patoloji-ders-notlari

Title

Serdar Balcı

Liver Cirrhosis and Neoplasms

Serdar BALCI, MD

Robbins Basic Pathology

Cirrhosis

Diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules
Not focal but rather involve most (if not all) of the diseased liver
Fibrous septa
- delicate bands or broad scars around multiple adjacent lobules
- Long-standing fibrosis generally is irreversible so long as disease persists or if disease-associated vascular shunts are widespread
- regression is possible if the underlying cause of liver disease is reversed
Parenchymal nodules
- <3 mm micronodules
- >1 cm macronodules
- encircled by fibrous bands
Hepatocytes in these nodules derive from:
Preexistent, long-lived hepatocytes that, by the time cirrhosis is established, display features of replicative senescence
Newly formed hepatocytes capable of replication that are derived from stem/progenitor cells found adjacent to the canals of Hering and small bile ductules—the hepatobiliary stem cell niche
- also give rise to the ductular reactions found at the periphery of most cirrhotic nodules, where parenchyma meets stromal scar, and are accompanied by proliferating endothelial cells, myofibroblasts, and inflammatory cells

Death of hepatocytes

Extracellular matrix deposition

Vascular reorganization

Damaged hepatocytes or by stimulated Kupffer cells and sinusoidal endothelial cells

Produce

Reactive oxygen species, growth factors, and cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxins

Activate

Perisinusoidal stellate cells

Produce

Growth factors, cytokines, and chemokines, transforming growth factor-β (TGF-β)

Their further proliferation and collagen synthesis

Portal fibroblasts also participate

Even in late-stage disease, if the disease process is halted or eliminated, significant remodeling and even restoration of liver function (cirrhotic regression) is possible

Vascular injuries and changes
Inflammation and thrombosis of portal veins, hepatic arteries, and/or central veins
Alternating zones of parenchymal hypoperfusion
Parenchymal atrophy, and hyperperfusion, with overcompensating regeneration
Loss of sinusoidal endothelial cell fenestrations
Portal vein–hepatic vein and hepatic artery–portal vein vascular shunts
Fast-flowing vascular channels without solute exchange
Loss of microvilli from the hepatocyte surface
- diminishing its transport capacity

Robbins Basic Pathology

types I and III collagen and other ECM components

Robbins Basic Pathology

Portal Hypertension

Ascites

Portosystemic Shunt

Splenomegaly

Hepatorenal Syndrome

Portopulmonary Hypertension

Hepatopulmonary Syndrome

Robbins Basic Pathology

TUMORS AND HEPATIC NODULES

Tumors and Hepatic Nodules

Most common hepatic neoplasms are metastatic carcinomas
- Colon, lung, and breast as the primary sites
Primary hepatic malignancies are almost all hepatocellular carcinomas
Hepatoblastoma
- childhood hepatocellular tumor
Angiosarcoma
- exposure to vinyl chloride and arsenic

BENIGN TUMORS

Cavernous hemangiomas
- **The most common benign lesion **
- Usually less than 2 cm in diameter, often directly beneath the capsule
- Blind percutaneous needle biopsy may cause severe intra-abdominal bleeding
Von Meyenburg complexes
- congenital bile duct hamartomas
- usually isolated or present in small numbers
- bile duct–like structures separated by bland, densely collagenized stroma
- No malignant potential
- When multiple may indicate the presence of fibropolycystic disease of the liver, association with polycystic kidney disease

Von Meyenburg complex

Robbins and Cotran Pathologic Basis of Disease

Focal Nodular Hyperplasia

Found in otherwise normal livers
Localized, well-demarcated, but poorly encapsulated lesion
- Consisting of hyperplastic hepatocyte nodules
- Central, stellate fibrous scar
Not a true neoplasm
- Represents a response to abnormal vascular flow through a congenital or acquired vascular anomaly that gives rise to alternating areas of parenchymal regeneration and atrophy
May range in size from 1 cm to many centimeters across
Usually is an incidental finding
Most commonly in women of reproductive age
- may grow in response to estrogens
No risk for malignancy
Cause symptoms by pressing on the liver capsule

Robbins and Cotran Pathologic Basis of Disease

Hepatic Adenoma

Benign hepatocellular neoplasm

Occurs in women of child-bearing age

Oral contraceptive pills

Well-demarcated but unencapsulated tumors

Pale, yellow-tan, or bile-stained and up to 30 cm in diameter

Hepatic adenoma.

Robbins Basic Pathology

Sheets and cords of cells
Resemble normal hepatocytes
- minimal variation in cell and nuclear size
Portal tracts are absent
Prominent arterial vessels and draining veins are distributed throughout

B: Photomicrograph showing adenoma, with cords of normal-appearing hepatocytes, absence of portal tracts, and prominent neovascularization (asterisks). A large zone of infarcted tumor is present.

Robbins Basic Pathology

Also called as Liver cell adenomas
Intrahepatic mass, mistaken for hepatocellular carcinoma
Subcapsular adenomas are at risk for rupture
- during pregnancy (under estrogenic stimulation)
- life-threatening intraabdominal hemorrhage
With β-catenin mutations carry a risk of developing into hepatocellular carcinoma

Hepatic Adenoma Types

Biallelic inactivation through somatic (90%) or germline (10%) mutations of either the HNF1A gene (encoding a hepatocyte transcription factor) or the CYP1B1 gene (encoding cytochrome P-450)
- 35-40%
- Most common in women, sometimes associated with oral contraceptive use, and are often yellow from marked steatosis. They carry little risk for malignant transformation
Activating mutations of β-catenin
- 10-15%
- High risk for malignant transformation
- Most common in men
- May be related to anabolic steroid use and possibly nonalcoholic fatty liver disease
Inflammatory
- 50%
- Associated with increased expression of acute phase reactant proteins
  - serum amyloid A and C-reactive protein in the tumor and sometimes in the serum
- 10% of these tumors also have activating mutations of β-catenin and may undergo malignant transformation
- Most common in women
- Associated with obesity and fatty liver disease
- Identical to FNH, and the distinction may be made by demonstrating an inflammatory phenotype (such as by expression of serum amyloid A protein, SAA)

PRECURSOR LESIONS OF HEPATOCELLULAR CARCINOMA

Precursor Lesions of Hepatocellular Carcinoma

Cellular changes and nodular lesions
- Chronic liver disease
  - Chronic viral hepatitis
  - Alcoholic liver disease
  - Metabolic diseases
    - AAT deficiency
    - Hereditary hemochromatosis
Cellular Dysplasia
- common in the setting of chronic viral hepatitis
Usually they are found in late-stage disease
The processes that lead to cirrhosis and to malignant transformation usually take years to decades and run parallel to each other, rather than in sequence
Hepatocellular adenomas

Large cell change

Scattered hepatocytes

Periportal or periseptal regions

Larger than normal hepatocytes

Pleomorphic, often multiple nuclei

A: Large cell change. Very large hepatocytes with very large, often atypical nuclei are scattered among normal-size hepatocytes with round, typical nuclei.

Robbins Basic Pathology

Small cell change

Smaller than normal hepatocytes

Normal sized, often hyperchromatic, oval or angulated nuclei

May appear anywhere in the hepatic lobule

With formation of vaguely nodular clusters

Considered to be directly premalignant

**B: Small cell change (SCC). Normal-appearing hepatocytes are in the lower right corner. SCC is indicated by smaller than normal hepatocytes with thickened liver cell plates, and high nuclear : cytoplasmic **

Robbins Basic Pathology

Dysplastic Nodules

Major pathway to hepatocellular carcinoma in chronic liver disease

Most cirrhotic nodules range 0.3-0.8 cm

Dysplastic nodules often are 1- 2 cm

High risk for malignant transformation

Sometimes contain overtly malignant subnodules

A: Hepatitis C–related cirrhosis with a distinctively large nodule (arrows). Nodule-in-nodule growth in this dysplastic nodule suggests a high grade lesion.

Robbins Basic Pathology

B: Histologically the region within the box in A shows a well-differentiated hepatocellular carcinoma (HCC) (right side) and a subnodule of moderately differentiated HCC within it (center, left).

Robbins Basic Pathology

HEPATOCELLULAR CARCINOMAS

Hepatocellular Carcinomas

Infection with HBV or HCV, alcoholic cirrhosis, and aflatoxin exposure
NAFLD, hemochromatosis, α 1 -antitrypsin deficiency, tyrosinemia
Many variables, including age, gender, chemicals, viruses, hormones, alcohol, and nutrition, interact in the development of HCC
The disease most likely to give rise is hereditary tyrosinemia
Japan and Central Europe, chronic HCV infection
China and southern Africa, HBV is endemic
- high-level exposure to dietary aflatoxins derived from the fungus Aspergillus flavus is also common
- “moldy” grains and peanuts
- Aflatoxin can bind covalently with cellular DNA, resulting in mutations in genes such as TP53

Tumors may arise from both mature hepatocytes and progenitor cells (known as ductular cells or oval cells)

Grossly as

a unifocal, usually massive tumor

a multifocal tumor made of nodules of variable size

a diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver, blending imperceptibly into the cirrhotic background

Discrete tumor masses usually are yellow-white, punctuated sometimes by bile staining and areas of hemorrhage or necrosis

Strong propensity for vascular invasion

Extensive intrahepatic metastases are characteristic

Snakelike masses of tumor invade the portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even into the right side of the heart

Robbins and Cotran Pathologic Basis of Disease

Range from well-differentiated lesions that reproduce hepatocytes arranged in cords, trabeculae or glandular patterns

To poorly differentiated lesions, often composed of large, multinucleate anaplastic giant cells

Globules of bile may be found within the cytoplasm of cells and in pseudocanaliculi between cells

Acidophilic hyaline inclusions within the cytoplasm may be present, resembling Mallory bodies

There is little stroma in most hepatocellular carcinomas, explaining their soft consistency

Robbins Basic Pathology

Robbins and Cotran Pathologic Basis of Disease

Fibrolamellar HCC

Young male and female adults (20-40 years of age)

No association with cirrhosis or other risk factors

Single tumor with fibrous bands coursing through it

Superficially resembling focal nodular hyperplasia

Fibrolamellar variant has a better prognosis than that of the other, more common variants

Robbins and Cotran Pathologic Basis of Disease

Autopsy Pathology: A Manual and Atlas