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. -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. 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. 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. The Rt. lobe is the larger, measuring 6 to 7
inches in length. The left lobe is 3 inches in
length.
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. 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. 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
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. This liver is slightly
enlarged and is
pale yellow seen
both on the capsule
and cut surface
FATTY CHANGE: GROSS
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
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. 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
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)
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. MICRONODULAR CIRRHOSIS
- Seen along with moderate fatty change
- Note the regenerative nodule surrounded by fibrous connective tissue
extending between portal regions
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.
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. 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. 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
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. 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. 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. 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. 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. 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. 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. 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
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. 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. 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. LIVER CELL ADENOMA
Laboratory:
normal liver function tests, may have elevated alpha
fetoprotein
Hepatocellular adenomatosis:
10+ tumors
Treatment:
excision
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. LIVER CELL ADENOMA
At the upper right is a well-circumscribed neoplasm that is arising in
liver.
51. LIVER CELL ADENOMA
C /S
- Well circumscribed
-The remaining liver is a pale yellow brown because of fatty
change from chronic alcoholism.
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. 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
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
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. 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. 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. BDA
Positive stains:
Mucin (intracytoplasmic)
CEA
EMA
Keratin
PAS highlights basement membrane
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. 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. 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. 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
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. 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. 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.
71. 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
72. 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
73. 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
74. 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
75. 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
78. 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
79. 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
80. 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
81. 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
82. 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
83. 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
84. 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
85. 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
86. HCC
Poor prognostic factors:
Microscopic vascular invasion
High nuclear grade (grade 3 of 3)
Factors that are not prognostic:
Age
Gender
HBV status
87. 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
88. 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
89. 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.
90. 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
91. HCC
The satellite nodules - represent either intrahepatic
spread of the tumor or multicentric origin of the tumor.
92. 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
94. 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)
95. 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
96. 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
97. 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
98. 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
99. HEPATOCELLULAR CARCINOMA
The malignant cells (seen mostly on the right) are well
differentiated and interdigitate with normal, larger
hepatocytes (seen mostly at the left).
100. 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.
101. 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
102. 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
103. 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
105. 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)
106. 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)
107. 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
108. 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
111. 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
112. 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
113. 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
114. 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
115. 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
116. 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
117. 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
118. 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
120. 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
121. 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
122. 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
123. 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
124. 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
125. 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
127. 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
128. 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
129. 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
130. 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
131. 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
132. 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
133. 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
134. 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
135. 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)
136. 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
137. 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.
138. 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.
139. 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.
142. 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
143. 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)
144. 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
145. 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
146. 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
147. 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
148. 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)
149. 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
150. 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
152. 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%)
153. 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
154. INFANTILE
HEMANGIOENDOTHELIOMA
Type 2 change:
Equivalent to angiosarcoma with irregular branching
vascular structures lined by pleomorphic,
hyperchromatic endothelial cells, frequent mitotic
activity
155. 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
156. 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)
157. 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
158. 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
159. 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
161. 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
162. 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
163. 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
164. 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.
165. 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
170. 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
171. 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
172. 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
173. 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
174. 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
176. 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
177. 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
179. 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
180. 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
181. 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
182. 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
183. 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
188. 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.
189. 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.
190. 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
191. 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.
192. 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.
193. 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.
194. 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
195. 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.
197. 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.
198. CPC: NUTMEG PATTERN
Micro: the nutmeg pattern results from congestion around the central
veins. This is usually due to a "RIGHT SIDED" heart failure.
199. 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.
200. 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.
201. 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.
202. 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.
203. 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.
204. 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.
205. 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
206. 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.
207. 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
208. 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.
209. 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.
210. 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.
211. 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.
212. 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).
213. SCLEROSING CHOLANGITIS
This trichrome stain of the liver demonstrates extensive portal tract fibrosis
with sclerosing cholangitis. The hepatocytes are normal.
215. 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
216. 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.
217. 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
218. 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
220. 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
221. 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
222. 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
224. 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.
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