PATHOLOGY Flashcards
Reversible cell injury
- Decrease ATP –> decrease activity of Ca2+ and Na+/K+ pumps –> cellular swelling (earliest morphologic manifestation), mitochondrial swelling
- Ribosomal/polysomal detachment –> decrease protein synthesis
- Plasma membrane changes (eg, blebbing)
- Nuclear changes (eg, chromatin clumping)
- Rapid loss of function (eg, myocardial cells are noncontractile after 1-2 minutes of ischemia)
- Myelin figures (aggregation of peroxidized lipids)
Irreversible cell injury
- Breakdown of plasma membrane –> cytosolic enzymes (eg, troponin) leak outside of cell, influx of Ca2+ –> activation of degradative enzymes
- Mitochondrial damage/dysfunction –> loss of electron transport chain –> decrease ATP
- Rupture of lysosomes –> autolysis
- Nuclear degradation –> pyknosis (nuclear condensation) –> karyorrhexis (nuclear fragmentation caused by endonuclease-mediated cleavage) –> karyolysis (nuclear dissolution)
- Amorphous densities/inclusions in mitochondria
Red (hemorrhagic) Infarct
- Occurs in venous occlusion and tissues with multiple blood supplies (eg, liver, lungs, intestine, testes), and with reperfusion (eg, after angioplasty).
- Reperfusion injury is due to damage by free radicals.
Pale (anemic) Infarct
Occurs in solid organs with a single (end- arterial) blood supply (eg, heart, kidney, spleen).
TGF-β
Angiogenesis
Fibrosis
FGF
Stimulates angiogenesis
VEGF
Stimulates angiogenesis
PDGF
- Secreted by activated platelets and macrophages
- Induces vascular remodeling and smooth muscle cell migration
- Stimulates fibroblast growth for collagen synthesis
Metalloproteinases
Tissue remodeling
EGF
Stimulates cell growth via tyrosine kinases (eg, EGFR/ErbB1)
Brain Metastases Primary Tumor
Lung > breast > melanoma, colon, kidney
Lots of Brain Metastases Can Kill
Bone Metastases Primary Tumor
Prostate, breast > kidney, thyroid, lung
Painful Bones Kill The Lungs
Liver Metastases Primary Tumor
Colon >> stomach > pancreas
Cancer Sometimes Penetrates liver
Mention Oncogenes
ALK
BCR-ABL
BCL-2
BRAF
c-KIT
c-MYC
CDK4
CCND1
ERBB1
HER2/neu (c-erbB2)
JAK2
KRAS
MYCL1 (L-myc-1)
N-myc (MYCN)
RET
Mention Tumor Suppressors
APC
BRCA1/BRCA2
CDKN2A
DCC
SMAD4 (DPC4)
MEN1
NF1
NF2
PTEN
RB1
TP53
TSC1
TSC2
VHL
WT1
WT2
ALK
Oncogene (chromosome 2)
- Receptor tyrosine kinase
- Associated with lung adenocarcinoma
BCR-ABL
- Oncogene
- Non-receptor tyrosine kinase
- Associated with CML, ALL
BCL-2
- Oncogene (chromosome 18)
- Antiapoptotic molecule
- Associated with follicular lymphoma, diffuse large B cell lymphoma
BRAF
- Oncogene (chromosome 7q34)
- Serine/threonine kinase
- Associated with melanoma, non-Hodgkin lymphoma, papillary thyroid carcinoma, hairy cell leukemia
c-KIT
- Oncogene (chromosome 4q12)
- Cytokine receptor
- Associated with gastrointestinal stromal tumors, mastocytosis
c-MYC
Oncogene (chromosome 8) Transcription factor Associated with Burkitt lymphoma
CDK4
Oncogene (chromosome 12) Cyclin-dependent kinase Associated with liposarcoma, melanoma, glioblastoma multiforme
CCND1
Oncogene (chromosome 11) Cyclin D (regulatory protein of the cell cycle) Associated with mantle cell lymphoma
ERBB1
Oncogene (chromosome 7) Epidermal growth factor receptor (EGFR) Associated with non-small cell lung cancer
HER2/neu (c-erbB2)
Oncogene (chromosome 17q12) Receptor tyrosine kinase Associated with breast cancer, gastric cancer
JAK2
Oncogene (chromosome 9p24) Non-receptor tyrosine kinase Associated with chronic myeloproliferative disorders
KRAS
Oncogene (chromosome 12) GTPase Associated with colorectal cancer, lung cancer, pancreatic cancer
MYCL1 (L-myc-1)
Oncogene (chromosome 1) Transcription factor Associated with lung cancer
N-myc (MYCN)
Oncogene (chromosome 2) Transcription factor Associated with neuroblastoma
RET
Oncogene (chromosome 10) Receptor tyrosine kinase Associated with papillary thyroid cancer, pheochromocytoma, MEN 2A and MEN 2B
APC
Tumor Suppressor (chromosome 5) A protein that prevents unregulated cell proliferation by inhibiting β-catenin synthesis → inhibition of the β-catenin/Wnt pathway (β-catenin is involved in the Wnt pathway, which stimulates cell proliferation) Associated with familial adenomatous polyposis (associated with colorectal cancer), sporadic colorectal cancer
BRCA1
Tumor Suppressor (chromosome 17) DNA repair protein Associated with breast cancer, ovarian cancer, pancreatic cancer
CDKN2A
Tumor Suppressor (chromosome 9) p16 protein, which normally causes cell cycle arrest at the G1 phase Associated with melanoma, pancreatic cancer, lung cancer
DCC
Tumor Suppressor (chromosome 18) Transmembrane receptor involved in cell apoptosis Associated with colorectal cancer
SMAD4 (DPC4)
Tumor Suppressor (chromosome 18) A DNA binding protein involved in signal transduction from TGF-β receptors Associated with pancreatic cancer
MEN1
Tumor Suppressor (chromosome ) Associated with
NF1
Tumor Suppressor (chromosome 17) Neurofibromin (Ras GTPase-activating protein) Associated with neurofibromatosis type 1
NF2
Tumor Suppressor (chromosome 22) Merlin (schwannomin) Associated with neurofibromatosis type 2
PTEN
Tumor Suppressor (chromosome 10) Negatively regulates the PI3k/AKT pathway Associated with prostate cancer, endometrial cancer, breast cancer, Cowden syndrome
RB1
Tumor Suppressor (chromosome 13) Causes cell cycle arrest at the G1 phase by inhibiting E2F transcription factor Associated with retinoblastoma, osteosarcoma
TP53
Tumor Suppressor (chromosome 17) Causes cell apoptosis Activates proapoptotic genes (e.g., BAX) Causes cell cycle arrest at the G1 phase (by activating p21) Inhibits entry in the S phase via inhibition of pRb phosphorylation Associated with most human cancers, Li-Fraumeni syndrome
TSC1
Tumor Suppressor (chromosome 9) Hamartin protein Associated with tuberous sclerosis
TSC2
Tumor Suppressor (chromosome 16) Tuberin protein Associated with tuberous sclerosis
VHL
Tumor Suppressor (chromosome 3) Protein involved in the degradation of hypoxia-inducible factor 1a Associated with Von Hippel Lindau disease
WT1
Tumor Suppressor (chromosome 11) Transcription factor that regulates urogenital development Associated with nephroblastoma (Wilms tumor)
WT2
Tumor Suppressor (chromosome 11) Transcription factor that regulates urogenital development Associated with nephroblastoma (Wilms tumor)
BRCA2
Tumor Suppressor (chromosome 13) DNA repair protein Associated with breast cancer, ovarian cancer, pancreatic cancer
Benzene Carcinogen
Ocurrece: Gasoline Cigarette smoke Associated malignancy: Acute leukemia Non-Hodgkin lymphoma
Nitrosamines Carcinogen
Occurrence: Cured meats (e.g. bacon) and fish Cold-smoked foods (the major carcinogens produced during the smoking process (both cold and hot) are the polycyclic aromatic hydrocarbons, chemicals that are formed during the burning of solid fuels (e.g., wood, coal)) Tobacco Associated malignancy: Gastric cancer
Vinyl chloride Carcinogen
Occurrence: Production of polyvinyl chloride (PVC) and PVC-related manufacturing (e.g., of PVC pipes, cables) Associated malignancy: Lung cancer Hepatocellular carcinoma Glioblastoma Angiosarcoma
Aromatic amines (β-naphthylamine, benzidine) Carcinogen
Occurrence: Tobacco smoke Dyes (occupational exposure in the textile industry) Rubber Associated malignancy: Bladder cancer (transitional cell carcinoma)
Asbestos Carcinogen
Occurrence: Insulation material (formerly used in construction and shipbuilding) Asbestos cement (fibrolite), roofing, and siding Associated malignancy: Lung cancer (bronchogenic carcinoma) Mesothelioma The risk of developing bronchogenic carcinoma is greater than that of developing mesothelioma.
Wood dust Carcinogen
Occurrence: Woodworking (e.g., sawing, drilling, sanding) Associated malignancy: Adenocarcinoma of the nose and paranasal sinuses
Ethanol Carcinogen
Occurrence: Alcoholic beverages Associated malignancy: Squamous cell carcinoma of the esophagus Hepatocellular carcinoma (HCC) Breast cancer
Alkylating agents Carcinogen
Occurrence: Chemotherapeutic agents (e.g., cyclophosphamide, melphalan, busulfan, carmustine) Associated malignancy: Leukemia Lymphoma
Cigarette smoke Carcinogen
Occurrence: First-hand smoke (smoke inhaled by the smoker) Second-hand smoke (exhaled smoke that is inhaled by others in the vicinity of the smoker) Third-hand smoke (smoke particles that adhere to surfaces in the surroundings of the smoker) All three have been proven to be carcinogenic. Associated malignancy: Transitional cell carcinoma of the bladder Squamous cell carcinoma (cervix, oropharynx, esophagus, larynx, lung) Small cell lung cancer Pancreatic adenocarcinoma Adenocarcinoma of the esophagus Renal cell carcinoma
Radon Carcinogen
Occurrence: Accumulates in basements (a byproduct of uranium decay) Uranium is found in soil. The natural radioactive decay of uranium produces radon. Radon can accumulate in basements that are in direct contact with soil. Associated malignancy: Lung cancer (radon is the second most common cause following exposure to cigarette smoke)
Aflatoxin Carcinogen
Occurrence: Stored nuts and grains (Aspergillus flavus growth) Associated malignancy: HCC
Arsenic Carcinogen
Occurrence: Contaminated groundwater (esp. in developing countries) Pesticides, herbicides (e.g., vineyard workers) Metal smelting Associated malignancy: Lung cancer Squamous cell carcinoma Hepatic angiosarcomas
Beryllium Carcinogen
Occurrence: Occupations that involve beryllium production and processing (esp. melting and founding, welding manufacturing [industrial ceramics, electronics, automotive, aerospace, and defense components, dental supplies and prostheses]) Associated malignancy: Lung cancer
Silica Carcinogen
Occurrence: Occupations that involve cutting, drilling, chipping, or grinding crystalline silica (e.g., quartz) or materials that contain it (e.g., sand, granite), esp. sandblasting, glass manufacturing, construction work Associated malignancy: Lung cancer
Chromium
Occurrence: Significant in workers exposed to galvanization (chrome plating), paint and glass manufacturing, tanning leather, building materials Associated malignancy: Lung cancer
Nickel
Occurrence: Occupations that involve mining, smelting, welding, and casting of alloys (e.g., in coins, jewelry) Associated malignancy: Lung cancer
Nonionizing radiation
Occurrence: UV-B Associated malignancy: Skin cancers
Ionizing radiation
Occurrence: X-rays Gamma rays Associated malignancy: Leukemias (especially AML and CML) Papillary thyroid cancer Osteosarcoma Liver angiosarcoma
Apoptosis Histopathological Findings
- Shrunken and irregularly shaped cells with condensed chromatin and membrane blebbing - The cell detaches from other cells or the extracellular matrix. - The basophilic nucleus undergoes the following changes: 1. Pyknosis 2. Kareyorrhexis 3. Karyolysis - The eosinophilic cytoplasm and cell organelles form small bubbles and the endonucleases degrade the chromatin in the nucleus, resulting in nuclear fragmentation and apoptotic bodies that are phagocytized by macrophages. - DNA laddering (fragments in multiples of 180 base pairs) is seen on gel electrophoresis and can be used as a sensitive marker for apoptosis.
Coagulative Necrosis
Seen in: Ischemia/infarcts in most tissues (except brain) Myocardial, splenic, hepatic, and renal infarction Gangrene Organ damage caused by acidic solutions Due to: Ischemia or infarction; injury denatures enzymes –> proteolysis blocked Decreased oxygen delivery → ↓ ATP -Anaerobic metabolism → ↑ lactic acid production → ↓ pH → denaturation of proteins (including proteolytic enzymes) → cell death -Impaired Na+/K+-ATPase → ↑ intracellular Na+ → ↑ intracellular H2O → cell swelling Histology: Preserved cellular architecture (cell outlines seen) due to denaturation of lytic enzymes and disrupted proteolysis Cells become anucleated with eosinophilic cytoplasm Leukocytes eventually infiltrate necrotic tissue and digest cellular debris Increase cytoplasmic binding of eosin stain (–> increase eosinophilia; red/pink color)
Liquefactive Necrosis
Seen in: Focal bacterial infections that stimulate massive leukocyte recruitment, bacterial abscesses (purulent infection), brain infarcts due to lack of substantive supporting stroma, pancreatitis (due to enzymatic damage to the parenchyma), organ damage caused by alkaline solutions Due to: Neutrophils release lysosomal enzymes that digest the tissue forming a viscous liquid mass. Necrotic fluid is often creamy yellow due to presence of dead leukocytes (pu) Tissue softening → fluid necrosis → cavitation, pseudocyst formation Histology: Early → cellular debris and macrophages Late → cystic spaces and cavitation (brain) Neutrophils and cell debris seen with bacterial infection Brain infarcts eventually resolve into CSF-filled spaces
Caseous Necrosis
Seen in: TB, systemic fungi (eg, Histoplasma capsulatum, Coccidioides, Cryptococcus), Nocardia Due to: Macrophages, epitheloid cells, and multinucleated giant cells (Langhans giant cell) surround a site of infection → granular debris Histology: Fragmented cells and debris, surrounded by lymphocytes, epitheloid cells, and multinucleated giant cells, forming a granuloma Necrotic tissue has a cheesy tan-white gross appearance and consist of fragmented cells and acellular proteinaceous material
Fat Necrosis
Seen in: Enzymatic: acute pancreatitis (saponification of peripancreatic fat) Nonenzymatic: traumatic (eg, injury to breast tissue) Due to: A type of necrosis in which adipose cells die off prematurely, either caused by an enzymatic reaction, or traumatic injury. Enzymatic fat necrosis (release of lipase and triglycerides from cytoplasm of damaged cells → breakdown of triglycerides by lipase → binding of fatty acids to calcium → saponification → chalky-white appearance) Infiltrating foamy macrophages containing engulfed lipid debris and release of free fatty acids that combine with calcium to form basophilic deposits. Histology: Outlines of adipocytes with no peripheral nuclei Combination of fat saponification and calcium → dark blue appearance on H&E stain
Fibrinoid Necrosis
Seen in: Rheumatoid arthritis Peptic ulcer disease Immune vasculitis (e.g., polyarteritis nodosa) Vascular reactions Preeclampsia Hypertensive emergency Due to: Vessel wall damage caused by immune complex deposition (e.g., due to type III hypersensitivity reaction) → fragmentation of collagenous and elastic fibers → leakage of fibrin and other plasma proteins Histology: Vessel walls are thick and pink Visible damage → thick walls with fragments of embedded cellular debris, serum, and fibrin Affected necrotic areas stain intense red.
Gangrenous Necrosis
Seen in: Peripheral arterial disease Acute limb ischemia Intestinal ischemia Clostridium perfringens (gas gangrene) Sepsis Due to: Dry → ischemia Wet → superinfection of dry gangrene Histology: Dry → Coagulative Wet → Liquefactive superimposed on coagulative
Necrosis Histopathological Findings
-Large group of cells, tissues, or organs -Cell swelling, cell blebbing, cell organelle destruction, nuclear changes → cell bursts → inflammation (especially with an influx of neutrophils) → degradation of the necrotic tissue by leukocytes → organization of granulation tissue
Carbon Tetrachloride (CCl4) Toxicity
Conversion into CCl3 free radical by cytochrome P450 → fatty liver → cell injury → ↓ apolipoprotein synthesis → fatty change, centrilobular necrosis
Mallory bodies
Intracellular hyaline Inclusion bodies within the cytoplasm of hepatocytes that contain damaged intermediate filaments and appear eosinophilic (pink) on H&E stain Most common in alcoholic liver disease
Councilman bodies
Intracellular hyaline An eosinophilic remnant of apoptotic hepatocytes with pyknosis Particularly in yellow fever and viral hepatitis
Schaumann bodies
Intracellular hyaline Round calcium and protein inclusions in the cytoplasm with laminar stratification In granulomas in sarcoidosis
Russell bodies
Intracellular hyaline Accumulation of immunoglobulins Plasma cells in plasmacytoma or chronic inflammation
Primary Amyloidosis
(Light-chain amyloidosis, AL-amyloidosis)
- Most common form of amyloidosis in resource-limited nations Fibril Protein → AL (from Ig Light chains)
- Associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenstrom macroglobulinemia)
- Increased production of the light chains of immunoglobulins → deposition of amyloid light chain protein (AL protein) in various organs
- Rapidly progressive clinical course (the mean survival time without treatment is one year)
- Heart → restrictive cardiomyopathy, atrioventricular block
- Kidney → nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
- Tongue (macroglossia → obstructive sleep apnea)
- Autonomic nervous system → autonomic neuropathy
- Gastrointestinal tract → malabsorption
- Hematopoietic system → bleeding disorders, splenomegaly
- Musculoskeletal system → carpal tunnel syndrome
Secondary Amyloidosis
(Reactive amyloidosis, AA-amyloidosis) Secondary disease - Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever) - Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis) - Certain tumors (e.g., renal cell carcinoma, lymphomas) Chronic inflammatory process → ↑ production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs Clinical Features: -Rarely present with features of cardiac involvement. - Kidney → nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus - Adrenal glands → primary adrenal insufficiency - Liver and spleen → hepatomegaly, splenomegaly - Gastrointestinal tract → malabsorption - Musculoskeletal system → carpal tunnel syndrome
Senile Cardiac Amyloidosis
Normal (wild-type) transthyretin (ATTRwt) → deposition in cardiac ventricles → cardiac dysfunction (less drastic than in AL amyloidosis) Associated with old age
Isolated Atrial Amyloidosis
ANP → ↑ risk of atrial fibrillation Physiological in old age
Cerebral amyloidosis
Aβ (cleaved from the APP) → associated with Alzheimer disease APrP → associated with prion diseases
Endocrine amyloidosis
Islet amyloid polypeptide (IAPP) deposits in pancreatic islet → associated with type 2 diabetes mellitus Amyloid at insulin injection site (AIns) → associated with subcutaneous insulin injection in diabetes mellitus Calcitonin amyloid (ACal) → associated with medullary carcinoma of the thyroid
Familial amyloid cardiomyopathy
Mutated transthyretin (ATTR) Autosomal dominant disease (most common) > 20 years Deposition in ventricular endomyocardium → restrictive cardiomyopathy Atrial deposition → arrhythmia Common in African Americans (3% of African Americans carry the mutant allele for familial amyloid cardiomyopathy)
Familial amyloid polyneuropathy (FAP)
Mutated transthyretin (ATTR) Autosomal dominant disease (most common) > 20 years Affected sites → peripheral and autonomic nerves Common in Portugal, Sweden, Japan, and among people of Irish descent
Familial Mediterranean fever (FMF)
AA amyloid protein Autosomal recessive disease < 20 years Affected sites → Kidney, liver and spleen, adrenal glands Common among individuals of Mediterranean descent (e.g., Sephardic Jews, Arabs, Turks) Two types of FMF: -Type 1 FMF (characterized by recurrent episodes of polyserositis (pleuritis, pericarditis, peritonitis). Amyloidosis is a late feature.) -Type 2 FMF (asymptomatic until symptoms of amyloidosis occur)
Radiation-Related Malignancies
Papillary thyroid carcinoma Myelodysplastic syndromes, lymphomas, leukemias (eg, CML, AML, ALL) Angiosarcoma Osteosarcoma Solid tumors (eg, breast, ovarian, lung)
Acute Phase Reactants
Factors whose serum concentrations change by > 25% during periods of inflammation Produced by the liver in both acute and chronic inflammatory states Notably induced by IL-6 Positive (upregulated): C-reactive protein Ferritin Fibrinogen Hepcidin Serum amyloid A Ceruloplasmin Haptoglobulin von Willenbrand factor Complement Negative (downregulated): Albumin Transferrin Transthyretin (prealbumin)
Increase ESR
Inflammation (eg, giant cell [temporal] arteritis, polymyalgia rheumatica) Infection Malignancies (e.g., multiple myeloma, Waldenstrom macroglobulinemia, metastases) Autoimmune diseases (e.g., SLE, rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, de Quervain thyroiditis) Anemia Macrocytosis Renal disease (e.g., nephrotic syndrome, ESRD) Pregnancy (leads to ↑ fibrinogen) Old age
Decrease ESR
-Polycythemia (the increased number of RBCs lowers the concentration of aggregation factors) -Sickle cell disease (irregular and smaller RBCs sink slower) -Spherocytosis -Microcytosis -Leukocytosis with very high WBC count (e.g., in chronic lymphocytic leukemia) -Congestive heart failure (CHF) (ESR correlates inversely with the severity of CHF) -Hypofibrinogenemia (e.g., in DIC) -Hypogammaglobulinemia
Margination and Rolling
E-selectin (upregulated by TNF and IL-1) → Sialyl LewisX P-selectin (released from Weibel- palade bodies) → Sialyl LewisX GlyCAM-1, CD34 → L-selectin Defective in leukocyte adhesion deficiency type 2 (Sialyl LewisX) The two main mechanisms that allow for margination are: 1. Rouleaux formation - The liver releases increased amounts of fibrinogen in response to cytokines released by macrophages, monocytes, and other cells near the site of inflammation. - Increased fibrinogen → rouleaux formation → neutrophils are pushed against endothelium of the venules 2. Dilation of post-capillary venules - The release of inflammatory mediators results in vasodilation of the post-capillary venules. - As these venules expand, the velocity of blood flow in these areas slows, causing neutrophils to marginate against the endothelium of the venules. - The venules are the segment of microvasculature most sensitive to inflammation. Their intercellular endothelial junctions open to allow for the flow of plasma proteins and leukocytes between cells.
Tight Binding (Adhesion)
ICAM-1 (CD54) → CD11/18 integrins (LFA-1, Mac-1) VCAM-1 (CD106) → VLA-4 integrin Defective in leukocyte adhesion deficiency type 1 (CD18 integrin subunit)
Diapedesis (Transmigration)
Transmigration of leukocytes across endothelial barriers (can occur paracellularly or transcellularly) Mechanism: - Leukocytes leave the blood vessel by moving between endothelial cells. - Neutrophils release type IV collagenase, which dissolves the basement membrane and allows them to exit the interstitial space. - Requires expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, also called CD31) on neutrophils, endothelial cells, and platelets PECAM-1 (CD31) → PECAM-1 (CD31)
Migration
WBC travels through interstitium to site of injury or infection guided by chemotactic signals Chemotactic factors → C5a, IL-8, LTB4, kallikrein, platelet-activating factor (PAF), N-formylmethionyl peptides
Phagocyte Recognition Receptors & Their Ligands
Mannose receptor → mannose, fucose, N-acetylglucosamine Scavenger receptor → low-density lipoprotein Opsonin receptor → Fc fragment of IgG, C3b
Granulomatous inflammation by immune-mediated diseases
Sarcoidosis Crohn disease Subacute thyroiditis (de Quervain) Primary biliary cholangitis
Granulomatous Inflammation by Vasculitis
Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Giant cell arteritis Takayasu arteritis
Granulomatous Inflammation by Foreign Body Exposure
Berylliosis Talcosis Hypersensitivity pneumonitis Breast implants Penetrating trauma with glass, wood, etc.
Acute Phase Reactants
C-reactive protein (CRP) Procalcitonin Ferritin Hepcidin Haptoglobin Serum amyloid A (SAA) Fibrinogen Von Willebrand factor α1-antitrypsin Interleukin-6 (IL-6) Ceruloplasmin Complement components
C-reactive protein (CRP)
Promotes the opsonization of pathogens, which leads to increased phagocytosis by macrophages Activates the complement system High sensitivity for detecting inflammation but not specific to any disease or organ Increases 6–12 hours after the inflammatory process begins Half-life is 24 hours.
Procalcitonin
Sensitive parameter for monitoring the progression of bacterial infections, especially pneumonia and sepsis Peptide precursor of calcitonin
Ferritin
Serum ferritin levels increase in infection to limit the amount of free iron available to pathogens, as well as in malignancy to limit the amount available to tumor cells (proinflammatory cytokines upregulate the expression of the gene coding for ferritin) In contrast, some organisms (e.g., Pseudomonas) cause serum ferritin levels to drop (innate immunity against these pathogens involves an iron-withholding strategy, in which intracellular storage of iron is increased in order to withhold it from the invading pathogen)
Hepcidin
Reduces iron available to pathogens by: -Decreasing intestinal iron absorption (via ferroportin degradation) -Preventing the release of iron from macrophages Can cause anemia of chronic disease
Haptoglobin
Binds free hemoglobin Antimicrobial effects (in infection, haptoglobin is upregulated to make extracellular heme iron less available to pathogens) Antioxidative effects (free hemoglobin (e.g. in hemolysis) can cause oxidative damage) Haptoglobin levels decrease in hemolysis (haptoglobin levels may be normal in cases of inflammation with accompanying intravascular hemolysis. In this case, further parameters (e.g., hemoglobin, bilirubin, LDH, other acute phase proteins) should be determined)
Serum amyloid A (SAA)
Recruits immune cells to inflammatory sites Prolonged increased levels may cause amyloidosis.
Fibrinogen
Coagulant that promotes wound healing and endothelial repair Correlates with ESR
Ceruloplasmin
Binds free iron Antioxidative effects
Negative Acute Phase Reactants
-Albumin (reduced production of albumin conserves amino acids that can then be used to produce positive acute phase reactants) -Transferrin (macrophages take up transferrin and use it to remove iron from circulation, making it unavailable for pathogens) -Antithrombin -Transthyretin
Common Causes of Hyperlactatemia
-Tissue hypoperfusion (hypoxic states) (heart failure, sepsis and other infections, shock, infarction, lung disease (e.g., pulmonary embolism)) -Dehydration -Severe anemia and pancytopenia -Poisoning (CO (carbon monoxide), ethanol, methanol, ethylene glycol) -Liver disease (lactate produced via anaerobic glycolysis in the Cori cycle is metabolized in the liver) -Drugs (e.g., metformin or isoniazid) -Thiamine deficiency -Kidney disease (especially in individuals with diabetes) -Strenuous exercise
Exudative (or Hemostasis) Phase of Wound Healing
Day 1 Effector cells: Platelets Neutrophils Macrophages Characteristics: -Hemostasis (platelet aggregation → clot formation) -Scab formation -Immediate local vasoconstriction (lasts 5–10 minutes) due to the release of prostaglandins, kinins, leukotrienes, and thromboxane A2 (TXA2) from ruptured cell membranes and platelets -Followed by vasodilation and increased vessel permeability -Wound pain may occur (pain results from tissue swelling, tissue hypoxia, or alteration in pH from tissue destruction or infection) Involved tissue mediators: PDGF FGF EGF Prostaglandins TXA2
Inflammatory (Resorptive) Phase of Wound Healing
Day 1-3 Effector cells: Platelets Neutrophils Macrophages Characteristics: - Chemotaxis (via PAF, PDGF, and TGF-β) of inflammatory cells (i.e., neutrophils, macrophages, lymphocytes) to the site of injury. Additionally, the coagulation cascade leads to the activation of thrombin and fibrin. Together, these two factors promote extravasation of inflammatory cells. – Macrophages release growth factors and cytokines that recruit other immune cells, stimulate fibroblast proliferation (fibrosis) and resorb debris. – Lymphocytes migrate to injury approx. 72 hours after the injury to promote cellular immunity. - Continued vasodilation (release of histamine, prostaglandins, kinins, and leukotrienes from immune cells leads to vasodilation) - EGF induces tyrosine kinases such as EGFR → epithelium at wound margins begins to proliferate Involved tissue mediators: PAF PDGF TGF-β
Proliferative (or Epithelialization) Phase of Wound Healing
Day 3-7 Effector cells: Macrophages Fibroblasts Myofibroblasts, Endothelial cells Keratinocytes Characteristics: -Formation of granulation tissue – Fibroplasia (formation of fibrous tissue) → synthesis and deposition of type III collagen. – Growth factors (FGF, EGF, VEGF, PDGF, and TGF-β) from fibroblasts and epithelial cells promote angiogenesis. – PDGF stimulates smooth muscle cell migration and fibroblast growth → collagen synthesis – Wound contraction occurs as collagen synthesis increases and pulls the wound edges together. This process is facilitated by myofibroblasts. - Epidermal cells – Migrate across the collagen matrix to form a full layer – Secrete collagenase to dissolve the clot – Replicate along a provisional matrix formed by inflammatory cells to completely cover the wound Involved tissue mediators: FGF EGF PDGF VEGF TGF-β
Remodeling (or Maturation) Phase of Wound Healing
1 Week - year Effector cells: Fibroblasts Characteristics: -Scar forms with the proliferation of fibroblasts and remodeling of connective tissue. -Removal of excess collagen -Macrophages release matrix metalloproteinases and collagenases (require zinc), which facilitate the final remodeling of type III collagen into type I collagen. -Collagen becomes more organized, returning strength to the region of injury. -Peak tensile strength (∼ 80% of original strength) (collagenous network is replaced by parallel fibers within the scar) is reached ∼ 60 days after injury. -Sweat and sebaceous glands do not regenerate. Involved tissue mediators: Matrix metalloproteinase
Alpha fetoprotein (AFP) Tumor Marker
AFP is formed by endodermal tissue and the fetal liver and has the same function as albumin (fetal counterpart of albumin). AFP is normally produced by the fetus → transient elevation of maternal AFP levels ↑ AFP → abdominal wall defects, neural tube defects ↓ AFP → associated with trisomy 21, 18, and 13 (see prenatal diagnostics for details) Associated Conditions: Hepatocellular carcinoma (HCC) Hepatoblastoma Yolk sac tumor (endodermal sinus tumor) Mixed germ cell tumor Ataxia-telangiectasia
β-HCG Tumor Marker
Associated Conditions: -Testicular germ cell tumors (choriocarcinoma, embryonal cell carcinoma, mixed germ cell tumor, seminoma) -Ovarian cancer → choriocarcinoma (gestational trophoblastic disease) If detectable in urine Pregnancy marker (produced by the syncytiotrophoblast in the placenta) Molar pregnancy (hydatidiform mole)
Carcinoembryonic antigen (CEA) Tumor Marker
Associated Conditions: -Highly nonspecific marker; elevated in most adenocarcinomas -Colorectal cancer -Pancreatic cancer -Breast cancer -Lung cancer (especially in non-small cell cancers) -Gastric cancer -Endometrial cancer -Medullary thyroid cancer Smokers
Prostate-specific antigen (PSA) Tumor Marker
Associated Conditions: Prostate cancer Benign prostatic hyperplasia Prostatitis
Calcitonin Tumor Marker
Associated Conditions: Medullary thyroid cancer (both sporadic and associated with MEN 1 and MEN 2)
Alkaline phosphatase Tumor Marker
Associated Conditions: Metastases to bone or liver Paget disease of the bone
Placental Alkaline Phosphatase Tumor Marker
There is controversy regarding the use of placental alkaline phosphatase as a marker for seminoma and other germinative tumors because some studies report its low sensitivity. Associated Conditions: Seminoma Smokers
Lactate dehydrogenase Tumor Marker
Associated Conditions: Levels correlate with tumor burden, reflects growth and invasiveness of cancer (nonspecific marker of cell death; may be elevated because of tumor-related increase in cell turnover) Ovarian cancer (dysgerminoma) Testicular germ cell tumors (both seminoma and nonseminoma) Lymphomas Ewing’s sarcoma Hepatitis Hemolysis Myocardial infarction
Neuron specific enolase (NSE) Tumor Marker
Associated Conditions: Neuroendocrine tumors Small cell lung cancer Carcinoid tumor Neuroblastoma NSE is released secondary to brain injury (e.g., stroke) (not typically used in the clinical setting)
CA 19–9 Tumor Marker
Associated Conditions: Pancreatic adenocarcinoma Gastric cancer
CA 15–3 and CA 27–29 Tumor Marker
Associated Conditions: Breast cancer
CA 125 Tumor Marker
Associated Conditions: Ovarian carcinoma Other gynecologic malignancies (especially cervical adenocarcinoma) Malignant ascites Certain lymphomas
CA 72-4 Tumor Marker
Associated Conditions: Ovarian carcinoma (preferred tumor marker in mucinous cystadenocarcinoma) Gastric cancer
Chromogranin A Tumor Marker
Associated Conditions: Neuroendocrine tumors Medullary thyroid cancer
S-100 protein (S100A) and (S100B) Tumor Marker
Associated Conditions: Malignant melanoma
β2 microglobulin (β2M) Tumor Marker
Associated Conditions: Multiple myeloma Chronic lymphocytic leukemia Renal disease
Thyroglobulin Tumor Marker
Associated Conditions: Papillary thyroid carcinoma Follicular thyroid carcinoma
Monoclonal immunoglobulins Tumor Marker
Associated Conditions: Multiple myeloma Waldenstroms macroglobulinemia Monoclonal gammopathy Infections Certain autoimmune conditions (e.g., rheumatoid arthritis)
ALK Gene Rearrangement
Non-small cell lung cancer Anaplastic large cell lymphoma
EGFR Gene Mutation
Non-small cell lung cancer Certain head and neck cancers
HER2neu Receptor
Breast cancer
Estrogen and Progesterone Receptors
Breast cancer
Vimentin Marker
Natural occurrence: Intermediate filament in the cytoskeleton of mesenchymal cells (e.g., macrophages, fibroblasts, endothelial cells) Occurrence in Tumors: Sarcomas -Ewing sarcoma -Osteosarcoma -Chondrosarcoma -Soft tissue sarcomas (e.g., GIST, angiosarcoma, liposarcoma) Endometrial carcinoma Renal cell carcinoma Meningioma Mesothelioma (coexpression together with cytokeratins)
Desmin Marker
Natural occurrence: Intermediate filament in the cytoskeleton of smooth and skeletal muscle cells Occurrence in Tumors: Rhabdomyosarcoma Leiomyosarcoma
Mesothelin Marker
Natural occurrence: Membrane-bound glycoprotein Occurrence in Tumors: Mesothelioma Pancreatic, esophageal, and gastric carcinoma
Cytokeratin Marker
Natural occurrence: Intermediate filament in the cytoskeleton of epithelial cells Occurrence in Tumors: Squamous cell carcinoma (e.g. of the skin or lung) Basal cell carcinoma
Neurofilaments Marker
Natural occurrence: Neurons Occurrence in Tumors: Neuroendocrine tumors (e.g., carcinoid tumor) Neuroblastoma Medulloblastoma Small cell lung cancer (SCLC)
Chromogranin A Marker
Natural occurrence: Secretory granules of neuroendocrine cells Occurrence in Tumors: Neuroendocrine tumors (e.g., carcinoid tumor) Small cell lung cancer (SCLC) Medullary thyroid cancer
Synaptophysin Marker
Natural occurrence: Secretory granules of neuroendocrine cells Occurrence in Tumors: Neuroendocrine tumors (e.g., carcinoid tumor) Small cell lung cancer (SCLC) Medullary thyroid cancer
S-100 Marker
Natural occurrence: Neural crest cells Occurrence in Tumors: Schwannoma Melanoma Langerhans cell histiocytosis
GFAP Marker
Natural occurrence: Intermediate filament in the cytoskeleton of neuroglia (e.g., oligodendrocytes, astrocytes, Schwann cells) Occurrence in Tumors: Glioblastoma Astrocytoma
PSA Marker
Natural occurrence: Prostate epithelium Occurrence in Tumors: Prostate cancer
TRAP Marker
Natural occurrence: Tartrate-resistant acid phosphatase Occurrence in Tumors: Hairy cell leukemia
CD20 Marker
Natural occurrence: B lymphocytes Occurrence in Tumors: B cell lymphoma
CD3 Marker
Natural occurrence: T lymphocytes Occurrence in Tumors: T cell lymphoma CD3-positive T lymphocytes can also be found around Reed-Sternberg cells, which are characteristic for Hodgkin lymphoma.
CD8 Marker
Natural occurrence: T killer cells (cytotoxic T lymphocytes) Occurrence in Tumors: T cell lymphoma
CD4 Marker
Natural occurrence: T helper cells Occurrence in Tumors: T cell lymphoma
CD45 Marker
Natural occurrence: Hematopoietic cells Occurrence in Tumors: Malignant lymphoma
Psammoma Bodies
Concentric lamellar calcifications Seen in diseases associated with calcific degeneration -Papillary thyroid carcinomas (evidence of psammoma bodies in thyroid tissue should always raise suspicion of malignancy) -Serous papillary cystadenocarcinoma of ovary and endometrium -Somatostatinoma -Adrenals (calcifying fibrous pseudotumor) -Meningioma -Malignant Mesothelioma -Ovarian serous carcinoma -Prolactinoma (Milk)
Cachexia
Progressive wasting of skeletal muscle mass with or without loss of body fat that occurs in patients with advanced cancer Excess in proinflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α) as a result of tumor growth → ↑ basal metabolic rate and catabolism Negative nitrogen balance Proteasomal activation and breakdown of myosin in skeletal muscle with loss of adipose tissue Weight loss, poor appetite, decreased adipose tissue, muscle wasting, fatigue Treatment Progesterone analogs (e.g., megestrol acetate) Corticosteroids (e.g., prednisolone) The use of cannabinoids (e.g., dronabinol) remains controversial. Nutritional counseling
Lambert-Eaton Myasthenic Paraneoplastic Syndrome
Presynaptic voltage-gated calcium channels (VGCC) (P/Q-type) autoantibodies Associated cancer: Small cell lung cancer (SCLC) Characteristic Features: Proximal muscle weakness Reduced or absent reflexes Autonomic symptoms (e.g., dry mouth, constipation)
Myasthenia Gravis Paraneoplastic Syndrome
Autoantibodies against nicotinic AChRs of neuromuscular endplates Associated cancer: Thymoma Characteristic Features: Fatigable weakness of skeletal muscles Eye muscle weakness Bulbar muscle weakness Proximal limb weakness Respiratory muscle weakness Possibly cough, dysphagia, dyspnoea, hoarseness (due to anterior mediastinal mass)
Polymyositis Paraneoplastic Syndrome
Cell-mediated cytotoxicity against unidentified skeletal muscle antigens, chiefly affecting the endomysium Associated cancer: Adenocarcinoma (most common) Ovarian cancer Cervix cancer Lung cancer Pancreas cancer Stomach cancer Bladder cancer Characteristic Features: Proximal muscle weakness affecting both sides (progresses within weeks to months) Muscle tenderness
Dermatomyositis Paraneoplastic Syndrome
Paraneoplastic antibody-mediated vasculopathy Associated cancer: Adenocarcinoma (most common) Ovarian cancer Cervix cancer Lung cancer Pancreas cancer Stomach cancer Bladder cancer Characteristic Features: Proximal muscle weakness affecting both sides (progresses within weeks to months) Muscle tenderness
Paraneoplastic Encephalomyelitis Syndrome
Immune reaction against neural antigens (e.g., Hu antigens, NMDA glutamate receptors) Associated cancer: Small cell lung cancer (SCLC) Anti-NMDA encephalitis → ovarian teratoma Characteristic Features: Symptoms of encephalitis -Cognitive defects (e.g., memory deficits, speech impairment, psychiatric manifestations) (cognitive disturbance with psychotic features is especially common in anti-NMDA encephalitis) -Seizures -Dyskinesias Symptoms of myelitis (different patterns of limb paresis and sensory loss depending on area affected) Autonomic instability CSF pleocytosis
Paraneoplastic Cerebellar Degeneration
Immune reaction against neural antigens in the cerebellum (e.g., Yo antigens of Purkinje cells, Tr antigens, Hu antigens) Associated cancer: Anti-Yo antibodies → gynecological malignancies (breast, ovarian, or endometrial cancer) Anti-Hu antibodies → small cell lung cancer Anti-Tr antibodies → Hodgkin lymphoma Characteristic Features: Ataxia, vertigo Nystagmus, diplopia Dysmetria, dysarthria
Opsoclonus-myoclonus Paraneoplastic Syndrome
The exact pathophysiology remains unclear. Cellular immune reaction against onconeural antigens → disinhibition of the fastigial nucleus of the cerebellum Associated cancer: Small cell lung cancer (in adults) Pediatric cases of neuroblastoma Ovarian cancer Breast cancer Characteristic Features: Rapid, multidirectional, involuntary movements of the eyes (opsoclonus) and muscles (myoclonus) Ataxia Irritability, sleep disturbance
Cushing Paraneoplastic Syndrome
Neoplastic tissue produces ectopic ACTH (occasionally with CRH) → increased cortisol in the adrenal glands Associated cancer: Small cell lung cancer Pancreas cancer CNS tumors Characteristic Features: Moon facies, buffalo hump Hirsutism, hyperpigmentation Lethargy, depression, sleep disturbance Osteopenia, osteoporosis Muscle atrophy/weakness
Syndrome of inappropriate ADH secretion Paraneoplastic Syndrome
Neoplastic tissue produces ectopic ADH (endogenous) → increased free-water reabsorption and retention and hyponatremia Associated cancer: CNS tumors Small cell lung cancer Characteristic Features: Anorexia, nausea, vomiting Headache Muscle cramps, muscle weakness Lethargy, confusion
Hypercalcemia of Malignancy Paraneoplastic Syndrome
- Humoral hypercalcemia of malignancy (pseudohyperparathyroidism) → PTHrP secretion by the tumor Associated cancer: Squamous cell carcinomas (lung, head, and neck) Renal cancer Bladder cancer Breast cancer Ovarian cancer 2. Ectopic vitamin D production due to 1α-hydroxylase activity in tumor cells Associated cancer: Hodgkin lymphoma Non-Hodgkin lymphoma 3. Local osteolytic hypercalcemia → osteolytic activity at sites of skeletal metastases Associated cancer: Multiple myeloma Breast cancer Characteristic Features: Nephrolithiasis, nephrocalcinosis Bone pain, arthralgias, myalgias Constipation, abdominal pain Nausea, vomiting, anorexia
Malignant Acanthosis Nigricans Paraneoplastic Syndrome
Ectopic transforming growth factor TGF-α and epidermal growth factor (EGF) Associated cancer: Gastric adenocarcinoma and other gastrointestinal cancers Lung cancer Ovarian cancer Breast cancer Characteristic Features: Brown to black, intertriginous and/or nuchal hyperpigmentation and dermal thickening Can turn into itching, papillomatous, poorly-defined rash Rapid growth and verrucous or papulous surface (this helps to differentiate it from benign acanthosis nigricans) Most commonly localized in the axilla, groin, neck, and genital/anal region (other, less common, locations include flexor regions (e.g., elbows, knee), navel, or under the breasts.)
Leser-Trélat sign Paraneoplastic Syndrome
Activation of epidermal growth factor receptors Associated cancer: Solid cancers (especially gastrointestinal adenocarcinoma) Characteristic Features: Multiple, sudden-onset seborrheic keratoses
Necrolytic Migratory Erythema Paraneoplastic Syndrome
Associated cancer: Glucagonoma Characteristic Features: Multiple areas of centrifugally spreading erythema Predominantly face, perineum, and lower extremities affected Develop into painful and pruritic crusty patches with central areas of bronze-colored induration Tend to resolve and reappear in a different location
Hypertrophic pulmonary osteoarthropathy (Bamberger-Marie syndrome) Paraneoplastic Syndrome
Likely ectopic vascular endothelial GF, platelet-derived GF, and/or prostaglandin E2 → increased angiogenesis as well as fibroblast and osteoblast activity → connective-tissue matrix and bone synthesis Features include clubbing, joint pain, thickening of tubular bones, periostosis, and joint effusions Associated cancer: Non-small cell lung cancer (especially lung adenocarcinoma) Characteristic Features: Digital clubbing
Polycythemia Paraneoplastic Syndrome
EPO produced by tumor (activation of the EPO gene in neoplastic tissue → high increase in EPO production → polycythemia) Associated cancer: Renal cell carcinoma Pheochromocytoma Hemangioblastoma Leiomyoma Hepatocellular carcinoma Cerebellar hemangioma Characteristic Features: Hyperviscosity syndrome Plethora Facial flushing Pruritus Dizziness, headache Hypertension
Pure Red Cell Aplasia Paraneoplastic Syndrome
Absence of red cell precursor cells → anemia (with low reticulocyte) Associated cancer: Thymoma Characteristic Features: Pallor Fatigue Exertional dyspnea Possibly cough, dysphagia, dyspnea, hoarseness (due to anterior mediastinal mass)
Good syndrome Paraneoplastic Syndrome
↓ B-cell counts → hypogammaglobulinemia → immunodeficiency Associated cancer: Thymoma Characteristic Features: Possibly cough, dysphagia, dyspnea, hoarseness (due to anterior mediastinal mass)
Troussea (thrombophlebitis migrans) Paraneoplastic Syndrome
Malignancy-related hypercoagulability → recurring clots that resolve and appear again elsewhere in the body (migrans) Associated cancer: Pancreatic cancer Lung cancer Gliomas Characteristic Features: Pain, tenderness, induration, and erythema overlying the affected vein
Nonbacterial Thrombotic Endocarditis Paraneoplastic Syndrome
Deposition of noninfectious thrombi on the heart valves Associated cancer: Commonly associated with adenocarcinomas (e.g., pancreas cancer, colorectal cancer) Characteristic Features: Fever, chills General malaise, weakness, night sweats, weight loss Dyspnea, cough, pleuritic chest pain Arthralgias, myalgias New heart murmur
Neoplastic Fever Paraneoplastic Syndrome
Likely cytokine-mediated Associated cancer: Most cancers Characteristic Features: Fever, general malaise, weight loss
Membranous Glomerulonephritis Paraneoplastic Syndrome
Membrane attack complex (MAC) that forms on glomerular epithelial cells (neoplastic tissue induces immune complex formation → MAC attaches to glomerular epithelial cells → complement activation → inflammation → leaky capillaries) Associated cancer: Lung cancer Colon cancer Characteristic Features: Edema (periorbital edema and(or peripheral edema) Hypoalbuminemia, hyperlipidemia Hypercoagulable state (increased risk of thrombosis) Increased susceptibility to infection Possibly hypertension Possibly frothy urine
Rubor and Calor Mediators
Histamine Prostaglandins Bradykinin NO
Tumor (swelling) Mediators
Leukotrienes (C4, D4, E4) Histamine Serotonin
Dolor Mediators
Bradykinin PGE2 Histamine Sensitization of sensory nerve endings.
Fever Mechanism
Pyrogens (eg, LPS) induce macrophages to release IL-1 and TNF → COX activity in perivascular cells of anterior hypothalamus → ↑ PGE2 temperature set point.
