Slide 1
LIVER PATHOLOGY
BERNADETTE R. ESPIRITU, M.D. FPSP
Anatomic & Clinical Pathologist
LIVER
1.41.6 kg (3.13.5 lb)
reddish brown soft organ with four lobes of unequal size and shape
It is both the largest internal organ (the skinbeing the largest organ overall) and the largest glandin the human body
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Located in theRUQof 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
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 intestineand 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.
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).
The Rt. lobe is the larger, measuring 6 to 7 inches in length. The left lobe is 3 inches in length.
EXTERNAL SURFACE OF A NORMAL LIVER
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
NORMAL LIVER ZONES
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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
Functionally divided into lobules with a central vein and peripheral triads. Hepatic cords radiate from the central vein as single plates of one hepatocyte thickness sandwiching a bile canaliculus flowing towards the triad
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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
STEATOSIS
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
This liver is slightly enlarged and is pale yellow seen both on the capsule and cut surface
FATTY CHANGE: GROSS
C/S
subcapsular
yellow-white foci
often multiple
up to 10 cm
Lipid accumulates in the hepatocytes as vacuoles
FATTY CHANGE: MICRO
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
FATTY CHANGE: MICRO
diffuse or focal steatosis
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
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
CIRRHOSIS
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)
MACRONODULAR CIRRHOSIS
CAUSES: Viral hepatitis (B or C) - most common cause
Wilson's disease
Alpha-1-antitrypsin deficiency
MICRONODULAR CIRRHOSIS
The regenerative nodules - quite small, averaging
< 3 mm in size
CAUSES: Chronic Alcoholism Most Common
Wilson's disease
Primary biliary cirrhosis
Hemochromatosis.
MICRONODULAR CIRRHOSIS
Liver - yellowish hue, indicating that fatty change (also caused by alcoholism) is present.
MICRONODULAR CIRRHOSIS
Micronodular cirrhosis with fatty change demonstrates the small, yellow nodules.
.
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.
MICRONODULAR CIRRHOSIS
Seen along with moderate fatty change
Note the regenerative nodule surrounded by fibrous connective tissue
extending between portal regions
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.ALCOHOLICHEPATITIS
Mallory's hyaline, neutrophils, necrosis of
hepatocytes, collagen deposition, and fatty
change
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
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.
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
PIGMENTARY DISORDERS OF THE LIVER
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).
Kupffer cells, also known asBrowicz-Kupffer cells, are specialized macrophages located in the liverlining the walls of the sinusoids that form part of the reticuloendothelial system (RES) (aka: mononuclear phagocyte system)
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).
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.
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)
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
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.
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
TUMORS OF THE LIVER & INTRAHEPATIC DUCTS
BENIGN EPITHELIAL TUMORS
MALIGNANT EPITHELIAL TUMORS
BENIGN MESENCHYMAL TUMORS
MALIGNANT MESENCHYMAL TUMORS
HEMATOPOIETIC NEOPLASM
TUMOR-LIKE LESIONS
BENIGN EPITHELIAL TUMORS
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, Klinefelters syndrome or other abnormal secretion of sex steroids
LIVER CELL ADENOMA
Associated with glycogen storage disease types Ia and III, Fanconis anemia, familial adenomatous polyposis, familial diabetes mellitus, Hurlers disease or tyrosinemia
Spontaneous
2-4% of hepatic tumors in children
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
LIVER CELL ADENOMA
Laboratory:
normal liver function tests, may have elevated alpha fetoprotein
Hepatocellular adenomatosis:
10+ tumors
Treatment:
excision
LIVER CELL ADENOMA
CLINICAL PRESENTATION:
RUQ pain & discomfort
Severe abdominal pain
Hemorrhages
Shock
Overall Mortality : 20%
Surgical resection
No excess -fetoprotein
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
LIVER CELL ADENOMA
At the upper right is a well-circumscribed neoplasm that is arising in liver.
LIVER CELL ADENOMA
C /S
Well circumscribed
The remaining liver is a pale yellow brown because of fatty
change from chronic alcoholism.
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
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
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, Mallorys hyaline, granulomatous inflammation
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
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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)
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
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
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
BDA
Positive stains:
Mucin (intracytoplasmic)
CEA
EMA
Keratin
PAS highlights basement membrane
BDA: Differential Diagnosis
Evolving Bile Duct Carcinoma
Biliary Hamartoma (von Meyenburg complexes)
Mesenchymal Hamartoma
Cholangiocarcioma
Adenocarcinoma
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)
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
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)
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
HEPATOBILIARY CYSTADENOMA
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
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
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
Positive stains: epithelial cells - cytokeratin, EMA, CEA, CA19-9; stromal cells - muscle specific actin, vimentin; usually ER and PR (Dig Dis Sci 2006;51:623)
Positive stains:
Epithelial cells - cytokeratin, EMA, CEA, CA19-9
stromal cells - muscle specific actin, vimentin; usually ER and PR
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
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 Carolis 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
BILIARY PAPILLOMATOSISGROSS:
Inner surface of ducts has velvety friable papillary growths / excrescences with masses filling dilated major bile ducts
Masses are soft, friable, white-red-tan
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
MALIGNANT EPITHELIAL TUMOR
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 Wilms tumor patients
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
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
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
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
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
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
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
HCC
Poor prognostic factors:
Microscopic vascular invasion
High nuclear grade (grade 3 of 3)
Factors that are not prognostic:
Age
Gender
HBV status
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
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
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.
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
HCC
The satellite nodules - represent either intrahepatic spread of the tumor or multicentric origin of the tumor.
HEPATOCELLULAR CARCINOMA
- Greenish yellow hue
- One clue to the presence of such a neoplasm - serum -fetoprotein
- May focally obstruct the biliary tract and lead to an alkaline phos
Involvement of Inferior Vena Cava & other large vessels
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)
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
Cells:
Also intranuclear pseudoinclusions
Mallorys 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
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
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
HEPATOCELLULAR CARCINOMA
The malignant cells (seen mostly on the right) are well differentiated and interdigitate with normal, larger hepatocytes (seen mostly at the left).
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.
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
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
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
HCC
Molecular: 50-92% hyperploid or aneuploid
EM: numerous mitochondria, microbodies, abundant glycogen; intracytoplasmic bile products (bile canaliculi, peroxisomes)
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)
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)
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
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, Mallorys hyaline and
cytoplasmic vacuolation
HCC: CYTOLOGY
DD:
Reactive hepatocytes (finely granular chromatin)
Focal nodular hyperplasia
Hepatic adenoma
VARIANTS OF HCC
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
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
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
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
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
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
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
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
FIBROLAMELLAR VARIANT - HCC
DD:
Focal nodular hyperplasia
Sclerosing variant of hepatocellular carcinoma
Cholangiocarcinoma
Adenosquamous carcinoma with sclerosis
Metastatic carcinoma with sclerotic stroma
Paraganglioma
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
PLEOMORPHIC (GIANT CELL) VARIANT
4-10 cm) only rarely rupture
Fibrotic tumors may be precursor of solitary necrotic nodules
Solitary capillary hemangiomas are extremely rare
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)
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
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
GLOMANGIOMA
Rare,