Liver surgical pathology

LIVER PATHOLOGY
BERNADETTE R. ESPIRITU, M.D. FPSP
Anatomic & Clinical Pathologist

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

-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

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.

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.

- brown
- smooth
- soft
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
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

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

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
 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 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.

- 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.

ALCOHOLIC
HEPATITIS
- 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 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)

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

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

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

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 α-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

 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

 Degenerative changes include:
 Dilated sinusoids
 Blood filled (pelioid) spaces
 Myxoid stroma
 Focal necrosis
 Infarction
 Hematoma
 Rarely contains abundant fat, oncocytic changes,
Mallory’s hyaline, granulomatous inflammation

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

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

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

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
Positive stains:
Epithelial cells -
cytokeratin, EMA, CEA,
CA19-9
stromal cells - muscle
specific actin, vimentin;
usually ER and PR

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 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

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

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

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

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.

- 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

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
 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

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

The malignant cells (seen mostly on the right) are well
differentiated and interdigitate with normal, larger
hepatocytes (seen mostly at the left).

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, Mallory’s hyaline and
cytoplasmic vacuolation

HCC: CYTOLOGY
 DD:
 Reactive hepatocytes (finely granular
chromatin)
 Focal nodular hyperplasia
 Hepatic adenoma

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
 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

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
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

 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

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
 <1% of all hepatocellular carcinomas, although 15%
have some tumor giant cells
 Multinucleated tumor giant cells predominate,
marked loss of cell cohesion

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

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

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

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

SCLEROSING VARIANT: HCC
 Positive stains: AFP
 Negative stains: Mucin
 DD:
 CholangioCA
 Metastatic carcinoma of pancreas
 Fibrolamellar variant
 Epithelioid hemangioendothelioma (CD34+, factor
VIII+, mucin-)
 Post-Chemoradiation therapy

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

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

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

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

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

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

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

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

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)

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

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.

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.

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.

METASTATIC CARCINOMA
Microscopically, metastatic infiltrating ductal carcinoma from breast is seen
on the right, with normal liver parenchyma on the left.

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

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, <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

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

 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)

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

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

INFANTILE
 Laboratory: normal AFP
 Xray: multiple small nodules
 Poor prognostic factors:
 Congestive heart failure
 Jaundice
 Multiple nodules
 Lack of cavernous differentiation
 Treatment: resection if solitary, otherwise steroids,
radiation therapy, embolization, transplantation

INFANTILE
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%)

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

INFANTILE
Type 2 change:
 Equivalent to angiosarcoma with irregular branching
vascular structures lined by pleomorphic,
hyperchromatic endothelial cells, frequent mitotic
activity

 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

INFANTILE
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)

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

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

 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

ANGIOMYOLIPOMA
HMB45, MelanA/MART-1, microphthalmia
transcription factor (50%), S100, smooth muscle
actin, desmin, c-kit/CD117 (all cell types)
 Negative stains:
Cytokeratin
 EM:
Epithelioid myoid cells have premelanosomes,
numerous mitochondria, abundant rough
endoplasmic reticulum, glycogen, tight junctions and
basal lamina, but no thick filaments

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

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

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

 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.

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

 Positive stains: CK7, vimentin, smooth muscle
actin, desmin, actin
 Negative stains: CK20
 Molecular: interstitial deletion near 19q13.4

EM:
 Myofibroblastic features
DD:
 Bile duct adenoma (no hepatocyte islands) or
cystadenoma (adults)
 Bile duct hamartoma (usually multiple with fibrous
background)
 Infantile hemangioendothelioma (more vascular)
 Embryonal sarcoma (marked cellularity and atypical
cells)

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

ANGIOSARCOMA: CAUSES
 Patients with exposure to vinyl chloride or Thorotrast
may have synchronous cholangiocarcinoma or
 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

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

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

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

ANGIOSARCOMA: MICRO
 Pleomorphic epithelial cells in sinusoidal pattern
 CD31

 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

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

ANGIOSARCOMA
DD:
 Reactive disorders (lack atypical endothelial lining
cells)
 HCC (atypical hepatocytes, normal endothelial cells)
 Kaposi’s sarcoma (HIV+, have extrahepatic nodules,
portal distribution, lack angiosarcomatous foci)
 Peliosis Hepatis
 Epithelioid hemangioendothelioma (less atypia, less
mitotic activity, less necrosis)

EPITHELIOID
 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

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

 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

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

 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

 Microvascular channels
and intracytoplasmic
vacuoles

EHE
 Positive stains: factor VIII related antigen and
CD34 for vacuoles, CD31, trichrome and elastic
stains accentuate obliteration of hepatic venules and
hepatic vein branches, NSE, smooth muscle actin
(25%), 15% positive for cytokeratin (also trapped
hepatocytes and bile ductules)
 Negative stains: AE1/AE3 (cytokeratin), CK7,
CK20, alpha fetoprotein, bile, CEA, HepPar1, mucin
 EM: Weibel-Palade bodies, intermediate filaments
 Cytogenetics: t(1;3)(p36.3;q25), ? involving PAX7
gene at 1p36.3 and MLF1 gene at 3q25

EPITHELIOID
DD:
 Signet ring adenocarcinoma
 Scirrhous cholangiocarcinoma
 Sclerotic hepatocellular carcinoma
 Sclerosed hemangioma (well circumscribed, no
venous invasion, no atypia)
 Leiomyosarcoma
 Chondrosarcoma
 Metastatic tumor from lung or elsewhere,
 Angiosarcoma (different stroma, more atypia)

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.

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.

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

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.

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.

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.

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

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.

MISC PARENCHYMAL
DISEASES
&
TUMOR-LIKE LESIONS

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.

CPC: NUTMEG PATTERN
Micro: the nutmeg pattern results from congestion around the central
veins. This is usually due to a "RIGHT SIDED" heart failure.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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).

SCLEROSING CHOLANGITIS
This trichrome stain of the liver demonstrates extensive portal tract fibrosis
with sclerosing cholangitis. The hepatocytes are normal.

SCLEROSING CHOLANGITIS
Microscopically, this bile duct in a case of sclerosing cholangitis is surrounded
by marked collagenous connective tissue deposition.

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

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.

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

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

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

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

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

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.

FNH
 Positive stains: alpha-1-antitrypsin
 Negative stains: p53, CD143 (angiotensin I-converting
enzyme: reduced expression
 DD:
 Osler-Weber-Rendu disease
 Budd-Chiari syndrome or cirrhosis (adjacent liver is not
normal)
 Fibrolamellar hepatocellular carcinoma (marked atypia of
hepatocytes)
 Hepatocellular adenoma (encapsulated, monoclonal)
 Peritumoral hyperplasia
 Liver cell adenoma
 Mesenchymal hamartoma

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