liver surgical pathology

Slide 1

LIVER PATHOLOGY

BERNADETTE R. ESPIRITU, M.D. FPSP

Anatomic & Clinical Pathologist

LIVER

1.41.6 kg (3.13.5 lb)

reddish brown soft organ with four lobes of unequal size and shape

It is both the largest internal organ (the skinbeing the largest organ overall) and the largest glandin the human body

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Located in theRUQof the abd cavity, resting just below the diaphragm. The liver lies to the right of the stomach and overlies the GB.

The Rt lobe is larger.

-The falciform ligament is the dividing line between the two lobes.

NORMAL LIVER: GROSS

BLOOD SUPPLY

Two large BV, one called the HEPATIC ARTERY and one called the PORTAL VEIN.

The HA carries blood from the aorta whereas the PV carries blood containing digested nutrients from the Small intestineand the descending colon.

These blood vessels subdivide into capillaries which then lead to a lobule.

Each lobule is made up of millions of hepatic cells which are the basic metabolic cells.

It is one of only two organs to have two blood supplies, receiving blood from the hepatic arteries [20%] and the portal vein [80%] (carrying blood from the intestines).

The Rt. lobe is the larger, measuring 6 to 7 inches in length. The left lobe is 3 inches in length.

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

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2

3

PT Bile ducts, Hepatic artery & PV

CV

Periportal receives blood with highest oxygen conc

Midzonal encompasses the central portion of the liver lobule

Centrilobular

Functionally divided into lobules with a central vein and peripheral triads. Hepatic cords radiate from the central vein as single plates of one hepatocyte thickness sandwiching a bile canaliculus flowing towards the triad

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Histologically Divided into

LOBULES

Center of the lobule - CV

Periphery of the lobule - PT

Functionally, Divided into :

3 ZONES, based upon

oxygen supply

Zone 1- Encircles the PT where the oxygenated blood from hepatic arteries enters.

Zone 3 is located around CV, where oxygenation is poor.

Zone 2 is located in between.

NORMAL LIVER: STRUCTURE

CV

PT

STEATOSIS

FATTY CHANGE

Clinical:

Incidental finding at autopsy

Most common cause in developed nations is Alcoholism

In developing nations - Kwashiorkor in children

DM, obesity, & severe GI malabsorption

Unknown cause; may be due to focal tissue hypoxia or local effects of insulin

Stable or regresses if underlying condition improves

This liver is slightly enlarged and is pale yellow seen both on the capsule and cut surface

FATTY CHANGE: GROSS

C/S

subcapsular

yellow-white foci

often multiple

up to 10 cm

Lipid accumulates in the hepatocytes as vacuoles

FATTY CHANGE: MICRO

The lipid accumulates

when lipoprotein

transport is disrupted

and/or when fatty acids

accumulate.

Alcohol, the most

common cause, is a

hepatotoxin that

interferes with

mitochondrial and

microsomal function in

hepatocytes, leading to accumulation of lipid.

FATTY METAMORPHOSIS

FATTY CHANGE: MICRO

diffuse or focal steatosis

DIFFERENTIAL DIAGNOSIS: FC

Angiomyolipoma

Coelomic fat ectopia

Diffuse steatosis

Focal nodular hyperplasia - nodular, but not a fatty tumor; has hepatocyte nodules surrounded by fibrous septa with large malformed arterial branches

Hepatic adenoma - neoplastic hepatocytes

Lipoma - no trapped hepatocytes

Myelolipoma

Hepatocellular carcinoma may have fatty change

MYELOLIPOMA

Greasy, yellow tumor with reddish-brown areas at the periphery corresponding to hematopoieti c elements

Intimately admixed adipose tissue and hematopoietic elements. Note the large multilobate megakaryocyte.

Inset : A few bony spicules present amidst the mature adipocytes

CIRRHOSIS

CIRRHOSIS

Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis.

nodular, firm liver

Nodules - larger than 3 mm ("macronodular cirrhosis)

MACRONODULAR CIRRHOSIS

CAUSES: Viral hepatitis (B or C) - most common cause

Wilson's disease

Alpha-1-antitrypsin deficiency

MICRONODULAR CIRRHOSIS

The regenerative nodules - quite small, averaging

< 3 mm in size

CAUSES: Chronic Alcoholism Most Common

Wilson's disease

Primary biliary cirrhosis

Hemochromatosis.


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.

ALCOHOLICHEPATITIS

Mallory's hyaline, neutrophils, necrosis of

hepatocytes, collagen deposition, and fatty

change

CAPUT MEDUSAE : CIRRHOSIS

- Results from the abnormal blood flow pattern in liver

The increased pressure is transmitted to collateral venous

channels. Sometimes these venous collaterals are dilated.

- Dilated veins seen on the abdomen

ESOPHAGEAL VARICES

- Produced by Portal HPN

results when submucosal veins in the esophagus become dilated.

Varices are seen here in the lower esophagus as linear blue dilated veins. There is hemorrhage around one of them.

Such varices are easily eroded, leading to massive gastrointestinal hemorrhage.

PORTAL HYPERTENSION: SPLENOMEGALY

One of the most common findings in CIRRHOSIS

SPLEEN- Is enlarged (normal 300 grams or less) 500 - 1000 gm.

- irregular pale tan plaques of collagen over the purple capsule known as "sugar icing" or "hyaline perisplenitis" which follows the splenomegaly and/or multiple episodes of peritonitis that are a common accompaniment to cirrhosis of the liver

PIGMENTARY DISORDERS OF THE LIVER

HEMOSIDEROSIS

The hepatocytes and Kupffer cells here are full of granular brown deposits of hemosiderin from accumulation of excess iron in the liver.

The term "hemosiderosis" is used to denote a relatively benign accumulation of iron.

The term "hemochromatosis" is used when organ dysfunction occurs.

The iron accumulation may lead to a micronodular cirrhosis (so called "pigment" cirrhosis).

Kupffer cells, also known asBrowicz-Kupffer cells, are specialized macrophages located in the liverlining the walls of the sinusoids that form part of the reticuloendothelial system (RES) (aka: mononuclear phagocyte system)

HEMOSIDEROSIS

A Prussian blue iron stain demonstrates the blue granules of hemosiderin in hepatocytes and Kupffer cells.

Hemochromatosis can be primary (the cause is probably an autosomal recessive genetic disease) or secondary (excess iron intake or absorption, liver disease, or numerous transfusions). Hemochromatosis leads to bronze pigmentation of skin, DM (from pancreatic involvement), and cardiac arrhythmias (from myocardial involvement).

HEREDITARY HEMOCHROMATOSIS (HHC): GROSS

- Dark brown - liver, the pancreas and lymph nodes -due to

extensive iron deposition

- HHC results from a mutation involving the hemochromatosis gene (HFE)

that leads to increased iron absorption from the gut.

- Prevalence - 1:200 & 1:500 persons in the U.S.

HEREDITARY HEMOCHROMATOSIS (HH). CIRRHOSIS

Prussian blue iron: reveals extensive hepatic hemosiderin deposition

Excessive iron deposition in persons with HH can affect many organs, but the MOST SEVERELY AFFECTED:

Heart (congestive failure)

Pancreas (diabetes mellitus)

Liver (cirrhosis and hepatic failure)

Joints (arthritis)

LIPOFUSCIN PIGMENT

Pale golden brown finely granular pigment in nearly all hepatocytes is

lipochrome (lipofuscin).

This is a "wear and tear" pigment from the accumulation of

autophagolysosomes over time.

- This pigment is of no real pathologic importance

CHOLESTASIS: MICRO

- accumulations of pigment - bile

- often this is due to extrahepatic biliary tract obstruction

Bile may also accumulate in liver (called cholestasis) when there is

hepatocyte injury.

INTRAHEPATIC LITHIASIS

Small stone in an intrahepatic bile duct

Produce a localized cholestasis, but the serum bilirubin is NOT

increased, because there is plenty of non-obstructed

liver to clear the bilirubin from the blood

Serum Alkaline Phos is increased with biliary tract obstruction at any

level

TUMORS OF THE LIVER & INTRAHEPATIC DUCTS

BENIGN EPITHELIAL TUMORS

MALIGNANT EPITHELIAL TUMORS

BENIGN MESENCHYMAL TUMORS

MALIGNANT MESENCHYMAL TUMORS

HEMATOPOIETIC NEOPLASM

TUMOR-LIKE LESIONS

BENIGN EPITHELIAL TUMORS

LIVER CELL ADENOMA

Arises in normal or nearly normal liver in patients with abnormal hormonal or metabolic condition

95% women, usually child-bearing age (very rare in children), history of 5+ years of oral contraceptives in 85% (occasionally regress after discontinuation)

Associated with anabolic steroids (in men), anti-estrogens, Klinefelters syndrome or other abnormal secretion of sex steroids

LIVER CELL ADENOMA

Associated with glycogen storage disease types Ia and III, Fanconis anemia, familial adenomatous polyposis, familial diabetes mellitus, Hurlers disease or tyrosinemia

Spontaneous

2-4% of hepatic tumors in children

LIVER CELL ADENOMA

Subcapsular tumors may rupture, particularly during pregnancy

Benign, but may contain hepatocellular carcinoma or cause severe hemorrhage

10% or lower risk of hepatocellular carcinoma if not resected; definite risk in young men with glycogen storage disease type Ia

Must sample generously to rule out coexisting hepatocellular carcinoma

May contain hepatic progenitor cells

LIVER CELL ADENOMA

Laboratory:

normal liver function tests, may have elevated alpha fetoprotein

Hepatocellular adenomatosis:

10+ tumors

Treatment:

excision

LIVER CELL ADENOMA

CLINICAL PRESENTATION:

RUQ pain & discomfort

Severe abdominal pain

Hemorrhages

Shock

Overall Mortality : 20%

Surgical resection

No excess -fetoprotein

GROSS: LIVER CELL ADENOMA

Solitary (70%, anabolic steroid related more often multiple), pale, yellow-tan (different from surrounding liver), frequently bile-stained nodules, often subcapsular, 10-30 cm, sharply demarcated or encapsulated

Usually right lobe, may be pedunculated (10%)

May have hemorrhagic, necrotic or infarcted foci

Usually no fibrous septa or central scar

Adjacent liver is noncirrhotic

LIVER CELL ADENOMA

At the upper right is a well-circumscribed neoplasm that is arising in liver.

LIVER CELL ADENOMA

C /S

Well circumscribed

The remaining liver is a pale yellow brown because of fatty

change from chronic alcoholism.

LIVER CELL ADENOMA: MICRO

Sheets and cords 1-3 cells thick of normal appearing hepatocytes with variable glycogen

No/rare mitotic figures

No portal tracts, no central veins or connection with biliary system but see prominent free floating arterial vessels and draining veins throughout the tumor

Intact reticulin framework

Pseudoglands may be present


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, Mallorys hyaline, granulomatous inflammation

LIVER CELL ADENOMA

Composed of cells that closely resemble normal hepatocytes, but the neoplastic liver tissue is disorganized hepatocyte cords and does not contain a normal lobular architecture

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LIVER CELL ADENOMA

Positive stains: ER, PR

Negative stains: p53

DD:

HEPATOCELLULAR CARCINOMA (mitotic activity, atypia, trabecular growth, cell plates > 2 cells thick, vascular invasion, infiltrative, often different clinical features)

FOCAL NODULAR HYPERPLASIA (central stellate scar and radiating fibrous septa)

BILE DUCT ADENOMA (Cholangioma)

30% - incidental finding

Clinical significance: mistaken as metastasis

GROSS:

Small, well-circumscribed but unencapsulated, firm, gray-white, tan, subcapsular nodules; 85% solitary; usually 5 mm or less but 7% are larger than 1 cm; may have central depression

BDA: MICRO:

Small tubules set in a fibrous

stroma with lymphocytes

Single layer of cuboidal cells; possible mucin secretion; no bile in the lumen

Normal portal tracts often included

May actually represent peribiliary gland hamartoma

BDA: MICRO

Compact network of simple tubular ducts or more complex tortuous arrangement, with small or indistinct lumina

Epithelium has abundant cytoplasm and pale nuclei compared to interlobular bile ducts in adjacent liver

Variable fibrous stroma, granulomas, calcification, inflammatory cells

Usually no cystic change, no cytoplasmic or intraluminal bile, no atypia, no mitotic figures, no angiolymphatic invasion

BDA

Positive stains:

Mucin (intracytoplasmic)

CEA

EMA

Keratin

PAS highlights basement membrane

BDA: Differential Diagnosis

Evolving Bile Duct Carcinoma

Biliary Hamartoma (von Meyenburg complexes)

Mesenchymal Hamartoma

Cholangiocarcioma

Adenocarcinoma

HEPATOBILIARY CYSTADENOMA

CLINICAL:

Rare, 5% of all hepatic solitary cysts

Resembling cystadenoma of the pancreas/ovary, Associated with polycystic liver disease, abnormal hepatobiliary anatomy

84% are intrahepatic, also in common bile duct (6%), hepatic ducts (4%), cystic duct (4%), gallbladder (2%)

ectopic embryonal tissue (gallbladder precursor)

Middle-aged woman, 95% occur in women, mean age 45 years (range 2-87 years)

Usual presentation: pain & discomfort

Slow growth, symptomatic with increase in size

Surgical resection always indicated, malignant transformation possible

Usually slow growing with good prognosis after surgical excision, although 25% have coexisting borderline or malignant lesions

Complications:

intracystic hemorrhage

Bacterial infection

Rupture


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

HEPATOBILIARY CYSTADENOMA: MICRO:

serous - lined by bland, flat to cuboidal cells with clear, glycogen-rich cytoplasm, no spindle cell stroma; no mucin; may represent hepatic metastasis from pancreatic serous cystadenoca

Positive stains: epithelial cells - cytokeratin, EMA, CEA, CA19-9; stromal cells - muscle specific actin, vimentin; usually ER and PR (Dig Dis Sci 2006;51:623)

Positive stains:

Epithelial cells - cytokeratin, EMA, CEA, CA19-9

stromal cells - muscle specific actin, vimentin; usually ER and PR

HEPATOBILIARY CYSTADENOMA: Differential Diagnosis:

Developmental Cyst

Cystadenocarcinoma

Borderline tumors (have high grade dysplasia and complex architecture)

invasive tumors (put through numerous sections to exclude)

Borderline

Tumors with high grade dysplasia with complex architecture

BILIARY PAPILLOMATOSIS

CLINICAL:

Rare, 50 cases reported

2/3 men, usually ages 40+ years

Multiple papillary adenomas extensively throughout intra- or extrahepatic biliary tract

Often recurs, 25% have malignant transformation, but only rare metastases (to lung)

Associated with Carolis disease, choledochal cyst, polyposis coli and ulcerative colitis

Most patients die within 3 years due to cholangitis and hepatic failure

Treatment: difficult to treat because multifocal; liver transplant may be helpful

BILIARY PAPILLOMATOSISGROSS:

Inner surface of ducts has velvety friable papillary growths / excrescences with masses filling dilated major bile ducts

Masses are soft, friable, white-red-tan

BILIARY PAPILLOMATOSIS

Micro:

Dilated ducts contain multiple papillary tumors composed of fibrovascular cores lined by columnar, pseudostratified, biliary-type cells with numerous cytoplasmic mucin vacuoles

Tumor may be solid or cribriform

Varying cytologic atypia and mitotic activity

May have associated tubular adenocarcinoma with invasion

MALIGNANT EPITHELIAL TUMOR

HEPATOCELLULAR CA

Also called LIVER CELL CARCINOMA, HEPATOMA

85% of hepatic malignancies (30% in children)

Major cause of cancer death worldwide (20-40% in China, Japan, sub-Saharan African), although not in North America

Primary carcinomas are rare in North America, but more common in countries bordering Mediterranean Sea endemic for viral hepatitis

Highest rates in Korea, Taiwan, southeast China, Mozambique

250,000 worldwide cases annually

Higher rates in blacks vs. whites (4:1)

Most are age 60+ years with cirrhosis or ages 20-40 years without cirrhosis, occasionally are second tumors in Wilms tumor patients

HCC: Risk factors/causes

Hepatitis B virus (HBV) (infant carriers have 200x risk)

Cirrhosis (85% in West with HCC have cirrhosis, 3% with cirrhosis develop HCC annually)

Hepatitis C virus (HCV)

Alcohol abuse, aflatoxins

Genetic variation (all act synergistically)

Small cell change but probably not large cell change

Thorotrast exposure

Androgenic steroids

Tyrosinemia

HCC: RISK FACTORS/CAUSES

Hepatitis B virus:

HBV DNA is integrated into host cell genome, inducing genomic instability

HBV contains 4 open reading frames

HBV X protein may disrupt normal growth control by transcriptional activation of insulin like growth factor II, receptors for insulin-like growth factor I

HBV X binds to p53; HBV vaccination may dramatically reduce HCC incidence

HCC

Aflatoxins:

aflatoxin B1, a metabolite of the fungus Aspergillus flavus, is a potent carcinogen in some areas endemic for HCC

is activated by hepatocytes, products intercalate into DNA to form mutagenic adducts with guanosine

in sub-Saharan Africa and China, patients have mutation in hepatic enzymes that normally detoxify aflatoxin

HCC

Cirrhosis:

major risk factor,caused by HCV, Alcoholism, primary hemochromatosis, hereditary tyrosinemia (40% develop HCC even with dietary control);

Due to stimulation of hepatocellular division in background of ongoing necrosis and inflammation

Symptoms: abdominal pain, ascites, hepatomegaly, obstructive jaundice; also systemic manifestations

HCC

Laboratory: elevated serum AFP (70% sensitive), reduced sensitivity in alcohol-related cirrhosis (65%), tumors arising in noncirrhotic liver (33%), tumors 2 cm or less (25%)

Screening: recommended to use ultrasound and serum AFP in patients with chronic liver disease; leads to diagnosis of tumors 2 cm or less, may not reduce deaths

Other causes of elevated serum AFP: yolk sac tumors of gonads, cirrhosis, massive liver necrosis, chronic hepatitis, normal pregnancy, fetal distress or death, fetal neural tube defects, hepatoblastoma, hepatoid adenocarcinoma

HCC

5 year survival: 10% normally to 50% in tumors 5 cm or less with resection; death usually within 1 year from cachexia, GI bleed, liver failure, rupture of tumor (10%)

Metastases: initially within liver, distant metastases late to lungs, bone, adrenal gland or porta hepatis lymph nodes

HCC

Favorable prognosis factors:

low stage, encapsulation, single lesion, tumor size < 5 cm, fibrolamellar variant, no cirrhosis (independent of fibrolamellar subtype), no vascular invasion, negative surgical margins

another study: low nuclear grade (grade 1 of 3) regardless of vascular invasion or intermediate nuclear grade (2 of 3) without microscopic vascular invasion

HCC

Poor prognostic factors:

Microscopic vascular invasion

High nuclear grade (grade 3 of 3)

Factors that are not prognostic:

Age

Gender

HBV status

HCC

Classification:

Either small (< 2 cm) or advanced (2 cm or more)

Treatment:

Resection

Transplantation (if solitary tumor 5 cm or less or multiple nodules 3 cm or less)

Radiofrequency ablation

HCC: GROSS

Unifocal, multifocal or diffusely infiltrative soft tumor, paler than normal tissue, may be green due to bile

Extensive intrahepatic metastases are common

Snakelike masses of tumor may involve the portal vein (35-80%), hepatic vein (20%) or inferior vena cava (similar to renal cell carcinoma)

Hemorrhage and necrosis are common

Occasionally tumor is pedunculated

Liver usually cirrhotic, often enlarged

HEPATOCELLULAR CARCINOMA

- Arise in the setting of cirrhosis

Worldwide, viral hepatitis is the most common cause, but in the U.S.,

chronic alcoholism is the most common cause.

large and bulky and has a greenish cast because it contains bile

To the right of the main mass are smaller satellite nodules.

HCC: GROSS

Soft yellow-green or reddish

masses of varying sizes:

3 basic patterns

Multinodular

Solitary

Massive or diffuse

For symptomatic individuals- most common is a large mass surrounded by several satellite nodules, multinodular appearance may be difficult to distinguish from cirrhosis. Diffuse pattern rare

Tumor thrombi in veins are common as is spontaneous rupture of larger masses

HCC

The satellite nodules - represent either intrahepatic spread of the tumor or multicentric origin of the tumor.


- Greenish yellow hue

- One clue to the presence of such a neoplasm - serum -fetoprotein

- May focally obstruct the biliary tract and lead to an alkaline phos

Involvement of Inferior Vena Cava & other large vessels

HCC: MICRO

Patterns:

Trabecular (most common) with 4+ cells surrounded by

layer of flattened endothelial cells

Solid (compact)

Pseudoglandular (acinar with proteinaceous material or

bile in lumina, may resemble thyroid follicles),

Pelioid

Giant cell

Sarcomatoid

Clear cell patterns

Sinusoidal vessels surrounding tumor cells is important diagnostic feature

Scanty stroma, from well differentiated to bizarre (often within same tumor)

HCC: MICRO

Cells

Polygonal with distinct cell membranes

Higher N/C ratio

Abundant granular eosinophilic cytoplasm

Round nuclei with coarse chromatin and

thickened nuclear membrane

Prominent nucleoli

Cells:

Also intranuclear pseudoinclusions

Mallorys hyaline (2-25%)

Bile (5-33%) and bile canaliculi

Vascular invasion and portal vein thrombosis are common

Mitotic figures are common

Minimal desmoplasia

Occasionally fibrous variants, vascular lakes (pelioid pattern), abundant fat, no central veins

HCC: MICRO

Well differentiated:

Thin plates (1-3 hepatocytes thick), cells smaller than normal, abnormal reticulin network

Minimal nuclear atypia, nuclear density 2x normal liver

Commonly fatty change and pseudoglands; may resemble hepatocyte adenoma

Common pattern for small hepatocellular carcinoma

HCC:MICRO

Moderately differentiated:

trabecular pattern with 4+ cells thick

larger tumor cells than well differentiated HCC with more eosinophilic cytoplasm, distinct nucleoli, pseudoglands, bile, tumor giant cells

most common pattern in advanced HCC

Poorly differentiated:

Large tumor cells with hyperchromatic nuclei in compact growth pattern with rare trabeculae or bile

Prominent pleomorphism, may have spindle cell or small cell areas

May not appear to be hepatocellular


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, Mallorys hyaline and

cytoplasmic vacuolation

HCC: CYTOLOGY

DD:

Reactive hepatocytes (finely granular chromatin)

Focal nodular hyperplasia

Hepatic adenoma

VARIANTS OF HCC

CLEAR CELL VARIANT - HCC

Predominant appearance in 5-16% of cases, but some clear cells present in 20-40% of cases

Tumor cells have prominent clear cytoplasm due to cytoplasmic fat or glycogen

May need to hunt for typical HCC to rule out metastatic tumor

May have bland nuclear features

Elevated serum AFP in 92%

Similar prognosis to classic tumor

HCC VARIANTS CLEAR CELL

Laboratory: elevated serum AFP; may have hypoglycemia or hypercholesterolemia

Micro: trabecular, pseudoacinar, solid or mixed patterns of large number of neoplastic hepatocytes with abundant clear cytoplasm (glycogen or lipid) and round nuclei; may have intracytoplasmic bile (5-33%); usually no intratumoral fibrosis except in areas of hemorrhage and necrosis

FIBROLAMELLAR VARIANT - HCC

Young adults 20-40 years

Fewer than 10% of all cases of HCC, but 35% of all cases in patients younger than 50 years

Similar symptoms as classic HCC; rarely associated with gynecomastia and Budd-Chiari syndrome

Not associated with hepatitis B virus, cirrhosis or metabolic abnormalities; pathogenesis unknown

5 year survival is 60-75%, better than classic hepatocellular carcinoma

Metastasizes to abdominal lymph nodes, peritoneum, lung

FIBROLAMELLAR VARIANT- HCC

GROSS:

Single (75%)

Large (mean 13 cm)

Hard

Scirrhous

Well-circumscribed

Bulging

White-brown tumor with fibrous bands throughout and central stellate scar

Most cases involve left lobe, but may involve both lobes

Variable bile staining, hemorrhage and necrosis


Micro:

Nests, sheets or cords of well differentiated oncocytic cells in background of dense, acellular collagen bundles that may contain small, thick-walled vessels

Cells are large and polygonal with well defined cell borders, abundant granular and eosinophilic cytoplasm, often pale bodies (ground glass cells) or PAS+ hyaline globules, vesicular nuclei, prominent nucleoli

Vascular invasion and necrosis common

Fibrotic tissue coalesces into central scar

Remaining liver is unremarkable

Radiologic calcification corresponds to necrosis with foreign body type reaction

Other possible features include focal nuclear pleomorphism, conventional hepatocellular carcinoma

Trabecular, adenoid or pelioid patterns

a. HCA: peliotic changes with dilated sinusoids and areas of hemorrhage

b. HCA: normochromatic nuclei without mitotic activity and cytoplasm with hydropic changes but without globular inclusions

c. HCA: well-preserved reticulin framework

d. HCA: focal sinusoidal positive immunohistochemical staining for CD34

e. FLC: large polygonal cells with granular eosinophilic cytoplasm, evident nucleoli, and paranuclear pale bodies

f. FLC: solid aggregates of tumor cells surrounded by typical prominent lamellar fibrosis

g. FLC: Diffuse strands of dense fibrosis

h. FLC: Diffuse and strong sinusoidal immunohistochemical staining for CD34

A

B

C

D

E

F

G

H

FIBROLAMELLAR VARIANT -HCC

Cytology: discohesive cells with inconspicuous strands of collagen; may contain bile

Positive stains:

HepPar and CK7

Fibrinogen (pale bodies)

Copper, copper-binding protein

Bile

Alpha-1-antitrypsin

Polyclonal CEA

CAM 5.2 (CK 8/18)

Negative stains:

Mucin

Alpha fetoprotein


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

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,

liver surgical pathology

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