Liver Pathology III: Hepatocellular Carcinoma PDF

Liver Pathology III: Hepatocellular Carcinoma, Oral Manifestations Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the most common form of liver cancer o Most primary liver cancers (originating from liver) are HCC o Aggressive (fast-growing) cancer most common in people w advanced liver d...

Liver Pathology III: Hepatocellular Carcinoma, Oral Manifestations Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the most common form of liver cancer o Most primary liver cancers (originating from liver) are HCC o Aggressive (fast-growing) cancer most common in people w advanced liver dz (such as liver cirrhosis = ‘end stage’) Initially, hepatocellular carcinoma grows slowly o Surgery to remove tumor or liver transplant can treat HCC in its early stages More common in men > 60 years old Causes 4 major etiologic factors: (1) Chronic alcoholism/cirrhosis o ROS production o LPS from dead bacteria causing inflammation o FA synthesis (Excess NADH leads to synthesis of TG) (2) Viral Induced Hepatocarcinogenesis (HBV, HCV, HDV) o HBV leads to HCC w/o cirrhosis, has DIRECT oncogenic effect by integration of HBV DNA into host genome § Induces genetic instability/mutagenesis of cancer genes o HCV works exclusively w advanced cirrhosis (indirect oncogenic effect, advanced liver damage is already present) § Oxidative stress § Cell proliferation § Alternation of apoptotic pathway (3) Toxin Induced Hepatocarcinogens Aflatoxin (microtoxin) comes o Aflatoxins B1 reacts w DNA to form mutagenic adducts (leads to dysplasia) from excessive ingestion of o Alcohol grain, corn, peanuts o Tobacco (4) Non-Alcoholic Fatty Liver Dz (NAFLD) o Due to metabolic syndrome (ex. insulin resistance, 3 out of 5 metabolic syndrome must be present to diagnose NAFLD) o Metabolic syndrome (3 of 5): Obesity, HTN, Diabetes, Hypertriglyceridemia, Hyperlipidemia (↑ LDL, ↓ HDL) Continuous cycle of proliferation and degeneration leads to CHRONIC liver disease o Histologic features of cirrhosis § Caused by HBV, HCV, Alc, AflatoxinB1 § Proliferation and degeneration causes necrosis § Proliferation arrests and HSC activated (create fibrotic tissues via collagen) leading to cirrhosis § Abnormal nodules in cirrhosis become hyperplastic leading to moderate genomic instability § After instability, these nodules become dysplastic à HCC o HCC cells classified as: § Well Differentiated § Moderately Differentiated § Poorly Differentiated (worst one) HCC Pathogenesis 2 mechanisms of pathogenesis of HCC o Two most common early mutational events: § β-catenin activation: Protein that regulates proliferation, differentiation, apoptosis of liver cells § Inactivation of p53 (tumor suppressor gene): associated with aflatoxin Repeated cycles of cell death and regeneration, such as seen in chronic hepatitis of any cause o Continuous cell division damages DNA repair mechanisms with subsequent accumulation of mutations o IL-6 (inflamm. cytokine) increases signaling pathway, resulting in lack of differentiation and uncontrolled proliferation HCC Morphology Morphology occurs in different size and shapes o More pale than surrounding liver o Varying color (green- malignant hepatocytes are secreting bile) May be unifocal, multifocal, or diffusely infiltrative o Unifocal: one large/massive mass at a single location, well differentiated o Multifocal: multiple large masses spread throughout, well differentiated o Diffuse: multiple tiny nodules spread w no dominant nodule, poorly differentiated o Well-differentiated § Resembles normal hepatocytes with trabecular or pseudoglandular architecture § No portal triads in tumor o Moderately differentiated o Poorly differentiated § Anaplastic (rapidly dividing, little/no resemblance to normal cells) § Tumor cells varying from large giant cells à to small cells à to spindled sarcomatous appearance Intrahepatic metastasis (mets) o Spread of cancer cells in liver o Due to direct extension or vascular invasion (small tumor nodules scattered around dominant mass) o Invasion of portal vein causes occlusion of portal circulation or inferior vena cava Extrahepatic metastasis occurs at advance stage of HCC o Spreads from liver to other organs o Lung mets occur late in disease o Lymph node mets HCC Diagnosis Blood test and imaging scan results are NOT definitive for diagnosis Blood test: Alpha-fetoprotein (AFP) o Tumor marker o Normal range 10-20 ng/ml o HCC > 400 ng/ml o Elevated AFP: HCC or a condition that can lead to HCC (ex. hepatitis or cirrhosis of liver) o If this cannot be determined then move to imaging scans Imaging scans show tumors or signs of tumor o Ultrasound o Computed tomography (CT) scan o Magnetic resonance imaging (MRI) o Angiography o If this cannot be determined then move to biopsy Liver biopsy o Biopsy tumor to test tissue for cancer cells HCC Treatment Medical Therapy o Surgery: Hepatectomy or Liver transplant (hepatectomy removes part of liver, remember the liver can regenerate) o Ablation therapy: Needle to burn tumors (Very hot, cold to burn tumor) o Embolization: Implants a substance that stop blood flow toward the tumor to kill it o Radiation therapy: NOT for large tumors, ONLY small that can’t be removed with surgery or ablation o Immunotherapy: Medicines to help immune system identify and fight cancer cells o Targeted therapy: Drugs/substance specifically bind to receptor of tumor cells, a radioactive particle enters, killing cancer cell (Side note: Chemotherapy kills any cell that is multiplying, Chemo is NOT targeted therapy) Lifestyle Changes o Stop drinking alcohol and smoking o Maintain a healthy weight Treat underling cause (HBV, NALFD..) Oral Manifestations of Liver Disease Pts w chronic liver disease in general have poor oral health with several oral symptoms and signs. Signs are causal, secondary to therapeutic interventions, or attributable to other factors that patients with liver disease may have in common In these patients, chronic periodontal disease is a common finding Liver dysfunction is reflected in the oral cavity: o Mucosal membrane jaundice o Bleeding disorders (lack of clotting factors, platelet problems- thrombocytopenia) o Petechiae o Vulnerable to bruising easily o Gingivitis o Gingival bleeding o Fetor hepaticus (a characteristic odor of advanced liver disease) o Cheilitis o Tongue (smooth, atrophic and fissured) o Xerostomia o Bruxism o Crusted perioral rash Liver synthesizes bile acid, and bile absorbs nutrients in health o Oral lichen planus Nutrients do NOT absorb when liver is damaged Impairment of Mucosal Integrity Depletion of iron, VitB12 or folic acid (common in liver dz) due to: o Impaired absorption o Altered metabolism o Portal HTN: Shunts blood away from liver, increased BP will not allow nutrients for liver o Blood loss: leading to Iron deficiency anemia Oral mucosal membrane is similar to inner lining of intestine, hence similar lesions are found in oral cavity and other parts of GI Oral Lichen Planus (OLP) Common chronic inflammatory condition that affects skin and mucous membranes Strong link exists btwn HCV and OLP Biopsy early for diagnosis: Small percentage of OLP progress to squamous cell carcinoma Hyperbilirubinemia From liver/gallbladder dysfunction o Yellow tint of the sclera, skin and inside mouth (jaundice) o Greyish-green discoloration of dentin due to bile leakage GERD Common in chronic liver disease Acidic regurgitation causes tooth erosion Tooth erosion: enamel pH falls < 5.5 Xerostomia Subjective feeling of dry mouth Common in liver disease patients and detrimental to oral health and quality of life Primary biliary cirrhosis (PBC) is caused by chronic liver disease leading to dry eyes, dry mouth and both biliary and pancreatic hyposecretion, aka “Dry gland syndrome” Dry mouth is a major risk factor for dental caries Impaired salivary flow due to: o Systemic diseases and many medications § Susceptible to periodontitis § Susceptible to mucosal lesions (such as candidiasis, angular cheilitis, and painful stomatitis) § All have been reported in chronic liver disease (caries, dry mouth, periodontitis, mucosal lesions) Permanent Teeth discolored Early childhood liver disease Biliary atrasia: duct blocked that carries bile from liver to gallbladder Tongue Fissured tongue: Common in dry mouth, prevalence in liver disease is around 30–40% Smooth, atrophic tongue: Typical in alcohol-related liver disease Gum Bleeding Increased risk of bleeding is PRIMARY adverse effect in patients with compromised liver function Cirrhotic patients have imbalance of coagulation system bc of defects in both prothrombotic and antithrombotic components, which increases gingival bleeding o Advanced liver disease: Vit K significantly reduced (Vit K helps w clotting, low Vit K = poor clotting) o Decrease coagulation factors produced o Portal HTN scavenges platelets formed in the spleen, leading to thrombocytopenia (↓ platelet count) Periodontal Infections Chronic liver disease CAUSES poor oral health and hygiene Poor oral health and hygiene = caries 25% - 70% have periodontal disease when diagnosed with liver cirrhosis Tooth ext may be needed due to severe caries (deep caries reaching pulp, root tips, apical periodontitis in non-restorable teeth) Tooth ext must be performed BEFORE liver transplant to prevent its complications Gum oral microbiome axis o Causes periodontal disease o Liver cirrhosis with compromised immune system causes gut dysbiosis (increase bad bacteria) o Due to gut-oral microbiome axis, bad metabolites reach oral cavity o Increasing pathogenic oral bacteria lead to Periodontal infections and diseases Dental Management from Liver Disease MANAGEMENT needed for oral infections during liver disease o Cross-infection management: § HBV and HCV: high risk in dental office due to transmission routes (blood and oral secretions of infected pts) § Accidents with sharp or cutting instruments § Manage by correct sterilization and disinfection measures o Bleeding management § Treatment determined based on lab tests: fresh plasma, platelets and vitamin K may be advisable o Medication intake management § Drug metabolism is altered in liver disease § Consult pt’s physician to establish which drugs are being taken, doses and interactions § Drugs metabolized in liver have to be used with extra caution or doses need to be reduced Active oral disease must be treated BEFORE liver transplant to prevent further more oral infections Dental treatment plan is tailored based on severity of liver disease with emphasis on PREVENTATIVE measures All oral diseases can be prevented through good oral hygiene practices