the neoplastic liver tissue is disorganized hepatocyte cords and does not contain a normal lobular architecture 21
  56. 56. LIVER CELL ADENOMA  Positive stains: ER, PR  Negative stains: p53  DD:  HEPATOCELLULAR CARCINOMA (mitotic activity, atypia, trabecular growth, cell plates > 2 cells thick, vascular invasion, infiltrative, often different clinical features)  FOCAL NODULAR HYPERPLASIA (central stellate scar and radiating fibrous septa)
  57. 57. BILE DUCT ADENOMA (Cholangioma)  30% - incidental finding  Clinical significance: mistaken as metastasis  GROSS: Small, well-circumscribed but unencapsulated, firm, gray-white, tan, subcapsular nodules; 85% solitary; usually 5 mm or less but 7% are larger than 1 cm; may have central depression
  58. 58. BDA: MICRO:  Small tubules set in a fibrous stroma with lymphocytes  Single layer of cuboidal cells; possible mucin secretion; no bile in the lumen  Normal portal tracts often included  May actually represent peribiliary gland hamartoma
  59. 59. BDA: MICRO  Compact network of simple tubular ducts or more complex tortuous arrangement, with small or indistinct lumina  Epithelium has abundant cytoplasm and pale nuclei compared to interlobular bile ducts in adjacent liver  Variable fibrous stroma, granulomas, calcification, inflammatory cells  Usually no cystic change, no cytoplasmic or intraluminal bile, no atypia, no mitotic figures, no angiolymphatic invasion
  60. 60. BDA  Positive stains:  Mucin (intracytoplasmic)  CEA  EMA  Keratin  PAS highlights basement membrane
  61. 61. BDA: Differential Diagnosis  Evolving Bile Duct Carcinoma  Biliary Hamartoma (von Meyenburg complexes)  Mesenchymal Hamartoma  Cholangiocarcioma  Adenocarcinoma
  62. 62. HEPATOBILIARY CYSTADENOMA CLINICAL:  Rare, 5% of all hepatic solitary cysts  Resembling cystadenoma of the pancreas/ovary, Associated with polycystic liver disease, abnormal hepatobiliary anatomy  84% are intrahepatic, also in common bile duct (6%), hepatic ducts (4%), cystic duct (4%), gallbladder (2%) ectopic embryonal tissue (gallbladder precursor)  Middle-aged woman, 95% occur in women, mean age 45 years (range 2-87 years)
  63. 63.  Usual presentation: pain & discomfort  Slow growth, symptomatic with increase in size  Surgical resection always indicated, malignant transformation possible  Usually slow growing with good prognosis after surgical excision, although 25% have coexisting borderline or malignant lesions Complications:  intracystic hemorrhage  Bacterial infection  Rupture
  64. 64. HEPATOBILIARY CYSTADENOMA Laboratory:  Elevated CA 19-9 (in cases with ovarian type stroma) and CEA in cyst fluid and serum Xray:  Calcification in 20% (resemble echinococcal cyst) Treatment:  Complete excision (rarely has delayed recurrence)
  65. 65. HEPATOBILIARY CYSTADENOMA: Gross:  Encapsulated  Solitary, mean 15 cm (range 3-28 cm)  Usually mucinous, multilocular  Contains up to several liters of fluid  Smooth inner surface with few trabeculations or polypoid cystic projections  Rarely contains gallstones  Nodules of solid tissue suggests malignancy
  66. 66. HEPATOBILIARY CYSTADENOMA
  67. 67. HBCA MICRO: mucinous :  Lining: single layer of columnar-cuboidal mucinous epithelium with basal nuclei and apical mucin  spindle-cell ovarian type stroma only in women (resembles pancreatic mucinous cystic neoplasms)  spindle cells may contain fat and smooth muscle  may have collagenous zone above stroma (resembling collagenous colitis)  capsule composed of dense collagen with blood vessels, variable bile ducts
  68. 68. HBCA: MICRO  May have squamous or intestinal metaplasia, often neuroendocrine cells  May have dysplastic or borderline foci  May have ulceration with macrophages containing lipofuscin or hemosiderin, cholesterol clefts with FB giant cell reaction or calcification  no/rare atypia, no/rare mitotic figures
  69. 69. HEPATOBILIARY CYSTADENOMA: MICRO:  serous - lined by bland, flat to cuboidal cells with clear, glycogen-rich cytoplasm, no spindle cell stroma; no mucin; may represent hepatic metastasis from pancreatic serous cystadenoca
  70. 70. Positive stains: epithelial cells - cytokeratin, EMA, CEA, CA19-9; stromal cells - muscle specific actin, vimentin; usually ER and PR Positive stains: Epithelial cells - cytokeratin, EMA, CEA, CA19-9 stromal cells - muscle specific actin, vimentin; usually ER and PR
  71. 71. HEPATOBILIARY CYSTADENOMA: Differential Diagnosis:  Developmental Cyst  Cystadenocarcinoma  Borderline tumors (have high grade dysplasia and complex architecture)  invasive tumors (put through numerous sections to exclude) Borderline  Tumors with high grade dysplasia with complex architecture
  72. 72. BILIARY PAPILLOMATOSIS CLINICAL:  Rare, 50 cases reported  2/3 men, usually ages 40+ years  Multiple papillary adenomas extensively throughout intra- or extrahepatic biliary tract  Often recurs, 25% have malignant transformation, but only rare metastases (to lung)  Associated with Caroli’s disease, choledochal cyst, polyposis coli and ulcerative colitis  Most patients die within 3 years due to cholangitis and hepatic failure  Treatment: difficult to treat because multifocal; liver transplant may be helpful
  73. 73. BILIARY PAPILLOMATOSIS GROSS:  Inner surface of ducts has velvety friable papillary growths / excrescences with masses filling dilated major bile ducts  Masses are soft, friable, white-red-tan
  74. 74. BILIARY PAPILLOMATOSIS Micro:  Dilated ducts contain multiple papillary tumors composed of fibrovascular cores lined by columnar, pseudostratified, biliary-type cells with numerous cytoplasmic mucin vacuoles  Tumor may be solid or cribriform  Varying cytologic atypia and mitotic activity  May have associated tubular adenocarcinoma with invasion
  75. 75. MALIGNANT EPITHELIAL TUMOR
  76. 76. HEPATOCELLULAR CA  Also called LIVER CELL CARCINOMA, HEPATOMA  85% of hepatic malignancies (30% in children)  Major cause of cancer death worldwide (20-40% in China, Japan, sub-Saharan African), although not in North America  Primary carcinomas are rare in North America, but more common in countries bordering Mediterranean Sea endemic for viral hepatitis  Highest rates in Korea, Taiwan, southeast China, Mozambique  250,000 worldwide cases annually  Higher rates in blacks vs. whites (4:1)  Most are age 60+ years with cirrhosis or ages 20-40 years without cirrhosis, occasionally are second tumors in Wilm’s tumor patients
  77. 77. HCC: Risk factors/causes  Hepatitis B virus (HBV) (infant carriers have 200x risk)  Cirrhosis (85% in West with HCC have cirrhosis, 3% with cirrhosis develop HCC annually)  Hepatitis C virus (HCV)  Alcohol abuse, aflatoxins  Genetic variation (all act synergistically)  Small cell change but probably not large cell change  Thorotrast exposure  Androgenic steroids  Tyrosinemia
  78. 78. HCC: RISK FACTORS/CAUSES Hepatitis B virus:  HBV DNA is integrated into host cell genome, inducing genomic instability  HBV contains 4 open reading frames  HBV X protein may disrupt normal growth control by transcriptional activation of insulin like growth factor II, receptors for insulin-like growth factor I  HBV X binds to p53; HBV vaccination may dramatically reduce HCC incidence
  79. 79. HCC Aflatoxins:  aflatoxin B1, a metabolite of the fungus Aspergillus flavus, is a potent carcinogen in some areas endemic for HCC  is activated by hepatocytes, products intercalate into DNA to form mutagenic adducts with guanosine  in sub-Saharan Africa and China, patients have mutation in hepatic enzymes that normally detoxify aflatoxin
  80. 80. HCC Cirrhosis:  major risk factor,caused by HCV, Alcoholism, primary hemochromatosis, hereditary tyrosinemia (40% develop HCC even with dietary control);  Due to stimulation of hepatocellular division in background of ongoing necrosis and inflammation Symptoms: abdominal pain, ascites, hepatomegaly, obstructive jaundice; also systemic manifestations
  81. 81. HCC  Laboratory: elevated serum AFP (70% sensitive), reduced sensitivity in alcohol-related cirrhosis (65%), tumors arising in noncirrhotic liver (33%), tumors 2 cm or less (25%)  Screening: recommended to use ultrasound and serum AFP in patients with chronic liver disease; leads to diagnosis of tumors 2 cm or less, may not reduce deaths  Other causes of elevated serum AFP: yolk sac tumors of gonads, cirrhosis, massive liver necrosis, chronic hepatitis, normal pregnancy, fetal distress or death, fetal neural tube defects, hepatoblastoma, hepatoid adenocarcinoma
  82. 82. HCC  5 year survival: 10% normally to 50% in tumors 5 cm or less with resection; death usually within 1 year from cachexia, GI bleed, liver failure, rupture of tumor (10%)  Metastases: initially within liver, distant metastases late to lungs, bone, adrenal gland or porta hepatis lymph nodes
  83. 83. HCC Favorable prognosis factors:  low stage, encapsulation, single lesion, tumor size < 5 cm, fibrolamellar variant, no cirrhosis (independent of fibrolamellar subtype), no vascular invasion, negative surgical margins  another study: low nuclear grade (grade 1 of 3) regardless of vascular invasion or intermediate nuclear grade (2 of 3) without microscopic vascular invasion
  84. 84. HCC Poor prognostic factors:  Microscopic vascular invasion  High nuclear grade (grade 3 of 3) Factors that are not prognostic:  Age  Gender  HBV status
  85. 85. HCC Classification:  Either small (< 2 cm) or advanced (2 cm or more) Treatment:  Resection  Transplantation (if solitary tumor 5 cm or less or multiple nodules 3 cm or less)  Radiofrequency ablation
  86. 86. HCC: GROSS  Unifocal, multifocal or diffusely infiltrative soft tumor, paler than normal tissue, may be green due to bile  Extensive intrahepatic metastases are common  Snakelike masses of tumor may involve the portal vein (35-80%), hepatic vein (20%) or inferior vena cava (similar to renal cell carcinoma)  Hemorrhage and necrosis are common  Occasionally tumor is pedunculated  Liver usually cirrhotic, often enlarged
  87. 87. HEPATOCELLULAR CARCINOMA - Arise in the setting of cirrhosis - Worldwide, viral hepatitis is the most common cause, but in the U.S., chronic alcoholism is the most common cause. - large and bulky and has a greenish cast because it contains bile - To the right of the main mass are smaller satellite nodules.
  88. 88. HCC: GROSS  Soft yellow-green or reddish masses of varying sizes: 3 basic patterns  Multinodular  Solitary  Massive or diffuse  For symptomatic individuals- most common is a large mass surrounded by several satellite nodules, multinodular appearance may be difficult to distinguish from cirrhosis. Diffuse pattern – rare  Tumor thrombi in veins are common as is spontaneous rupture of larger masses
  89. 89. HCC The satellite nodules - represent either intrahepatic spread of the tumor or multicentric origin of the tumor.
  90. 90. HEPATOCELLULAR CARCINOMA - Greenish yellow hue - One clue to the presence of such a neoplasm - serum α-fetoprotein - May focally obstruct the biliary tract and lead to an alkaline phos
  91. 91. Involvement of Inferior Vena Cava & other large vessels
  92. 92. HCC: MICRO Patterns:  Trabecular (most common) with 4+ cells surrounded by layer of flattened endothelial cells  Solid (compact)  Pseudoglandular (acinar with proteinaceous material or bile in lumina, may resemble thyroid follicles),  Pelioid  Giant cell  Sarcomatoid  Clear cell patterns  Sinusoidal vessels surrounding tumor cells is important diagnostic feature  Scanty stroma, from well differentiated to bizarre (often within same tumor)
  93. 93. HCC: MICRO Cells  Polygonal with distinct cell membranes  Higher N/C ratio  Abundant granular eosinophilic cytoplasm  Round nuclei with coarse chromatin and thickened nuclear membrane  Prominent nucleoli
  94. 94. Cells:  Also intranuclear pseudoinclusions  Mallory’s hyaline (2-25%)  Bile (5-33%) and bile canaliculi  Vascular invasion and portal vein thrombosis are common  Mitotic figures are common  Minimal desmoplasia  Occasionally fibrous variants, vascular lakes (pelioid pattern), abundant fat, no central veins
  95. 95. HCC: MICRO Well differentiated:  Thin plates (1-3 hepatocytes thick), cells smaller than normal, abnormal reticulin network  Minimal nuclear atypia, nuclear density 2x normal liver  Commonly fatty change and pseudoglands; may resemble hepatocyte adenoma  Common pattern for small hepatocellular carcinoma
  96. 96. HCC:MICRO Moderately differentiated:  trabecular pattern with 4+ cells thick  larger tumor cells than well differentiated HCC with more eosinophilic cytoplasm, distinct nucleoli, pseudoglands, bile, tumor giant cells  most common pattern in advanced HCC Poorly differentiated:  Large tumor cells with hyperchromatic nuclei in compact growth pattern with rare trabeculae or bile  Prominent pleomorphism, may have spindle cell or small cell areas  May not appear to be hepatocellular
  97. 97. HEPATOCELLULAR CARCINOMA The malignant cells (seen mostly on the right) are well differentiated and interdigitate with normal, larger hepatocytes (seen mostly at the left).
  98. 98. HEPATOCELLULAR CARCINOMA Composed of liver cords that are much wider than the normal liver plate that is two cells thick. There is no discernable normal lobular architecture, though vascular structures are present.
  99. 99. HCC Positive stains:  HepPar1 (80-90%, cytoplasmic and granular)  Polyclonal CEA in canalicular pattern (50-90% in better differentiated tumors)  AFP (15-70%, not in small tumors)  Alpha-1-antitrypsin (55-93%)  CEA-Gold 5 (76%)  Albumin mRNA ISH, CD10 (52%)  Transferrin  Copper (7-41%), CAM 5.2 (CK 8/18), Fas, Fas ligand
  100. 100. Note:  Polyclonal CEA in canalicular pattern is specific for hepatocellular carcinoma, probably due to cross reactivity to biliary glycoprotein I present in bile canaliculi of normal liver and hepatocellular neoplasms  Monoclonal CEA is usually negative
  101. 101. HCC  Negative stains: AE1-AE3, CK7 (80%), CK13, CK19 (>90%), CK20, keratin 903 (>90%), EMA, monoclonal CEA (present in 0-10%), CD15, mucin (mucicarmine), MOC31, BerEP4  Recommended panel: p-CEA or CEA-Gold 5  Less recommended: CD10, HepPar-1, mucicarmine or MOC31
  102. 102. HCC  Molecular: 50-92% hyperploid or aneuploid  EM: numerous mitochondria, microbodies, abundant glycogen; intracytoplasmic bile products (bile canaliculi, peroxisomes)
  103. 103. HCC: DD  Metastatic Hepatoid Adenoca from stomach or lung (CK19+, CK20+, CK7-, HepPar1 negative, no cirrhosis)  Neuroendocrine tumors from pancreas or small bowel  Poorly differentiated metastatic adenocarcinoma or cholangioca (desmoplastic stroma, mucin+)  Renal cell carcinoma (RCC+, HepPar1-, biopsy may be from renal mass)
  104. 104.  Melanoma  Angiosarcoma  Epithelioid angiomyolipoma (spindle cell component, thick walled vessels, HMB45+, actin+, CK-)  Adenoma or macroregenerative nodule (no trabecular growth pattern, different clinical history, minimal atypia; difficulties usually relate to limited sampling)
  105. 105. HCC: CYTOLOGY  90% sensitive and specific  Cell blocks helpful for obtaining stains (reticulin-no framework)  False positives due to regenerative nodules  False negatives in well differentiated tumors
  106. 106. HCC: CYTOLOGY Diagnostic features: - Polygonal cells with central nuclei, malignant cells separated by sinusoidal epithelial cells, bile, increased nuclear to cytoplasmic ratio, trabecular pattern, atypical naked nuclei Micro: - Highly cellular, polygonal tumor cells with abundant eosinophilic cytoplasm, central hyperchromatic nuclei or variable prominent nucleoli - Increased N/C ratio ; Naked tumor cell nuclei - Aggregates may appear trabecular - Tumor cells may be arranged in rosettes or acini - Variable bile, hyaline globules, Mallory’s hyaline and cytoplasmic vacuolation
  107. 107. HCC: CYTOLOGY  DD:  Reactive hepatocytes (finely granular chromatin)  Focal nodular hyperplasia  Hepatic adenoma
  108. 108. VARIANTS OF HCC
  109. 109. CLEAR CELL VARIANT - HCC  Predominant appearance in 5-16% of cases, but some clear cells present in 20-40% of cases  Tumor cells have prominent clear cytoplasm due to cytoplasmic fat or glycogen  May need to hunt for typical HCC to rule out metastatic tumor  May have bland nuclear features  Elevated serum AFP in 92%  Similar prognosis to classic tumor
  110. 110. HCC VARIANTS – CLEAR CELL  Laboratory: elevated serum AFP; may have hypoglycemia or hypercholesterolemia  Micro: trabecular, pseudoacinar, solid or mixed patterns of large number of neoplastic hepatocytes with abundant clear cytoplasm (glycogen or lipid) and round nuclei; may have intracytoplasmic bile (5- 33%); usually no intratumoral fibrosis except in areas of hemorrhage and necrosis
  111. 111. FIBROLAMELLAR VARIANT - HCC  Young adults 20-40 years  Fewer than 10% of all cases of HCC, but 35% of all cases in patients younger than 50 years  Similar symptoms as classic HCC; rarely associated with gynecomastia and Budd-Chiari syndrome  Not associated with hepatitis B virus, cirrhosis or metabolic abnormalities; pathogenesis unknown  5 year survival is 60-75%, better than classic hepatocellular carcinoma  Metastasizes to abdominal lymph nodes, peritoneum, lung
  112. 112. FIBROLAMELLAR VARIANT- HCC GROSS:  Single (75%)  Large (mean 13 cm)  Hard  Scirrhous  Well-circumscribed  Bulging  White-brown tumor with fibrous bands throughout and central stellate scar  Most cases involve left lobe, but may involve both lobes  Variable bile staining, hemorrhage and necrosis
  113. 113. FIBROLAMELLAR VARIANT - HCC Micro:  Nests, sheets or cords of well differentiated oncocytic cells in background of dense, acellular collagen bundles that may contain small, thick-walled vessels  Cells are large and polygonal with well defined cell borders, abundant granular and eosinophilic cytoplasm, often pale bodies (ground glass cells) or PAS+ hyaline globules, vesicular nuclei, prominent nucleoli  Vascular invasion and necrosis common  Fibrotic tissue coalesces into central scar  Remaining liver is unremarkable  Radiologic calcification corresponds to necrosis with foreign body type reaction  Other possible features include focal nuclear pleomorphism, conventional hepatocellular carcinoma  Trabecular, adenoid or pelioid patterns
  114. 114. a. HCA: peliotic changes with dilated sinusoids and areas of hemorrhage b. HCA: normochromatic nuclei without mitotic activity and cytoplasm with hydropic changes but without globular inclusions c. HCA: well-preserved reticulin framework d. HCA: focal sinusoidal positive immunohistochemical staining for CD34 e. FLC: large polygonal cells with granular eosinophilic cytoplasm, evident nucleoli, and paranuclear pale bodies f. FLC: solid aggregates of tumor cells surrounded by typical prominent lamellar fibrosis g. FLC: Diffuse strands of dense fibrosis h. FLC: Diffuse and strong sinusoidal immunohistochemical staining for CD34 A B C D E F G H
  115. 115. FIBROLAMELLAR VARIANT -HCC  Cytology: discohesive cells with inconspicuous strands of collagen; may contain bile  Positive stains: HepPar and CK7 Fibrinogen (pale bodies) Copper, copper-binding protein Bile Alpha-1-antitrypsin Polyclonal CEA CAM 5.2 (CK 8/18)  Negative stains: Mucin Alpha fetoprotein
  116. 116. FIBROLAMELLAR VARIANT - HCC  EM: numerous mitochondria; pale bodies contain fibrinogen and are associated with intracytoplasmic luminal/bile canaliculi or accumulation of rough endoplasmic reticulum; may have dense core neuroendocrine-like granules but are not neuroendocrine  Molecular: often diploid; overall show fewer chromosomal abnormalities than classic HCC, and tumors with no cytogenetic changes appear to behave less aggressively
  117. 117. FIBROLAMELLAR VARIANT - HCC DD:  Focal nodular hyperplasia  Sclerosing variant of hepatocellular carcinoma  Cholangiocarcinoma  Adenosquamous carcinoma with sclerosis  Metastatic carcinoma with sclerotic stroma  Paraganglioma
  118. 118. ONCOCYTIC VARIANT -HCC  Oncocytes are present in fibrolamellar variant and occasionally in classic hepatocellular carcinoma  Rarely these cells predominate without fibrous stroma of fibrolamellar variant  Cytoplasm is intensely eosinophilic with coarse granules
  119. 119. PLEOMORPHIC (GIANT CELL) VARIANT  <1% of all hepatocellular carcinomas, although 15% have some tumor giant cells  Multinucleated tumor giant cells predominate, marked loss of cell cohesion
  120. 120. SARCOMATOID VARIANT - HCC  Spindle cell, pseudosarcomatous  1-9% of all HCC have prominent sarcomatoid pattern  Mean 62 years old, range 46-84 years, usually men  Metastases common, often to lung and lymph nodes  Most patients die of disease
  121. 121. SARCOMATOID VARIANT:HCC Micro:  Diffuse collection of spindle cells resembling fibrosarcoma or MFH  Classic HCC is also present; may have pleomorphic and osteoclast-like giant cells Positive stains: CK (60%) AFP variable HHF-35 Smooth muscle actin Desmin, CD68, S100 DD: Collision tumors Carcinomas with foci of spindle shaped epithelial cells
  122. 122. SCLEROSING VARIANT - HCC  called scirrhous : 1-2 % of all HCCs  May not be a distinct histopathologic entity  Associated with hypercalcemia and hypophosphatemia but not with bone metastases Gross:  Single  Large  Gray-white  Firm  Circumscribed mass, often with serrated border  Often satellite nodules  More diffuse fibrosis than fibrolamellar variant, no radiating fibrous bands, no central scar, usually no cirrhosis
  123. 123. SCLEROSING: HCC Micro:  Fibrous septa separate trabecular cell plates but no lamellar fibrosis  Cell plates 3 or more cells thick  Tumor cells may have pseudoglandular (acinar) features compared to fibrolamellar variant  Tumor cells are smaller  Lack vesicular nuclei and prominent nucleoli  Have less abundant and granular cytoplasm  No apparent endothelial sinusoidal cells
  124. 124. SCLEROSING VARIANT: HCC  Positive stains: AFP  Negative stains: Mucin  DD:  CholangioCA  Metastatic carcinoma of pancreas  Fibrolamellar variant  Epithelioid hemangioendothelioma (CD34+, factor VIII+, mucin-)  Post-Chemoradiation therapy
  125. 125. SMALL HCC  Tumors < 2 cm  Detected by screening of patients with chronic liver disease  May have normal serum AFP Gross:  May not be identifiable or nodules that bulge from cut surface  Gray, white, green or yellow  No necrosis  May be within borderline nodule (nodule within nodule)  Usually distinct fibrous capsule or fibrous septa  May have indistinct borders
  126. 126. SMALL HCC Micro:  Usually well differentiated morphology with trabeculae 2- 3 cells thick  Nuclear density is 2x normal, has mild but definite nuclear atypia  Enlarging nodules have less differentiated foci centrally  40% have fatty or clear cell change, often with Mallory bodies  May invade stroma or portal tract  Vascular invasion rare
  127. 127. CHOLANGIOCA (INTRAHEPATIC)  Called BILE DUCT CARCINOMA  10% of primary liver cancers  Adenoca arising from intrahepatic bile duct epithelial cells  High prevalence in southeast and eastern Asia, incl: Korea 10-20% are associated with :  Chronic bile stasis or cholangitis due to autosomal dominant polycystic disease  Congenitally dilated hepatic ducts (Caroli’s disease)  Congenital hepatic fibrosis  Infection by liver flukes Clonorchis sinensis or Opisthorchis viverrini  Thorotrast, anabolic steroids, intrahepatic lithiasis (5-10% of these patients)  Primary sclerosing cholangitis (7-42% of these patients)  Choledochal cysts
  128. 128. CHOLANGIOCARCINOMA (INTRAHEPATIC)  Rarely associated with neoplastic transformation of von Meyenburg complexes  Not associated with cirrhosis  Diagnosis of exclusion (must rule out metastatic adenocarcinoma)  Usually age 60+ years; no gender preference; but mean age 40 years in those with primary sclerosing cholangitis or chronic inflammatory bowel disease
  129. 129. CHOLANGIOCARCINOMA  Klatskin tumor [American internist]: hilar tumor arising at confluence of left and right hepatic ducts Laboratory: Normal AFP, occasional hypercalcemia Poor prognosis Death w/in 6 mos; 5 yr survival in resectable cases is 30%  50-75% metastasize to regional lymph nodes, lungs, vertebrae, adrenals, brain, elsewhere at autopsy  50% are metastatic to perihilar, peripancreatic and para-aortic nodes Poor prognostic factors: Lymphatic or intrahepatic metastases Reduced keratin 903 expression may be a favorable prognostic factor
  130. 130. CHOLANGIOCARCINOMA Gross:  Solitary, 7-10 cm, multinodular or diffuse small nodules < 1 cm; gray-white and firm;  Often hepatomegaly and satellite nodules  No peripheral hyperemic zone seen in metastatic disease  Rarely cirrhosis  Rarely bile stained, although may see bile in periphery  May invade portal vein
  131. 131. CHOLANGIOCA Micro:  Moderate to well differentiated adenoca with glandular and tubular structures, mucin production and dense desmoplasia  Epithelial cells are anaplastic, cuboidal to columnar with eosinophilic cytoplasm and round central nuclei, tumor cells are heterogeneous even within the same gland but resemble bile duct cells, not hepatocytes  Spread along hepatic plates, duct walls, via nerves (81% perineural), but not sinusoidal  Stroma may be circumferential around glands  Associated with neutrophils  Variable vascular invasion  NO bile production
  132. 132. CHOLANGIOCA Positive stains:  mucin (almost always)  CEA (cytoplasmic and luminal, not canalicular)  CAM 5.2, AE1-AE3, keratin 903 (74%), CK7 (90- 96%), CK19 (84%), CK20 (30-70%, more often positive in non-peripheral tumors), EMA, amylase, PTH-related peptide, p53 (10-94%), PCNA, MOC31, BerEP4 Negative stains: AFP Molecular: Kras mutations
  133. 133. CHOLANGIOCARCINOMA DD:  Metastatic adenocarcinoma from pancreas, extrahepatic biliary tree, breast, colon (CK7-/CK20+ [strong]) or gallbladder (must exclude based on clinical and radiographic findings)  HCC with ductular differentiation, epithelioid hemangioendothelioma (vascular markers+, mucin-), benign bile duct proliferations (smaller, no atypia, incidental)
  134. 134. Cholangiocarcinoma arising in Caroli disease. A. A cut surface of the liver showing saccular dilatation of the intrahepatic bile ducts filled with pigmented calculi and ill-defined gray-white areas involved by cholangiocarcinoma. B. Dilated bile duct is lined by columnar epithelium (right) with marked fibrosis and mild chronic inflammation. Shown on the left is adjacent cholangiocarcinoma C. A representative microscopic view of cholangiocarcinoma showing anastomosing glandular structures lined by cuboidal neoplastic epithelial cells
  135. 135. CHOLANGIOCARCINOMA - has a glandular appearance - A liver CA may have both HCC & cholangiolar differentiation - DO NOT MAKE BILE, but the cells do make mucin, and they can be almost impossible to distinguish from mets Adenoca on biopsy or FNA.
  136. 136. METASTASES TO THE LIVER Note the numerous mass lesions that are of variable size. Some of the larger ones demonstrate central necrosis. The masses are metastases to the liver. The obstruction from such masses generally elevates alkaline phos, but not all bile ducts are obstructed, so hyperbilirubinemia is typically not present. Also, the transaminases are usually not greatly elevated.
  137. 137. METASTATIC ADENOCA Here are liver metastases from an adenocarcinoma primary in the colon, one of the most common primary sites for metastatic adenocarcinoma to the liver.
  138. 138. METASTATIC CARCINOMA Microscopically, metastatic infiltrating ductal carcinoma from breast is seen on the right, with normal liver parenchyma on the left.
  139. 139. BENIGN MESENCHYMAL TUMORS
  140. 140. HEMANGIOMA  Most common primary hepatic tumor  Usually an incidental finding, found in 1% of routine autopsies and 20% of autopsies with extensive investigation  More common in adults than children, 75% in women, who are more likely symptomatic  10% enlarge with follow-up, may be related to pregnancy or oral contraceptives  Associated with multiple focal nodular hyperplasia syndrome  Giant cavernous hemangiomas (> 4-10 cm) only rarely rupture  Fibrotic tumors may be precursor of solitary necrotic nodules  Solitary capillary hemangiomas are extremely rare
  141. 141. HEMANGIOMA  Treatment: excision or observation (may involute)  Positive stains: elastin and trichrome may expose vessels in old fibrous lesions  DD:  Peliosis hepatis (no fibrous septa)  Hereditary hemorrhagic telangiectasia (aberrant portal vessels, dilated vascular channels within portal tracts)  Hemangiomatosis  Infantile hemangioendothelioma (atypia present, although not necessarily everywhere)
  142. 142. HEMANGIOMA: GROSS Gross:  solitary (70-90%), usually 2-4 cm, although tumors up to 20 cm are overrepresented in studies of excisions  Soft, red-purple, well circumscribed  Subcapsular or deep  Collapse when sectioned as blood oozes out
  143. 143. HEMANGIOMA: MICRO Micro:  Variably sized vascular spaces lined by flat endothelial cells and myxoid or fibrous stroma  large fibrous septa may trap bile ducts  variable thrombosis, calcification, phleboliths  Increased fibrosis with age of lesion may obliterate lumen
  144. 144. GLOMANGIOMA  Rare, <10 cases reported  Type of glomus tumor (neoplasm of glomus apparatus) with prominent vascular structures  Case report in 57 year old man with flank pain and 3 cm liver mass  Xray images: hypervascular mass  Positive stains: vimentin, smooth muscle actin, CD34, calponin (focal)  Negative stains: desmin, S100, chromogranin, CD117
  145. 145. GLOMANGIOMA  Micro: small to medium branched vessels with stroma containing small, round regular cells with sharply outlined round/oval nuclei  Composed of a trabeculated network of vessels surrounded by bland, small tumor cells.  The neoplastic cells have sharply outlined round-to-oval nuclei with bland chromatin and scant-to-moderate eosinophilic cytoplasm
  146. 146.  Immunostaining for smooth muscle actin that shows scattered tumor cells with cytoplasmic positivity (smooth muscle actin).CD34 immunostain highlighting the vascular network and the outlining of a few tumor cells (CD34)
  147. 147. INFANTILE HEMANGIOENDOTHELIOMA  Also called hepatic infantile hemangioma  Most common hepatic mesenchymal tumor in childhood  20% of all pediatric hepatic tumors  90% are less than 6 months old at diagnosis, slight female predominance  10-40% have coexisting cutaneous cavernous hemangiomas  50% are incidental findings at autopsy
  148. 148. INFANTILE HEMANGIOENDOTHELIOMA Symptoms:  Hepatic mass (48%), high output cardiac failure due to shunting through tumor (15%)  Also Kasabach-Merritt syndrome (bleeding diathesis due to platelet sequestration and severe thrombocytopenia)  May be asymptomatic  70% survival, as tumors often involve and almost always have benign behavior  Tumors often involute after 6-8 months  Deaths usually within 1 month of diagnosis due to congestive heart failure, platelet consumption leading to bleeding diathesis or massive hemoperitoneum
  149. 149. INFANTILE HEMANGIOENDOTHELIOMA  Laboratory: normal AFP  Xray: multiple small nodules  Poor prognostic factors:  Congestive heart failure  Jaundice  Multiple nodules  Lack of cavernous differentiation  Treatment: resection if solitary, otherwise steroids, radiation therapy, embolization, transplantation
  150. 150. INFANTILE HEMANGIOENDOTHELIOMA Gross:  solitary or multiple  mean 4 cm (range 0.1 to 15 cm)  circumscribed but not encapsulated  white-red-tan, soft, spongy  larger nodules may have hemorrhagic or calcified areas Micro:  well demarcated or infiltrative (35%)
  151. 151. INFANTILE HEMANGIOENDOTHELIOMA Pure type 1 change:  80%, orderly proliferation of small, capillary-like vascular spaces, relatively bloodless, may be dilated (particularly centrally), slightly irregular  Lined by bland or plump endothelial cells that may occlude the lumen  Vascular channels separated by variable connective tissue  May have interspersed small bile ducts  Extramedullary hematopoiesis in 60%, often in vascular lumina  Often trapped hepatocytes at periphery  Large lesions show thrombosis, fibrosis, myxoid change, calcification  No/rare mitotic figures, no malignant spindle cell component
  152. 152. INFANTILE HEMANGIOENDOTHELIOMA Type 2 change:  Equivalent to angiosarcoma with irregular branching vascular structures lined by pleomorphic, hyperchromatic endothelial cells, frequent mitotic activity
  153. 153.  Figure 1. Monomorphic tumor cells with regular small to medium nuclei and conspicuous nucleoli  Figure 2.The neoplastic cells stained with factor VIII–related antigen. The cells are seen spreading into the adjacent liver
  154. 154. INFANTILE HEMANGIOENDOTHELIOMA Positive stains:  Factor VIII related antigen, CD31, CD34, GLUT1 DD:  Angiosarcoma (adequate sampling is important; has solid sarcomatous areas, vascular and sinusoidal permeation, marked pleomorphism)  Mesenchymal hamartoma (vessels lack irregular thin walls, primitive mesenchymal stroma present)  Hepatic vascular malformation  Hemangioma (lacks peripheral small vascular proliferation)
  155. 155. ANGIOMYOLIPOMA (AML)  <100 cases reported; often misdiagnosed  Mesenchymal tumor arising from perivascular epithelioid cells; also lymphangioleiomyomas, clear cell sugar tumors of lung, rare myomelanocytic tumors  Similar histologically to renal angiomyolipoma  Mean age 50 years, range 9-79 years; 80% women  Only 6-10% associated with tuberous sclerosis, these cases are associated with renal AML and may be multiple  Myoid and vascular components are clonal; adipose tissue component may be reactive
  156. 156. AML  Gross: well circumscribed, solitary masses up to 20 cm, yellow-gray-white; necrosis present in larger tumors, background liver is normal  Micro: mature adipose tissue, smooth muscle cells and thick walled blood vessels with spindle cells radiating from walls; extramedullary hematopoiesis (40%); smooth muscle cells are epithelioid or spindled with clear or eosinophilic cytoplasm; mast cells common; occasional features are cellularity, nuclear pleomorphism with intranuclear inclusions, tumor giant cells; no/rare mitotic figures; unusual subtypes are oncocytic and trabecular
  157. 157.  Figure 1. Hepatic angiomyolipoma composed of admixture of blood vessels, fat cells, and smooth muscle cells  Figure 2.Hepatic angiomyolipoma with strong and diffuse granular cytoplasmic immunoreactivity for HMB-45 in epithelioid smooth muscle cells, with intense perinuclear staining in the vacuolated cells. Fat cells are not stained with HMB-45  Figure 3.Hepatic angiomyolipoma with intense and widespread cytoplasmic melan-A expression with similar staining pattern to that of HMB-45  Figure 4.Renal angiomyolipoma with positive nuclear immunoreactivity for microphthalmia transcription factor in more than 50% of epithelioid smooth cells, some of which are indicated with arrows  Figure 5.Renal angiomyolipoma. Positive cytoplasmic SMA with membranous accentuation  Figure 6.Hepatic angiomyolipoma. Wall of a thick artery is composed of multiple concentric smooth muscle fibers that strongly express SMA
  158. 158. ANGIOMYOLIPOMA  Positive stains: HMB45, MelanA/MART-1, microphthalmia transcription factor (50%), S100, smooth muscle actin, desmin, c-kit/CD117 (all cell types)  Negative stains: Cytokeratin  EM: Epithelioid myoid cells have premelanosomes, numerous mitochondria, abundant rough endoplasmic reticulum, glycogen, tight junctions and basal lamina, but no thick filaments
  159. 159. Mesenchymal Hamartoma  Formerly called cavernous lymphangioadenomatoid tumor, cystic hamartoma, benign mesenchymoma  75% are age one year or less (rarely adults), 60-70% male  8% of pediatric liver tumors  Usually asymptomatic  Serum AFP is usually normal or mildly elevated; occasionally is markedly elevated  Origin either neoplastic or a developmental anomaly in bile duct plate formation
  160. 160. MESENCHYMAL HAMARTOMA  Rarely associated with undifferentiated sarcoma  Adult cases are usually women with abdominal pain, more prominent fibrosis and a lesser myxoid component than childhood cases, usually no extramedullary hematopoiesis Treatment:  Excision (curative, but surgery has high mortality for large masses)  Liver transplantation may be necessary
  161. 161. MESENCHYMAL HAMARTOMA Gross:  Well circumscribed, solitary, 5-23 cm, 20% pedunculated, myxoid mass with fluid filled cysts; may be multiloculated  Becomes fibrotic with age  Cysts are variable sized, contain mucoid or pink fluid with adjacent solid, pink-white areas  May have satellite nodules  Usually no necrosis, hemorrhage or calcification
  162. 162.  Fig1. The cut surface of the 1058-g mass removed from the left lateral segment of the liver. Numerous cysts filled with gelatinous material separated by loose, white fibrous connective tissue are seen.  Fig 2.Area with smaller cysts demonstrating a hypocellular, edematous stroma with numerous nonlined cysts. Note the entrapped hepatic parenchyma and haphazard bile ducts to the left  Fig 3.Karyotype of mesenchymal hamartoma of the liver displaying an abnormality in the long arm of chromosome 19.  Fig 4.Enlarged view of chromosome 19 from a separate metaphase spread exhibiting the interstitial deletion near 19q13.4.
  163. 163. MESENCHYMAL HAMARTOMA Micro:  Branching bile ducts without atypia in a loose, myxoid stroma with myofibroblast-like cells, dilated vessels and lymphatics  May resemble breast fibroadenoma at low power; also normal appearing hepatocytes, thick walled veins, variable collagen  Bile ducts may have mesenchymal collars and are often cystically dilated  Usually extramedullary hematopoiesis (90%); often pools of fluid  No tumor giant cells  Adult cases have densely hyalinized or fibrotic stroma and only focal myxoid areas
  164. 164.  Positive stains: CK7, vimentin, smooth muscle actin, desmin, actin  Negative stains: CK20  Molecular: interstitial deletion near 19q13.4
  165. 165. MESENCHYMAL HAMARTOMA EM:  Myofibroblastic features DD:  Bile duct adenoma (no hepatocyte islands) or cystadenoma (adults)  Bile duct hamartoma (usually multiple with fibrous background)  Infantile hemangioendothelioma (more vascular)  Embryonal sarcoma (marked cellularity and atypical cells)
  166. 166. MALIGNANT MESENCHYMAL TUMORS
  167. 167. ANGIOSARCOMA  Rare (10-30 annual cases in US), but most common hepatic primary sarcoma in adults (2% of all primary liver tumors)  75% men, usually age 50+ years  Rare in children  Non-operative biopsy may cause severe bleeding and death Causes:  25-42% associated with exposure to vinyl chloride, arsenic, Thorotrast (thorium dioxide) or androgen steroids  Rarely associated with copper sulfate, estrogenic steroids, phenelzine, radiotherapy, chemotherapy, hereditary hemochromatosis  Cases with known cause usually have latent period of 20-35 years, are accompanied by fibrosis or cirrhosis, have precursor conditions of hypertrophy and atypia of hepatocytes and sinusoidal lining cells, but are histologically similar to idiopathic cases
  168. 168. ANGIOSARCOMA: CAUSES  Patients with exposure to vinyl chloride or Thorotrast may have synchronous cholangiocarcinoma or hepatocellular carcinoma  Thorotrast’s alpha particle emissions can be detected by autoradiography  Most patients die within 6 months from hepatic failure, intraabdominal bleeding; metastasizes widely, often to lung, except for vinyl chloride cases which usually lack distant metastases
  169. 169. ANGIOSARCOMA Gross:  Multicentric, involves right and left lobes  Diffusely infiltrative, hemorrhagic and gray-white solid nodules with blood filled cavities  Thorotrast-associated tumors have subcapsular hepatic and splenic deposits of yellow chalky material
  170. 170. ANGIOSARCOMA: MICRO  Tumor composed of infiltrative, freely anastomosing vascular channels  Tumor cells grow along sinusoids adjacent to hepatic cords  Tumor cells have abundant, pale eosinophilic cytoplasm, poorly defined cell borders, are usually pleomorphic with hyperchromatic nuclei, but may be only mildly atypical  Also variably prominent nucleoli, blood filled cavities present are lined by tumor cells that may be papillary  75% have vascular invasion of portal or hepatic vein branches  Frequent mitotic activity
  171. 171. ANGIOSARCOMA: MICRO  Also epithelioid cells with abundant cytoplasm and prominent nucleoli, bizarre tumor giant cells, fibrosarcoma-like spindle cells, cholestatic hepatocellular rosettes with bile plugs, tumor cell phagocytic activity, extramedullary hematopoiesis  Childhood cases may have kaposiform areas of spindle cells with PAS+ intracytoplasmic globules  No prominent myxoid areas  Thorotrast exposed patients have brown-gray refractile but not birefringent granules of Thorotrast free or within macrophages  Also precursor stage with endothelial hypertrophy and hyperplasia
  172. 172. ANGIOSARCOMA: MICRO  Pleomorphic epithelial cells in sinusoidal pattern  CD31
  173. 173.  Fig 1. FNA specimen showing spindle cells with fine cytoplasmic processes and vascular lumen (microacinar) formation (Diff-Quik).  Fig2. FNA specimen showing focally prominent intracytoplasmic vacuoles  Fig3. FNA specimen demonstrating an intracytoplasmic lumen containing fragmented RBC by-products, which stained densely basophilic (Paps)  Fig 4. Autopsy liver specimen showing discohesive anastomosing vascular channels lined by plump malignant spindle cells. Intracytoplasmic RBC and RBC by-products in various stages of degeneration are readily apparent
  174. 174. ANGIOSARCOMA Positive stains:  CD34  CD31  Factor VIII related antigen  Ulex europaeus lectin type 1 (may not be present in poorly vasoformative areas) Negative stains:  Keratin (but positive in 12-35%) EM:  Weibel-Palade bodies Molecular:  50% of vinyl chloride associated cases have A:T to T:A transversion in p53
  175. 175. ANGIOSARCOMA DD:  Reactive disorders (lack atypical endothelial lining cells)  HCC (atypical hepatocytes, normal endothelial cells)  Kaposi’s sarcoma (HIV+, have extrahepatic nodules, portal distribution, lack angiosarcomatous foci)  Peliosis Hepatis  Epithelioid hemangioendothelioma (less atypia, less mitotic activity, less necrosis)
  176. 176. EPITHELIOID HEMANGIOENDOTHELIOMA  Malignant endothelium derived neoplasm with intermediate clinical course between hemangioma and angiosarcoma, but unpredictable  Mean age 47 years, but occurs at any age, 60% ♀  No predisposing factors  FNA not recommended as even small biopsies can be misleading  50% have extrahepatic involvement at diagnosis, which does not preclude long survival  Often misdiagnosed
  177. 177. E. HEMANGIOENDOTHELIOMA  Symptoms: abdominal pain, weight loss, hepatic venous outflow obstruction; 40% are asymptomatic  Xray: calcifications in 20%; peripheral nodules with capsular retraction by CT scan  Prognostic factors: high cellularity is unfavorable, but histology is otherwise of no value  Indolent and slow growing; 5 year survival 43%; metastases to lung, spleen, abdominal lymph nodes, omentum, peritoneum  Treatment: resection, liver transplant
  178. 178.  Gross: multiple (80%), tan-gray, firm, circumscribed, focally confluent nodules 1-12 cm with infiltrative borders that may involve venous structures as intravascular proliferations or fibrothrombotic occlusions; remaining liver is normal  Left hepatectomy. Most of the lobe is occupied by a ill-defined, mottled tumorous mass (arrowheads) corresponding to epithelioid hemangioendothelioma. Note a cavernous hemangioma
  179. 179. EHE -MICRO:  Zonal pattern  Periphery shows sinusoidal proliferation with tufting of tumor cells within portal vein branches  Midzone has sinusoidal obliteration with atrophic hepatocyte plates and increased myxochondroid and sclerotic stroma  Perivenular stroma is paucicellular and often calcified  Variable inflammatory infiltrate  Epithelioid and fibromyxoid tumor cells have focal intracytoplasmic vacuoles containing red blood cells embedded in fibromyxoid matrix  Epithelioid cells are rounded with eosinophilic cytoplasm, mild to moderately atypical nuclei with prominent nucleoli, rare/no mitotic figures  Extramedullary hematopoiesis  May have myxoid areas  Often has infiltrative margins  Adjacent liver usually normal
  180. 180.  Fig. 2. Tumoral cells are embedded in a fibrous stroma and show evidence of vascular differentiation with large intracytoplasmic vacuoles containing blood red cells (arrows)  Figure 3.Papillary projections of epithelioid hemangioendothelioma cells into the lumen of a medium hepatic vein
  181. 181.  Microvascular channels and intracytoplasmic vacuoles
  182. 182. EHE  Positive stains: factor VIII related antigen and CD34 for vacuoles, CD31, trichrome and elastic stains accentuate obliteration of hepatic venules and hepatic vein branches, NSE, smooth muscle actin (25%), 15% positive for cytokeratin (also trapped hepatocytes and bile ductules)  Negative stains: AE1/AE3 (cytokeratin), CK7, CK20, alpha fetoprotein, bile, CEA, HepPar1, mucin  EM: Weibel-Palade bodies, intermediate filaments  Cytogenetics: t(1;3)(p36.3;q25), ? involving PAX7 gene at 1p36.3 and MLF1 gene at 3q25
  183. 183. EPITHELIOID HEMANGIOENDOTHELIOMA DD:  Signet ring adenocarcinoma  Scirrhous cholangiocarcinoma  Sclerotic hepatocellular carcinoma  Sclerosed hemangioma (well circumscribed, no venous invasion, no atypia)  Leiomyosarcoma  Chondrosarcoma  Metastatic tumor from lung or elsewhere,  Angiosarcoma (different stroma, more atypia)
  184. 184. VIRAL HEPATITIS
  185. 185. VIRAL HEPATITIS: GROSS Grossly, there are areas of necrosis and collapse of liver lobules seen here as ill-defined areas that are pale yellow. Such necrosis occurs with hepatitis.
  186. 186. VIRAL HEPATITIS: GROSS The necrosis and lobular collapse is seen here as areas of hemorrhage and irregular furrows and granularity on the cut surface of the liver.
  187. 187. VIRAL HEPATITIS Leads to liver cell destruction. A mononuclear inflammatory cell infiltrate extends from portal areas and disrupts the limiting plate of hepatocytes which are undergoing necrosis, the so-called "piecemeal" necrosis of chronic active hepatitis. In this case, the hepatitis B surface antigen (HbsAg) and hepatitis B core antibody (HbcAb) were positive
  188. 188. VIRAL HEPATITIS Individual hepatocytes are affected by viral hepatitis. Viral hepatitis A rarely leads to signficant necrosis, but hepatitis B can result in a fulminant hepatitis with extensive necrosis. A large pink cell undergoing "ballooning degeneration" is seen below the right arrow. At a later stage, a dying hepatocyte is seen shrinking down to form an eosinophilic "councilman body" below the arrow on the left.
  189. 189. HEP C -Leads to chronic liver disease in 50% of cases. -Extent of chronic hep can be graded by the degree of activity (necrosis and inflammation) & staged by the degree of fibrosis. -Necrosis & inflammation are prominent, + steatosis -Regardless of the grade or stage, the etiology of the hep must be sought, - treatment depend upon knowing the cause, & chronic liver diseases of different etiologies may appear microscopically & grossly similar.
  190. 190. VIRAL HEPATITIS C High stage - extensive fibrosis and progression to macronodular cirrhosis - evidenced by the large regenerative nodules Screening laboratory test - Hepatitis C antibody test. Hepatitis C accounts for most formerly called "non-A, non-B hepatitis". In addition to this serologic test PCR and genotyping can be performed.
  191. 191. HCV  Nucleic acid sequencing identifies of 6 common HCV types (1a,b-5) which have different clinical courses and responsiveness to α-interferon therapy.  Infection with HCV type 1b or 4 leads to more severe liver disease, faster progression to chronic hepatitis, and less responsiveness to interferon therapy.  Type 1a, 2, 3, and 5 infections have a more favorable prognosis  Type 2 and 3 infections may be treated with shorter therapeutic regimens
  192. 192. VIRAL HEPATITIS: TRICHROME This trichrome stain demonstrates the collapse of the liver parenchyma with viral hepatitis. The blue-staining areas are the connective tissue of many portal tracts that have collapsed together.
  193. 193. MISC PARENCHYMAL DISEASES & TUMOR-LIKE LESIONS
  194. 194. CHRONIC PASSIVE CONGESTION "nutmeg" liver - chronic passive congestion of the liver. Note the dark red congested regions that represent accumulation of RBC's in centrilobular regions.
  195. 195. CPC: NUTMEG PATTERN Micro: the nutmeg pattern results from congestion around the central veins. This is usually due to a "RIGHT SIDED" heart failure.
  196. 196. CENTRILOBULAR NECROSIS If the passive congestion is pronounced, then there can be centrilobular necrosis, because the oxygenation in zone 3 of the hepatic lobule is not great. The light brown pigment seen here in the necrotic hepatocytes around the central vein is lipochrome.
  197. 197. CPC - CARDIAC CIRRHOSIS If chronic hepatic passive congestion continues for a long time, a condition called "cardiac cirrhosis" may develop in which there is fibrosis bridging between central zonal regions, so that the portal tracts appear to be in the center of the reorganized lobule. This process is best termed "cardiac sclerosis" because, unlike a true cirrhosis, there is minimal nodular regeneration.
  198. 198. INFARCTION OF THE LIVER Infarcts are uncommon because the liver has two blood supplies-portal venous system and hepatic arterial system. The infarcts seen here are yellow, with geographic borders and surrounding hyperemia. About half of liver infarcts occur with arteritis, and the remaining half are due to a variety of causes.
  199. 199. NECROSIS: ACETAMINOPHEN OVERDOSE There is extensive hepatocyte necrosis The hepatocytes at the right are dead, and those at the left are dying. This pattern can be seen with a variety of hepatotoxins. Acute liver failure leads to hepatic encephalopathy.
  200. 200. POLYCYSTIC LIVER DISEASE  Some patients are born with an inherited condition that causes them to develop many cysts within the liver.  Most do not require surgery  Some have cysts that become massively enlarged and press on adjacent organs. These cysts may require surgery to remove or open some of the cysts.  This surgery can be done using both laparoscopic and open techniques.  In rare cases, liver transplantation is recommended.
  201. 201. LIVER CYSTS  Often cysts do not cause symptoms and are only treated surgically if the patient experiences symptoms related to the cyst.  In some rare instances where the cyst comes from the bile ducts inside (biliary cystadenomas) or outside the liver (choledochal cysts), - may recommend surgery because they may turn into cancers.
  202. 202. CYSTS  Multiple intrahepatic cysts occur in polycystic disease, congenital hepatic fibrosis, Caroli’s disease & are developmental in origin  Rare, Solitary, non-neoplastic and non-parasitic cysts  Ciliated hepatic foregut cysts with differentiation towards bronchial structures
  203. 203. DOMINANT POLYCYSTIC KIDNEY DISEASE (DPKD)-POLYCYSTIC LIVER - Occur in adults and manifest with renal failure beginning in middle age – - Sometimes the liver can be affected as well by polycystic change. - Less commonly the pancreas is involved. - These patients with DPKD can also have berry aneurysms in the cerebral arteries.
  204. 204. PRIMARY BILIARY CIRRHOSIS -a rare autoimmune disease (mostly of middle-aged women) that is characterized by destruction of bile ductules within the triads of the liver. -Antimitochondrial antibody can be detected in serum. Seen here in a portal tract is an intense chronic inflammatory infiltrate with loss of bile ductules. Micronodular cirrhosis
  205. 205. EXTRAHEPATIC BILIARY ATRESIA This 3 month old child died with extrahepatic biliary atresia, a disease in which there is inflammation with stricture of hepatic or common bile ducts. This leads to marked cholestasis with intrahepatic bile duct proliferation, fibrosis, and cirrhosis. This liver was rock hard. The dark green color comes from formalin acting on bile pigments in the liver from marked cholestasis, turning bilrubin to biliverdin.
  206. 206. EXTRAHEPATIC BILIARY ATRESIA Micro: numerous brown-green bile plugs, bile duct proliferation (seen at lower center), and extensive fibrosis. If a large enough bile duct can be found to anastomose and provide bile drainage, then surgery can be curative.
  207. 207. NEONATAL GIANT CELL HEPATITIS This is the major differential diagnosis of biliary atresia There is lobular disarray with focal hepatocyte necrosis, giant cell transformation, lymphocytic infiltration, Kupffer cell hyperplasia, and cholestasis (not seen here). Neonatal hepatitis may be idiopathic or of viral origin. Many neonates recover in a couple of months.
  208. 208. α-1-ANTITRYPSIN DEFICIENCY The periportal red hyaline globules seen here with periodic acid-Schiff (PAS) stain are characteristic for alpha-1-antitrypsin (AAT) deficiency. More persons with AAT deficiency are likely to develop chronic obstructive pulmonary disease with panlobular emphysema. The globules are collections of alpha-1-antitrypsin not being excreted from hepatocytes. This may eventually lead to chronic hepatitis and cirrhosis. Liver disease is more likely to occur in children with AAT deficiency, while lung disease occurs in adults.
  209. 209. AAT  The gene for AAT is on chromosome 14.  There are over 100 known mutations.  The normal allele is designated PiM, and the two most common abnormal alleles are designated PiS and PiZ.  Heterozygotes PiMS and PiMZ may on occasion develop pulmonary and/or liver disease, but less often severe. The homozygotes PiSS and PiZZ, and the heterozygote PiSZ, are more likely to develop significant COPD and/or liver disease.  The persons most likely to develop severe AAT deficiency and its complications have PiZZ. About 1 in 10 persons of European ancestry has one of the 5 abnormal phenotypes (the normal is PiMM).
  210. 210. SCLEROSING CHOLANGITIS This trichrome stain of the liver demonstrates extensive portal tract fibrosis with sclerosing cholangitis. The hepatocytes are normal.
  211. 211. SCLEROSING CHOLANGITIS Microscopically, this bile duct in a case of sclerosing cholangitis is surrounded by marked collagenous connective tissue deposition.
  212. 212. FOCAL NODULAR HYPERPLASIA (FNH)  Common (#2 liver tumor after hemangioma)  Mass lesion of young (median age 38 years); some studies show female predominance  Represents 2-10% of pediatric hepatic tumors  May be associated with oral contraceptives (66-95% of cases), hepatic cavernous hemangioma (20%), glycogen storage disease type Ia, portal hypertension  Tumors associated with oral contraceptives often have hemorrhage, necrosis, infarction  Usually an incidental finding; present in 1% of autopsies  May have abdominal discomfort, pain, anorexia or fatigue  May represent hyperplastic response to arterial malformation or other vascular anomaly  NOT a neoplasm
  213. 213. Focal Nodular Hyperplasia (FNH)  These masses are typically found during a routine examination  When a diagnosis is made, recommend a wait and see approach  If the focal nodular hyperplasia does not grow, -no further treatment or monitoring.
  214. 214. FNH  Xray: mass with central scar, centrifugal hypervascularity by angiography; CT and MRI are important, but often cannot make a definite preoperative diagnosis  Treatment: excellent prognosis; adult women should discontinue oral contraceptives, if applicable; surgery if symptomatic, complications, compression of adjacent organs or lesion progression
  215. 215. FNH: GROSS  Well-demarcated, subcapsular, light brown to yellow (lighter than surrounding liver)  Bulging nodule, 70-80% solitary, up to 5 cm;  Rarely > 10 cm  Has central gray-white stellate scar (unless < 1 cm) from which fibrous septa radiate to periphery and create multiple smaller nodules  Hemorrhage, necrosis, infarction, bile staining often seen  Larger tumors may have multiple scars  Adjacent liver is normal
  216. 216. GROSS
  217. 217. FNH: MICRO  Hepatocyte nodules are surrounded by fibrous septa with large malformed arterial branches not accompanied by interlobular bile ducts or portal veins  Septal margins have foci of intense lymphocytic infiltrates and marked bile duct proliferation with histologic changes of chronic cholestasis (Mallory’s hyaline, bile pigment, copper deposits, pseudoxanthomatous change), variable neutrophilic infiltration  Ductules appear to arise from limiting plate
  218. 218. FNH: MICRO  Central scar contains central fibrous body with tortuous large vessels with fibromuscular hyperplasia and luminal narrowing  Hepatic plates are 1-2 cells thick, similar to surrounding liver, but may be larger and paler with fat or glycogen  No atypia, no mitotic figures  Telangiectatic variant has multiple dilated vascular channels in center of mass
  219. 219. FNH: MICRO  Most tumors (80%) have the 3 classic features of abnormal architecture, bile ductular proliferation and malformed vessels.  Non-classic forms lack either abnormal architecture or malformed vessels, and are divided into three types - (a) telangiectatic (b) mixed hyperplastic and adenomatous (c) atypia of large cell  Telangiectatic FNH is considered by some to be a variant of hepatocellular adenoma
  220. 220. FNH: MICRO
  221. 221. FNH ASS W/ FIBROLAMELLAR CA 53-y/o woman A solitary fibrolamellar CA measuring 8 cm found in the resected left lobe. Left, Immediately adjacent to the carcinoma (C) was a 15-mm, well-demarcated nodule of focal nodular hyperplasia (H). Most of the liver was normal, with slight atrophy (A) adjacent to the carcinoma. Within the nodule is a branched arterial supply. The areas in rectangles are magnified in the right panels .Top right, The nodule was supplied by a large artery (a) derived from a large portal tract invaded by carcinoma. Carcinoma invades periarterial tissues (arrows) and a large hepatic vein (v), causing intimal fibrous thickening. There is ductular proliferation adjacent to the arteries LR: 2 nerves adjacent to the supplying A are invaded and deformed by tumor.
  222. 222. FNH  Positive stains: alpha-1-antitrypsin  Negative stains: p53, CD143 (angiotensin I-converting enzyme: reduced expression  DD:  Osler-Weber-Rendu disease  Budd-Chiari syndrome or cirrhosis (adjacent liver is not normal)  Fibrolamellar hepatocellular carcinoma (marked atypia of hepatocytes)  Hepatocellular adenoma (encapsulated, monoclonal)  Peritumoral hyperplasia  Liver cell adenoma  Mesenchymal hamartoma
  223. 223. THANK YOU FOR YOUR ATTENTION

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