12-3 Liver Path 8 - Nodules & Tumors Flashcards
What are the 3 general categories of hepatic masses?
Nodular hyperplasia
Benign neoplasms
Malignant tumors
What are the benign neoplasms that affect the liver?
•Benign neoplasms
–Cavernous hemangioma
–Hepatic adenoma
What are the malignant tumors that affect the liver?
•Malignant tumors
–Hepatocellular carcinoma
–Cholangiocarcinoma
–Hepatoblastoma
–Metastatic tumors
What are some clinical pearls to keep in mind when diagnosing hepatic masses?
- Although the emphasis is on primary liver tumours, it is important to remember that metastases far outnumber primary tumours and so these are always considered in differential diagnosis.
- The clinical scenario is an important feature in the differential diagnosis of any mass lesion in the liver. Age, gender and predisposing factors such as underlying liver disease or exposure to drugs, chemicals or parasites influence the likelihood of development of many tumours
- Consequently, one should be very circumspect about diagnosing a tumour of infancy, like hepatoblastoma, in an adult or a tumour like hepatocellular adenoma that is strongly associated with oral contraceptive steroids in an elderly male.
Describe the cells and structures involved in focal nodular hyperplasia.
- Composed of hyperplastic nodules of hepatocytes, separated by fibrous septa which often form typical stellate scars
- Absence of true bile ducts and a connection to the biliary outflow tract
- Estrogen can enhance growth, but do not cause FNH
What is the hypothesis behind the pathology of focal hodular hyperplasia?
Hypothesis
•Focal nodular hyperplasia is usually thought to be due to hyperplastic growth of normal hepatocytes with a malformed biliary draining system and/or pre-existent arteriovenous malformation. The arterial supply is derived from the hepatic artery whereas the venous drainage is into the hepatic veins. FNH does not contain portal venous supply.
What are the demographics behind focal nodular hyperplasia?
- Most commonly found in adult women (20-30 yo)
- Benign, second most common benign tumor of the liver, after hemangioma
What are the diagnostic features of focal nodular hyperplasia?
•Diagnostic features of fibrous septa with a ductular reaction and irregularly thickened arteries unaccompanied by bile ducts, lying against nodular proliferation of hepatocytes without portal tracts or central veins.
What’s this?
Focal nodular hyperplasia
Resected and bisected specimen shows a discrete nodule with central scar. Normal liver tissue is not present
•Stellate scar with nodular parenchyma
What’s this?
Gross appearances of focal nodular hyperplasia
What’s this?
Focal nodular hyperplasia
Fibrosis with ductular proliferation
What happens in nodular regenerative hyperplasia?
- Liver is entirely transformed into nodules grossly similar to micronodular cirrhosis but without fibrosis
- Thought to represent a chronic ischemic injury secondary to disturbance to the blood flow (such as sinusoidal obstructive syndrome) within the liver
What is associated with nodular regenerative hyperplasia?
- Can be associated with the development of portal hypertension
- Thought to be a regenerative response to vascular injury (small vessel vasculitis??)
- Thought to represent a chronic ischemic injury secondary to disturbance to the blood flow (such as sinusoidal obstructive syndrome) within the liver
What can cause nodular regenerative hyperplasia?
•Chronic use of medications (commonly associated drugs include thiopurines, chemotherapeutic agents, and antiretroviral agents) can cause NRH
azathioprine- Treat autoimmune disease, transplant patient IBD
mercatopurine- Therapy for acute (lymphocytic,lymphoblastic) leukemia
•May be reversible with medication withdrawal
What’s this?
Nodular regenerative hyperplasia
There is sinusoidal dilation present (arrows). There are no inflammatory infiltrates, fibrosis and no areas of necrosis.
What are the SSXs of nodular regenerative hyperplasia?
- Nodular regenerative hyperplasia (NRH) is a form of noncirrhotic portal hypertension that can be caused by chronic use of medications.
- NRH typically presents with the insidious or unexpected onset of signs or symptoms of portal hypertension (weakness, ascites, splenomegaly, esophageal varices) in a patient with little evidence of chronic liver disease. The diagnosis is made by liver biopsy, showing absence of significant fibrosis and presence of nodularity usually best defined by reticulin staining. On superficial review, the liver biopsy may appear normal.
Serum enzymes are only modestly elevated and, by themselves, would be little matter of concern. The presence of jaundice, symptoms of fatigue and fluid overload with ascites and edema, however, indicates that the injury is potentially severe
What does nodular regenerative hyperplasia give rise to?
non-cirrhotic portal HTN
What is hepatic adenoma, and what is it associated with?
•Benign tumor of hepatocytes in young women taking oral contraceptives (increased 30-40 fold)
–If in males, associated with anabolic steroids
Why is the location of hepatic adenoma important?
•Subcapsular location prone to rupture especially in pregnancy. Resect if > 5cm or symptomatic, cessation of sex hormones can lead to full regression
Describe the histopathology of hepatic adenoma.
- Hepatocellular adenoma (HCA) is a benign neoplasm. HCA is composed of benign hepatocytes arranged in sheets and cords without acinar architecture. HCA lacks the central scar and large arteries of focal nodular hyperplasia.
- Diagnosis of HA is made on the basis of benign hepatocytes regularly arranged separated by non-dilated sinusoids but completely lacking portal tracts
What are the 3 subtypes of hepatic adenoma?
HNF1-alpha Inactivated hepatocellular adenoma
Beta-catenin activated hepatocellular adenomas
Inflammatory hepatocellular adenoma
What population is HNF1-alpha inactivated hepatocellular adenoma most commonly found in?
women
What is important pathologically about beta catenin activated hepatocellular adenomas?
•β-Catenin Activated Hepatocellular Adenomas (minority of adenomas)
–Very high risk for malignant transformation
–Often have a high degree of cytologic or architectural dysplasia
What populations does inflammatory hepatocellular adenoma affect?
both men and women
What is inflammatory hepatocellular adenoma associated with? Benign or malignant?
–Associated with non-alcoholic fatty liver disease
–Small but definite risk of malignant transformation
What’s this?
Hepatic adenoma
rounded smooth borders and no central scar
•Hepatic adenoma typically develop in women in the reproductive age group (15–45 years), nearly always associated with oral contraceptive steroid use. The incidence of OCP-related adenomas appears to have decreased in recent decades with the introduction of lower dose oral contraceptive preparations
What’s this?
Hepatic adenoma that lead to fatal hemorrhage
What’s this?
Hepatic adenoma
Arterial blood supply with no portal vein or bile duct
What are some important histological distinctions about hepatic adenomas?
- Adenomas have peripheral arterial vessels and lack the portal venous system and have sinusoids are similar to thin-walled capillaries. These aberrant vascular structures with extensive sinusoids and feeding arteries explain why adenomas are prone to bleeding.
- An additional characteristic finding is the absence of other portal tract elements: Hepatic adenoma contains no bile ducts or ductular structures. This finding is pivotal in the discrimination between adenoma and FNH, which does have bile ductules
What’s this?
Cavernous hemangioma
H & E - typical hemangioma with vascular channels
How are cavernous hemangiomas dx’ed?
Dx can be reliably made by several imaging modalities
What are the most common benign liver tumors?
Cavernous hemangiomas
What is the most common site of metastatic cancers from primary tumors of the colon, lung, and breast?
liver adenoma
What are hepatocelluar adenomas? How are they classified?
•Hepatocellular adenomas are benign tumors of neoplastic hepatocytes.
Most can be subclassified on the basis of molecular changes
What are the 3 classes of hepatocellular adenomas, and what are the salient features about each class?
–HNF1-α inactivated adenomas, with virtually no risk of malignant transformation, often associated with oral contraceptive pill use or in individuals with MODY-3
–β-Catenin activated adenoma, with mutations in the β-catenin gene leading to marked atypia and associated with a very high risk for malignant transformation
–Inflammatory adenomas, the hallmark of which is up-regulation of C-reactive protein and serum amyloid A (often derived from gp130 mutations); 10% of these have concomitant β-catenin activating mutations. Risk for malignant transformation is intermediate.
What are the malignant tumors of the liver?
Hepatoblastoma
Hepatocellular carcinoma
Cholangiocarcinoma
Angiosarcoma
Metastatic tumors - most common
What demographic is hematoblastoma associated with? Prognosis?
- Most common liver tumor of young childhood 90% before age of 5 years
- Usually fatal within first few years if not treated
What are the pathological variants of hepatoblastomas?
epithelial type
mixed epithelial-mesenchymal type
Describe the histology behind both epithelial type and mixed epithelial-mesenchymal type hepatoblastomas.
–Epithelial type composed of polygonal epithelial cells or embryonal cells growing in patterns recapitulating liver development
–Mixed epithelial-mesenchymal type contains mesenchymal elements, osteoid, cartilage, or striated muscle
What’s this?
Hepatoblastima
A lobectomy specimen, bulging from the surface with lobulations on cut screen
What’s this?
Hepatoblastoma, fetal epithelial type.
The tumour has a characteristic ‘light and dark’ appearance at low magnification.
What’s this?
Hepatoblastoma, mixed type, with osteoid. (H&E)
Mesenchymal components- primitive mesenchyme, osteoid, cartilage, striated muscle
What’s this?
Hepatoblastoma, mixed type. An area with primitive mesenchyme and cartilage. (H&E)
What causes hepatocellular carcinoma?
- Hepatocellular carcinogenesis secondary to viral infections (HBV, HCV) and toxic injury
- Majority of cases in the world are due to hepatitis B virus
Number of hepatitis C -associated cases increasing in the Western world.
- Cirrhosis is frequently present
- The most important underlying factors in hepatocellular carcinogenesis are viral infections (HBV, HCV) and toxic injuries (aflatoxin, alcohol)
How common is hepatocellular carcinoma?
- Most common primary hepatic malignancy of adults worldwide
- Significant male predominance
What toxins can cause hepatocellular carcinoma?
–Aflatoxin (Aspergillus mycotoxin moldy peanuts & grains)
What mutations are significant in hepatocellular carcinoma?
•Activation of β-catenin and inactivation of p53 are the two most common early mutational events.
What are the clinical features of hepatocellular carcinoma?
- Hepatocellular carcinoma is clinically silent and most patients present with advanced disease
- Upper abdominal pain, weight loss and signs of decompensated liver disease such as jaundice or ascites are frequent at presentation
- Elevated serum alpha-fetoprotein in 50% of patients (low sensitivity and specificity, not useful for screening
What is an important sequelae with hepatocellular carcinoma?
- The tumours can invade portal and hepatic veins and bile ducts and can destroy and replace functioning parenchyma in livers that are usually already compromised by cirrhosis,
- So that some patients present primarily with hepatic decompensation manifested by rapidly accumulating ascites, variceal hemorrhage, hepatic encephalopathy or obstructive jaundice.
- Patients who present with clinically evident disease are rarely candidates for any form of curative therapy.
- These patients have a median survival of 1 to 3 months and rarely survive beyond one year.
What is the method of choice for surveillance and detection of hepatocellular carcinoma in high risk patients?
ultrasound
What’s this?
CT scan showing multifocal hepatocellular carcinoma
•Can be multifocal in liver with intrahepatic metastases via vascular invasion
What’s this?
Hepatocellular carcinoma. Autopsy liver showing a massive neoplasm replacing most of the right hepatic lobe in a non-cirrhotic liver; a satellite tumor nodule is directly adjacent (arrow)
Occasionally arises in non-cirrhotic liver
What’s this?
Hepatocellular carcinoma associated with cirrhosis
- Usually associated with cirrhosis- Hepatitis B, Hepatitis C, Hemochromatosis
- The association of HCC with underlying chronic liver disease is so strong that development of cancer is frequently the terminal event for many patients with chronic liver disease.
What’s this?
Hepatocellular carcinoma associated with cirrhosis
What are the precursor lesions of hepatocellular carcinoma?
- Hepatocellular adenoma
- Chronic liver disease hepatocellular dysplasias
–Small cell change
–Large cell change
•Dysplastic nodules associated with cirrhosis
What’s this?
precursor lesion to hepatocellular carcinoma
Dysplastic foci showing small liver cell change (arrows).
What’s this?
precursor lesion to hepatocellular carcinoma
Dysplastic foci showing large liver cell change (arrows)
What’s this?
Well differentiated hepatocellular carcinoma
- Histologic appearance of HCC can range from well-differentiated to poorly differentiated lesions
- Vascular invasion is common
What’s this?
Hepatocellular carcinomain
•Cells look like hepatocytes
What’s this?
Hepatocellular carcinoma. Bile production in tumor cells and a dilated canaliculus. (H&E)
In well differentiated forms, tumor cells resemble hepatocytes, form cords and nests, and may contain bile pigment in cytoplasm.
What’s this?
Poorly differentiated hepatocellular carcinoma
with tumor anaplastic cells and tumor giant cells
What’s this?
Metastatic hepatocellular carcinoma
In well differentiated forms, tumor cells resemble hepatocytes, form cords and nests, and may contain bile pigment in cytoplasm.
- Vascular invasion is common
- Most common sites of metastasis are lung, intra-abdominal lymph nodes, bone, and adrenal gland
What demographics are associated with hepatocellular carcinoma fibrolamellar variant?
•85% occur under the age of 35 without gender predilection
What is the prognosis for hepatocellular carcinoma fibrolamellar variant? Any associations?
- Tumors are slow-growing and frequently surgically resectable
- Five-year survival rates range from 30 to 75%
- Fibrolamellar hepatocellular carcinoma seems to be a different biological entity from other types of HCC.
What are the gross and histological manifestations of hepatocellular carcinoma fibrolamellar variant?
- Fibrolamellar tumours are typically hard, due to the presence of fibrous stroma
- Tumour cells are larger than normal liver cells and have a deeply eosinophilic coarsely granular cytoplasm (large number of mitochondria in cytoplasm)
- arise from hepatocytes, some have considered these to be a subtype of HCC, while others have suggested that they are actually more closely related to cholangiocarcinoma.
•In most series, the clinical behaviour has been more like that of HCC and so they are often considered a special subtype of HCC rather than a separate tumour.
What’s this?
Fibrolamellar hepatocellular carcinoma. Nests of brightly eosinophilic tumour cells in a fibrous stroma. (H&E)
What’s this?
Fibrolamellar hepatocellular carcinoma. The fibrous stroma is composed of bundles of collagen arranged in parallel lamellae. (Trichrome stain)
- The stroma consists of thick, hyalinized bundles of collagen as well as thinner collagen and reticulin fibres that support individual and small groups of tumour cells.
- The bundles of collagen tend to be arranged in parallel lamellae of varied thickness, hence the name fibrolamellar
What are the key concepts behind hepatocellular carcinomas?
- The main primary malignancies are Hepatocellular carcinomas (HCCs) and cholangiocarcinomas
- HCCs are by far the most common.
–HCC is a common tumor in regions of Asia and Africa, and its incidence is increasing in the United States.
–The main etiologic agents for HCC are chronic hepatitis B and C, alcoholic cirrhosis, non-alcoholic fatty liver disease, and hemochromatosis. In the Western population, about 90% of HCCs develop in cirrhotic livers; in Asia, almost 50% of cases develop in noncirrhotic livers.
–The chronic inflammation and cellular regeneration associated with viral hepatitis or the activation of IL-6/JAK STAT pathway may be predisposing factors for the development of carcinomas.
–HCCs may be unifocal or multifocal, tend to invade blood vessels, and recapitulate normal liver architecture to varying degrees.
