straight segment of proximal tubule (medulla) thick ascending limb (medulla)

Pathology - First Aid Flashcards by Grazielle Verzosa

_____ are reversible changes that can be physiologic (eg. uterine enlargement during pregnancy) or pathologic (eg. myocardial hypertrophy 2° to systemic HTN to prevent injury). If stress is excessive or persistent, adaptations can progress to cell injury (eg. significant LV hypertrophy → injury to myofibrils → HF).

Cellular Adaptations

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Cellular Adaptations

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Cellular Adaptations:

↑ structural proteins and organelles → ↑ in size of cells.

Hypertrophy

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Cellular Adaptations:

controlled proliferation of stem cells and differentiated cells → ↑ in number of cells.
excessive stimulation → pathologic _____, which may progress to dysplasia and cancer

Hyperplasia

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Cellular Adaptations:

↓ in tissue mass due to ↓ in size (↑ cytoskeleton degradation via ubiquitin-proteasome pathway and autophagy; ↓ protein synthesis) and/or number of cells (apoptosis)
causes include disuse, denervation, loss of blood supply, loss of hormonal stimulation, poor nutrition

Atrophy

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Cellular Adaptations:

reprogramming of stem cells → replacement of one cell type by another that can adapt to a new stress
usually due to exposure to an irritant, such as gastric acid (Barrett esophagus) or cigarette smoke (respiratory ciliated columnar epithelium replaced by stratified squamous epithelium)
may progress to dysplasia → malignant transformation with persistent insult (eg. Barrett esophagus → esophageal adenocarcinoma)
connective tissue can also be affected (eg. myositis ossificans, the formation of bone within muscle after trauma)

Metaplasia

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Cellular Adaptations:

disordered, precancerous epithelial cell growth
characterized by loss of uniformity of cell size and shape (pleomorphism); loss of tissue orientation; nuclear changes (eg. ↑ nuclear:cytoplasmic ratio and clumped chromatin)
mild and moderate dysplasias (ie. do not involve entire thickness of epithelium) may regress with alleviation of inciting cause
severe dysplasia usually becomes irreversible and progresses to carcinoma in situ
usually preceded by persistent metaplasia or pathologic hyperplasia

Dysplasia

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Cell Injury

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Cell Injury:

ATP-dependent programmed cell death
intrinsic and extrinsic pathways; both pathways activate caspases (cytosolic proteases) → cellular breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies, which are then phagocytosed
characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis (nuclear shrinkage), and karyorrhexis (fragmentation caused by endonuclease- mediated cleavage
cell membrane typically remains intact without significant inflammation (unlike necrosis)
DNA laddering (fragments in multiples of 180 bp) is a sensitive indicator

Apoptosis

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Apoptosis:

involved in tissue remodeling in embryogenesis
occurs when a regulating factor is withdrawn from a proliferating cell population (eg, ↓ IL-2 after a completed immunologic reaction → apoptosis of proliferating effector cells)
also occurs after exposure to injurious stimuli (eg. radiation, toxins, hypoxia)
regulated by Bcl-2 family of proteins
BAX and BAK are proapoptotic, while Bcl-2 and Bcl-xL are antiapoptotic
BAX and BAK form pores in the mitochondrial membrane → release of cytochrome C from inner mitochondrial membrane into the cytoplasm → activation of caspases
Bcl-2 keeps the mitochondrial membrane impermeable, thereby preventing cytochrome C release
Bcl-2 overexpression (eg. follicular lymphoma t[14;18]) → ↓ caspase activation → tumorigenesis

Intrinsic (Mitochondrial) Pathway

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Apoptosis:

Fas-FasL interaction is necessary in thymic medullary negative selection
mutations in Fas ↑ numbers of circulating self-reacting lymphocytes due to failure of clonal deletion
defective Fas-FasL interactions cause autoimmune lymphoproliferative syndrome

Extrinsic (Death Receptor) Pathway

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Extrinsic (Death Receptor) Pathways

Ligand Receptor Interactions
- FasL binding to Fas [CD95] or TNF-α binding to its receptor
Immune Cell
- cytotoxic T-cell release of perforin and granzyme B

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Cell Injury:

enzymatic degradation and protein denaturation of cell due to exogenous injury → intracellular components leak
inflammatory process (unlike apoptosis)

Necrosis

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Necrosis:

seen in ischemia/infarcts in most tissues (except brain)
injury denatures enzymes → proteolysis blocked
preserved cellular architecture (cell outlines seen), but nuclei disappear
↑ cytoplasmic binding of eosin stain (↑ eosinophilia; red/pink color)

Coagulative

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Necrosis:

seen in bacterial abscesses and brain infarcts
neutrophils release lysosomal enzymes that digest the tissue
Early: cellular debris and macrophages
Late: cystic spaces and cavitation (brain)
neutrophils and cell debris seen with bacterial infection

Liquefactive

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Necrosis:

seen in TB, systemic fungi (eg. Histoplasma capsulatum), and Nocardia
macrophages wall off the infecting microorganism → granular debris
fragmented cells and debris surrounded by lymphocytes and macrophages (granuloma)

Caseous

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Necrosis:

Enzymatic: acute pancreatitis (saponification)
Nonenzymatic: traumatic (eg. injury to breast tissue)
damaged cells release lipase, which breaks down triglycerides liberated fatty acids bind calcium → saponification
outlines of dead cells without peripheral nuclei
saponification (combined with Ca²⁺) appears dark blue on H&E stain

Fat

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Necrosis:

immune reactions in vessels (eg. polyarteritis nodosa), preeclampsia, hypertensive emergency
immune complexes combine with fibrin → vessel wall damage (type III hypersensitivity reaction)
vessel walls are thick and pink

Fibrinoid

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Necrosis:

distal extremity and GI tract after chronic ischemia
Dry: ischemia, coagulative
Wet: superinfection, liquefactive superimposed on coagulative

Gangrenous

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Cell Injury:

inadequate blood supply to meet demand
mechanisms include ↓ arterial perfusion (eg. atherosclerosis), ↓ venous drainage (eg. testicular torsion, Budd-Chiari syndrome), and shock

Ischemia

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Ischemia:

Brain

ACA/MCA/PCA boundary areas

Watershed areas (border zones) receive blood supply from most distal branches of 2 arteries with limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion.
Neurons most vulnerable to hypoxic-ischemic insults include Purkinje cells of the cerebellum and pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6).

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Ischemia:

Heart

Subendocardium (LV)

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Ischemia:

Kidney

straight segment of proximal tubule (medulla)
thick ascending limb (medulla)

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Ischemia:

Liver

area around central vein (zone III)

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Ischemia: Colon

* Splenic flexure * Rectum Watershed areas (border zones) receive blood supply from most distal branches of 2 arteries with limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion.

Infarcts: * occur in venous occlusion and tissues with multiple blood supplies, such as liver, lung, intestine, testes; reperfusion (eg. after angioplasty) * reperfusion injury is due to damage by free radicals

Red (Hemorrhagic) Infarct **Re**d = **re**perfusion

Infarcts: occur in solid organs with a single (end-arterial) blood supply, such as heart, kidney, and spleen

Pale Infarct

Cell Injury: * response to eliminate initial cause of cell injury, to remove necrotic cells resulting from the original insult, and to initiate tissue repair * divided into acute and chronic * can be harmful to the host if the reaction is excessive (eg. septic shock), prolonged (eg. persistent infections such as TB), or inappropriate (eg. autoimmune diseases such as SLE)

Inflammation

Cardinal Signs of Inflammation

* Rubor (redness) * Calor (warmth) * Vasodilation (relaxation of arteriolar smooth muscle) * Tumor (swelling) * Dolor (pain) * Functio Laesa (loss of function)

Cardinal Signs of Inflammation: * vasodilation (relaxation of arteriolar smooth muscle) → ↑ blood flow * Mediators: * Histamine * Prostaglandins * Bradykinin

* Rubor (redness) * Calor (warmth)

Cardinal Signs of Inflammation: * endothelial contraction/disruption (eg. from tissue damage) → ↑ vascular permeability → leakage of protein-rich fluid from postcapillary venules into interstitial space (exudate) → ↑ oncotic pressure * Endothelial Contraction: * Leukotrienes (C₄, D₄, E₄) * Histamine * Serotonin

Tumor (swelling)

Cardinal Signs of Inflammation: * sensitization of sensory nerve endings * Mechanism: * Bradykinin, PGE₂

Dolor (pain)

Cardinal Signs of Inflammation: other cardinal signs impair function (eg. inability to make fist with hand that has cellulitis)

Functio Laesa (loss of function)

Systemic Manifestations (Acute-Phase Reaction) of Inflammation

* Fever * Leukocytosis * ↑ Plasma Acute-Phase Proteins

Systemic Manifestations (Acute-Phase Reaction) of Inflammation: pyrogens (eg. LPS) induce macrophages to release IL-1 and TNF → ↑ COX activity in perivascular cells of hypothalamus → ↑ PGE₂ → ↑ temperature set point

Fever

Systemic Manifestations (Acute-Phase Reaction) of Inflammation: * elevation of WBC count * type of cell that is predominantly elevated depends on the inciting agent or injury (eg. bacteria → ↑ neutrophils)

Leukocytosis

\_\_\_\_\_ is the severe elevation in WBC (\> 40,000 cells/mm³) caused by some stressors or infections (eg. *Clostridium difficile*).

Leukemoid Reaction

Systemic Manifestations (Acute-Phase Reaction) of Inflammation: * factors whose serum concentrations change significantly in response to inflammation * produced by the liver in both acute and chronic inflammatory states * induced by IL-6

↑ Plasma Acute-Phase Proteins

⊕ Acute Phase Reactants of Inflammation

More **FFiSH** in the **C** (sea). * **F**erritin * **Fi**brinogen * **S**erum Amyloid A * **H**epcidin * **C**-Reactive protein

⊕ Acute Phase Reactants of Inflammation: binds and sequesters iron to inhibit microbial iron scavenging

Ferritin

⊕ Acute Phase Reactants of Inflammation: * coagulation factor * promotes endothelial repair * correlates with ESR

Fibrinogen

⊕ Acute Phase Reactants of Inflammation: prolonged elevation can lead to amyloidosis

Serum Amyloid A

⊕ Acute Phase Reactants of Inflammation: ↓ iron absorption (by degrading ferroportin) and ↓ iron release (from macrophages) → anemia of chronic disease

Hepcidin

⊕ Acute Phase Reactants of Inflammation: * opsonin * fixes complement and facilitates phagocytosis * measured clinically as a nonspecific sign of ongoing inflammation

C-Reactive Protein

⊝ Acute Phase Reactants of Inflammation

* Albumin * Transferrin

⊝ Acute Phase Reactants of Inflammation: reduction conserves amino acids for positive reactants

Albumin

⊝ Acute Phase Reactants of Inflammation: internalized by macrophages to sequester iron

Transferrin

Products of inflammation (eg, fibrinogen) coat RBCs and cause aggregation. The denser RBC aggregates fall at a faster rate within a pipette tube → ↑ \_\_\_\_\_. Often co-tested with CRP levels.

Erythrocyte Sedimentation Rate (ESR)

↑ Erythrocyte Sedimentation Rate (ESR)

* Anemia * Infection * Inflammation (eg. giant cell [temporal] arteritis, polymyalgia rheumatica) * Cancer (eg. metastases, multiple myeloma) * Renal Disease (end-stage or nephrotic syndrome) * Pregnancy

↓ Erythrocyte Sedimentation Rate (ESR)

* Sickle Cell Anemia (altered shape) * Polycythemia (↑ RBCs “dilute” aggregation factors) * HF * Microcytosis * Hypofibrinogenemia

\_\_\_\_\_ is the transient and early response to injury or infection. Characterized by neutrophils in tissue, often with associated edema. Rapid onset (seconds to minutes) and short duration (minutes to days). Represents a reaction of the innate immune system (ie. less specific response than chronic inflammation).

Acute Inflammation

Acute Inflammation Stimuli

* Infections * Trauma * Necrosis * Foreign Bodies

Acute Inflammation Mediators

* Toll-Like Receptors * Arachidonic Acid Metabolites * Neutrophils * Eosinophils * Antibodies (pre-existing) * Mast Cells * Basophils * Complement * Hageman Factor (Factor XII)

\_\_\_\_\_ is a cytoplasmic protein complex that recognizes products of dead cells, microbial products, and crystals (eg. uric acid crystals) → activation of IL-1 and inflammatory response.

Inflammasome

Acute Inflammation Components: * vasodilation (→ ↑ blood flow and stasis) * ↑ endothelial permeability * brings cells and proteins to site of injury or infection

Vascular

Acute Inflammation Components: * extravasation of leukocytes (mainly neutrophils) from postcapillary venules * accumulation in the focus of injury followed by leukocyte activation

Cellular

Acute Inflammation Outcomes

* resolution and healing (IL-10, TGF-β) * persistent acute inflammation (IL-8) * abscess (acute inflammation walled off by fibrosis) * chronic inflammation (antigen presentation by macrophages and other APCs → activation of CD4+ Th cells) * scarring \*Macrophages predominate in the late stages of acute inflammation (peak 2–3 days after onset) and influence the outcome of acute inflammation by secreting cytokines.

\_\_\_\_\_ predominantly occurs at postcapillary venules. WBCs exit from blood vessels at sites of tissue injury and inflammation in 4 steps.

Leukocyte Extravasation

1. Margination and Rolling 2. Tight Binding (Adhesion) 3. Diapedesis (Transmigration) 4. Migration (Chemoattraction)

Leukocyte Extravasation: defective in leukocyte adhesion deficiency type 2 (↓ Sialyl-Lewis^X)

Margination and Rolling

Leukocyte Extravasation: Margination and Rolling Vasculature/Stroma—Leukocyte

* E-selectin (upregulated by TNF and IL-1)—Sialyl-Lewis^X * P-selectin (released from Weibel-Palade bodies)—Sialyl-Lewis^X * GlyCAM-1, CD34—L-selectin

Leukocyte Extravasation: defective in leukocyte adhesion deficiency type 1 (↓ CD18 integrin subunit)

Tight Binding (Adhesion)

Leukocyte Extravasation: Tight Binding (Adhesion) Vasculature/Stroma—Leukocyte

* ICAM-1 (CD54)—CD11/18 Integrins (LFA-1, Mac-1) * VCAM-1 (CD106)—VLA-4 Integrin

Leukocyte Extravasation: WBC travels between endothelial cells and exits blood vessel

Diapedesis (Transmigration)

Leukocyte Extravasation: Diapedesis (Transmigration) Vasculature/Stroma—Leukocyte

PECAM-1 (CD31)—PECAM-1 (CD31)

Leukocyte Extravasation: WBC travels through interstitium to site of injury or infection guided by chemotactic signals

Migration

Leukocyte Extravasation: Migration Vasculature/Stroma—Leukocyte

Chemotactic Products Released in Response to Bacteria: * C5a * IL‑8 * LTB4 * Kallikrein * Platelet-Activating Factor \*various leukocytes

\_\_\_\_\_ is inflammation of prolonged duration characterized by infiltration of tissue by mononuclear cells (macrophages, lymphocytes, and plasma cells). Tissue destruction and repair (including angiogenesis and fibrosis) occur simultaneously. May or may not be preceded by acute inflammation.

Chronic Inflammation

Chronic Inflammation Stimuli

* Persistent Infections (eg, TB, T pallidum, certain fungi and viruses) → Type IV Hypersensitivity * Autoimmune Diseases * Toxic Agents (eg. silica) * Foreign Material

Chronic Inflammation Mediators

* Macrophages * dominant cells * chronic inflammation is the result of their interaction with T lymphocytes * Th1 cells secrete INF-γ → macrophage classical activation (proinflammatory) * Th2 cells secrete IL-4 and IL-13 → macrophage alternative activation (repair and antiinflammatory)

Chronic Inflammation Outcomes

* Scarring * Amyloidosis * Neoplastic Transformation * chronic HCV infection → chronic inflammation → hepatocellular carcinoma * *Helicobacter pylori* infection → chronic gastritis → gastric adenocarcinoma

Granulomatous Diseases

* Bacterial: * *Mycobacteria* (tuberculosis, leprosy) * *Bartonella henselae* (cat scratch disease) * *Listeria monocytogenes* (granulomatosis infantiseptica) * *Treponema pallidum* (3° syphilis) * Fungal: endemic mycoses (eg. histoplasmosis) * Parasitic: schistosomiasis * Chronic Granulomatous Disease * Autoinflammatory: * Sarcoidosis * Crohn disease * Primary Biliary Cholangitis * Subacute (de Quervain/granulomatous) Thyroiditis * Granulomatosis with Polyangiitis (Wegener) * Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) * Giant Cell (temporal) Arteritis * Takayasu Arteritis * Foreign Material: berylliosis, talcosis, hypersensitivity pneumonitis

\_\_\_\_\_, a pattern of chronic inflammation, are composed of epithelioid cells (macrophages with abundant pink cytoplasm) with surrounding multinucleated giant cells and lymphocytes.

Granulomas

Th1 cells secrete \_\_\_\_\_, activating macrophages.

IFN-γ

\_\_\_\_\_ from macrophages induces and maintains granuloma formation.

TNF-α

\_\_\_\_\_ drugs can cause sequestering granulomas to break down → disseminated disease. Always test for latent TB before starting _____ therapy.

Anti-TNF

Granulomas are associated with hypercalcemia due to _____ production.

Calcitriol (1,25-[OH]2 vitamin D3)

\_\_\_\_\_ necrosis is more common with an infectious etiology (eg. TB).

Caseating

Diagnosis of Sarcoidosis requires _____ on biopsy.

Noncaseating Ggranulomas

Types of Calcification

* Dystrophic Calcification * Metastatic Calcification

Calcification: * Ca2+ deposition in abnormal tissues * tends to be localized (eg. calcific aortic stenosis) * 2° to injury or necrosis * patients are usually normocalcemic

Dystrophic Calcification

Calcification: * TB (lung and pericardium) and other granulomatous infections * liquefactive necrosis of chronic abscesses * fat necrosis * infarcts * thrombi * Schistosomiasis * Congenital CMV * Toxoplasmosis * Rubella * Psammoma Bodies * CREST Syndrome * atherosclerotic plaques

Dystrophic Calcification

Calcification: * Ca²⁺ deposition In normal tissues * widespread (ie. diffuse, metastatic) * metastatic calcifications of alveolar walls in acute pneumonitis (arrows) * patients usually have abnormal serum Ca²⁺ levels

Metastatic Calcification

Calcification: * predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues lose acid quickly; ↑ pH favors Ca²⁺ deposition) * nephrocalcinosis of collecting ducts may lead to nephrogenic diabetes insipidus and renal failure

Metastatic Calcification

Calcification: * Hypercalcemia * 1° hyperparathyroidism * sarcoidosis * hypervitaminosis D * High Calcium-Phosphate Product Levels * chronic renal failure with 2° hyperparathyroidism * long-term dialysis * calciphylaxis * multiple myeloma

Metastatic Calcification

\_\_\_\_\_ is a yellow-brown “wear and tear” pigment associated with normal aging. Formed by oxidation and polymerization of autophagocytosed organellar membranes. Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye, and other organs.

Lipofuscin

Free radicals damage cells via \_\_\_\_\_.

* Membrane Lipid Peroxidation * Protein Modification * DNA Breakage

Free radical injury is initiated via \_\_\_\_\_.

* Radiation (eg. cancer therapy) * Metabolism of Drugs (phase I) * Redox Reactions * Nitric Oxide (eg. inflammation) * Transition Metals * WBC (eg. neutrophils, macrophages) Oxidative Burst

Free radicals can be eliminated by \_\_\_\_\_.

* Scavenging Enzymes (eg. catalase, superoxide dismutase, glutathione peroxidase) * Spontaneous Decay * Antioxidants (eg. vitamins A, C, E) * Certain Metal Carrier Proteins (eg. transferrin, ceruloplasmin)

Free Radical Injuries

* Oxygen Toxicity * retinopathy of prematurity (abnormal vascularization) * bronchopulmonary dysplasia * reperfusion injury after thrombolytic therapy * Drug/Chemical Toxicity * acetaminophen overdose (hepatotoxicity) * carbon tetrachloride (converted by cytochrome P-450 into CCl3 free radical → fatty liver [cell injury → ↓ apolipoprotein synthesis → fatty change], centrilobular necrosis) * Metal Storage Diseases * hemochromatosis (iron) * Wilson disease (copper)

\_\_\_\_\_ occurs when repair cannot be accomplished by cell regeneration alone. Nonregenerated cells (2° to severe acute or chronic injury) are replaced by connective tissue. 70–80% of tensile strength regained at 3 months; little tensile strength regained thereafter.

Scar Formation

Scar Formation: * ↑ collagen formation—type III collagen * parallel collagen organization * confined to borders of original wound * infrequent recurrence * no predisposition

Hypertrophic

Scar Formation: * ↑↑↑ collagen formation—disorganized types I and III collagen * disorganized collagen * extends beyond borders of original wound with “claw-like” projections typically on earlobes, face, upper extremities * frequent recurrence * ↑ incidence in ethnic groups with darker skin

Keloid

Tissue Mediators: stimulates angiogenesis

* FGF * VEGF

Tissue Mediators: * angiogenesis * fibrosis

TGF-β

Tissue Mediators: * secreted by activated platelets and macrophages * induces vascular remodeling and smooth muscle cell migration * stimulates fibroblast growth for collagen synthesis

PDGF

Tissue Mediators: tissue remodeling

Metalloproteinases

Tissue Mediators: stimulates cell growth via tyrosine kinases (eg. EGFR/ErbB1)

EGF

Phases of Wound Healing

* Inflammatory—up to 3 days after wound * Proliferative—day 3–weeks after wound * Remodeling—1 week–6+ months after wound

Phases of Wound Healing: * up to 3 days after wound * Effector Cells: * platelets * neutrophils * macrophages * clot formation * ↑ vessel permeability and neutrophil * migration into tissue * macrophages clear debris 2 days later

Inflammatory

Phases of Wound Healing: * day 3–weeks after wound * Effector Cells: * fibroblasts * myofibroblasts * endothelial cells * keratinocytes * macrophages * deposition of granulation tissue and type III collagen * angiogenesis * epithelial cell * proliferation * dissolution of clot * wound contraction (mediated by myofibroblasts) * delayed wound healing in vitamin C deficiency and copper deficiency

Proliferative

Phases of Wound Healing: * 1 week–6+ months after wound * Effector Cells: fibroblasts * type III collagen replaced by type I collagen * ↑ tensile strength of tissue * collagenases (require zinc to function) break down type III collagen * zinc deficiency → delayed wound healing

Remodeling

Effusion: * cellular (cloudy) * ↑ protein (\> 2.9 g/dL) * due to: * lymphatic obstruction (chylous) * inflammation/infection * malignancy

Exudate

Effusion: * Hypocellular (clear) * ↓ protein (\< 2.5 g/dL) * due to: * ↑ hydrostatic pressure (eg. HF, Na+ retention) * ↓ oncotic pressure (eg. cirrhosis, nephrotic syndrome)

Transudate

Light Criteria

Fluid is _exudative_ if ≥ 1 of the following criteria is met: * pleural effusion/serum protein ratio \> 0.5 * pleural effusion/serum LDH ratio \> 0.6 * pleural effusion LDH \> 2⁄3 of the upper limit of normal for serum LDH

\_\_\_\_\_ is the abnormal aggregation of proteins (or their fragments) into β-pleated linear sheets → insoluble fibrils → cellular damage and apoptosis.

Amyloidosis

Amyloid deposits are visualized by \_\_\_\_\_.

* Congo Red sStain * Polarized Light (apple green birefringence) * H&E Stain

Amyloidosis: * Cardiac (eg. restrictive cardiomyopathy, arrhythmia) * GI (eg. macroglossia, hepatomegaly) * Renal (eg. nephrotic syndrome) * Hematologic (eg. easy bruising, splenomegaly) * Neurologic (neuropathy) * Musculoskeletal (carpal tunnel syndrome)

Systemic Amyloidosis

* Primary Amyloidosis * Secondary Amyloidosis * Dialysis-Related Amyloidosis

Systemic Amyloidosis: * Fibril Protein: AL (from Ig light chains) * seen in plasma cell disorders and multiple myeloma

Primary Amyloidosis

Systemic Amyloidosis: * Fibril Protein: Serum Amyloid A (AA) * seen in chronic inflammatory conditions * rheumatoid arthritis * IBD, * familial Mediterranean fever * protracted infection

Secondary Amyloidosis

Systemic Amyloidosis: * Fibril Protein: β2-Microglobulin * seen in patients with ESRD and/or on long-term dialysis

Dialysis-Related Amyloidosis

Localized Amyloidosis

* Alzheimer Disease * Type 2 Diabetes Mellitus * Medullary Thyroid Cancer * Isolated Atrial Amyloidosis * Systemic Senile (Age-Related) Amyloidosis

Localized Amyloidosis: * Fibril Protein: β-Amyloid Protein * cleaved from amyloid precursor protein (APP)

Alzheimer Disease

Localized Amyloidosis: * Fibril Protein: Islet Amyloid Polypeptide (IAPP) * caused by deposition of amylin in pancreatic islets

Type 2 Diabetes Mellitus

Localized Amyloidosis: Fibril Protein: Calcitonin (A Cal)

Medullary Thyroid Cancer

Localized Amyloidosis: * Fibril Protein: ANP * common in normal aging ↑ risk of atrial fibrillation

Isolated Atrial Amyloidosis

Localized Amyloidosis: * Fibril Protein: Normal (wild-type) Transthyretin (TTR) * seen predominantly in cardiac ventricles * cardiac dysfunction is more insidious than in AL amyloidosis

Systemic Senile (Age-Related) Amyloidosis

Hereditary Amyloidosis

* Familial Amyloid Cardiomyopathy * Familial Amyloid Polyneuropathies

Hereditary Amyloidosis: * Fibril Protein: Mutated Transthyretin (ATTR) * ventricular endomyocardium deposition → restrictive cardiomyopathy, arrhythmias * 5% of African Americans are carriers of mutant allele

Familial Amyloid Cardiomyopathy

Hereditary Amyloidosis: * Fibril Protein: Mutated Transthyretin (ATTR) * due to transthyretin gene mutation

Familial Amyloid Polyneuropathies

\_\_\_\_ is the uncontrolled, clonal proliferation of cells. Can be benign or malignant.

Neoplastic Progression

Hallmarks of Cancer

* evasion of apoptosis * growth signal self-sufficiency * anti-growth signal insensitivity * Warburg effect—shift of glucose metabolism away from mitochondria toward glycolysis * sustained angiogenesis * limitless replicative potential * tissue invasion * metastasis

Neoplastic Progression

1. _Normal Cells_ * normal cells with basal → apical polarity 2. _Dysplasia_ * _l_oss of uniformity of cell size and shape (pleomorphism) * loss of tissue orientation * nuclear changes (eg. ↑ nuclear:cytoplasmic ratio) 3. _Carcinoma In Situ/Preinvasive_ * irreversible severe dysplasia that involves the entire thickness of epithelium but does not penetrate the intact basement membrane 4. _Invasive Carcinoma_ * __cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases) * cell-cell contacts lost by inactivation of E-cadherin 5. _Metastasis_ * spread to distant organ(s) via lymphatics or blood * “Seed and Soil” theory of metastasis: * Seed = tumor embolus * Soil = target organ is often the first-encountered capillary bed (eg. liver, lungs, bone, brain, etc)

Tumor Nomenclature: * epithelial origin * malignant

Carcinoma

Tumor Nomenclature: * mesenchymal origin * malignant

Sarcoma

Tumor Nomenclature: * well differentiated * well demarcated * low mitotic activity * no metastasis * no necrosis

Benign Tumors

Tumor Nomenclature: * poor differentiation * erratic growth * local invasion * metastasis * ↓ apoptosis * upregulation of telomerase prevents chromosome shortening and cell death

Malignant Tumors

Tumor Nomenclature: * disorganized overgrowth of tissues in their native location * Peutz-Jeghers polyps

Hamartoma

Tumor Nomenclature: * normal tissue in a foreign location * gastric tissue located in distal ileum in Meckel diverticulum

Choristoma

Benign Epithelial Tumors

* Adenoma * Papilloma

Malignant Epithelial Tumors

* Adenocarcinoma * Papillary Carcinoma

Benign Mesenchymal Tumors: blood vessels

Hemangioma

Benign Mesenchymal Tumors: smooth muscle

Leiomyoma

Benign Mesenchymal Tumors: striated muscle

Rhabdomyoma

Benign Mesenchymal Tumors: connective tissue

Fibroma

Benign Mesenchymal Tumors: bone

Osteoma

Benign Mesenchymal Tumors: fat

Lipoma

Benign Mesenchymal Tumors: melanocyte

Nevus/Mole

Malignant Mesenchymal Tumors: blood cells

* Leukemia * Lymphoma

Malignant Mesenchymal Tumors: blood vessels

Angiosarcoma

Malignant Mesenchymal Tumors: smooth muscle

Leiomyosarcoma

Malignant Mesenchymal Tumors: striated muscle

Rhabdomyosarcoma

Malignant Mesenchymal Tumors: connective tissue

Fibrosarcoma

Malignant Mesenchymal Tumors: bone

Osteosarcoma

Malignant Mesenchymal Tumors: fat

Liposarcoma

Malignant Mesenchymal Tumors: melanocyte

Melanoma

\_\_\_\_\_ is the degree to which a tumor resembles its tissue of origin.

Differentiation * _well-differentiated_ tumors (often less aggressive) closely resemble their tissue of origin * _poorly differentiated_ tumors (often more aggressive) look almost nothing like their tissue of origin

\_\_\_\_\_ is the complete lack of differentiation of cells in a malignant neoplasm.

Anaplasia

\_\_\_\_\_ is the degree of cellular differentiation and mitotic activity on histology.

Grade

\_\_\_\_\_ is the degree of localization/spread based on site and size of 1° lesion, spread to regional lymph nodes, presence of metastases. Based on clinical (c) or pathology (p) findings. Generally has more prognostic value.

Stage **S**tage determines **S**urvival.

TNM Staging System

* *T** = **T**umor size/invasiveness * *N** = **N**ode involvement * *M** = **M**etastases (**S**tage = **S**pread) \*Each TNM factor has independent prognostic value; N and M are often most important.

Paraneoplastic Syndromes: Musculoskeletal and Cutaneous

* Dermatomyositis * Acanthosis Nigricans * Sign of Leser-Trélat * Hypertrophic Osteoarthropathy

Paraneoplastic Syndromes: * progressive proximal muscle weakness * Gottron papules * heliotrope rash * adenocarcinomas—especially ovarian

Dermatomyositis

Paraneoplastic Syndromes: * hyperpigmented velvety plaques in axilla and neck * gastric adenocarcinoma * visceral malignancies—associated with obesity and insulin resistance

Acanthosis Nigricans

Paraneoplastic Syndromes: * sudden onset of multiple seborrheic keratoses * GI adenocarcinomas * visceral malignancies

Sign of Leser-Trélat

Paraneoplastic Syndromes: * abnormal proliferation of skin and bone at distal extremities → clubbing, arthralgia, joint effusions, periostosis of tubular bones * adenocarcinoma of the lung

Hypertrophic Osteoarthropathy

Paraneoplastic Syndromes: Endocrine

* Hypercalcemia * Cushing Syndrome * Hyponatremia (SIADH)

Paraneoplastic Syndromes: * PTHrP—squamous cell carcinomas of lung, head, and neck; renal, bladder, breast, and ovarian carcinomas * ↑ 1,25-(OH)2 vitamin D3 (calcitriol)—lymphoma

Hypercalcemia

Paraneoplastic Syndromes: * ↑ ACTH * small cell lung cancer

Cushing Syndrome

Paraneoplastic Syndromes: * ↑ ADH * small cell lung cancer

Hyponatremia (SIADH)

Paraneoplastic Syndromes: Hematologic

* Polycythemia * Pure Red Cell Aplasia * Good Syndrome * Trousseau Syndrome * Nonbacterial Thrombotic (Marantic) Endocarditis

Paraneoplastic Syndromes: * ↑ Erythropoietin * pheochromocytoma * renal cell carcinoma * HCC * hemangioblastoma * leiomyoma

Polycythemia **P**araneoplastic **R**ise to **H**igh **H**ematocrit **L**evels: * Pheochromocytoma * Renal Cell Carcinoma * HCC * Hemangioblastoma * Leiomyoma

Paraneoplastic Syndromes: * anemia with low reticulocytes * thymoma

Pure Red Cell Aplasia

Paraneoplastic Syndromes: * hypogammaglobulinemia * thymoma

Good Syndrome

Paraneoplastic Syndromes: * migratory superficial thrombophlebitis * adenocarcinomas—especially pancreatic

Trousseau Syndrome

Paraneoplastic Syndromes: * deposition of sterile platelet thrombi on heart valves * adenocarcinomas—especially pancreatic

Nonbacterial Thrombotic (Marantic) Endocarditis

Paraneoplastic Syndromes: Neuromuscular

* Anti-NMDA Receptor Encephalitis * Opsoclonus Myoclonus Ataxia Syndrome * Paraneoplastic Cerebellar Degeneration * Paraneoplastic Encephalomyelitis * Lambert-Eaton Myasthenic Syndrome * Myasthenia Gravis

Paraneoplastic Syndromes: * psychiatric disturbance * memory deficits * seizures * dyskinesias * autonomic instability * language dysfunction * ovarian teratoma

Anti-NMDA Receptor Encephalitis

Paraneoplastic Syndromes: * “dancing eyes, dancing feet” * neuroblastoma (children) * small cell lung cancer (adults)

Opsoclonus Myoclonus Ataxia Syndrome

Paraneoplastic Syndromes: * antibodies against antigens in Purkinje cells * small cell lung cancer (anti-Hu) * gynecologic and breast cancers (anti-Yo) * Hodgkin lymphoma (anti-Tr)

Paraneoplastic Cerebellar Degeneration

Paraneoplastic Syndromes: * antibodies against Hu antigens in neurons * small cell lung cancer

Paraneoplastic Encephalomyelitis

Paraneoplastic Syndromes: * antibodies against presynaptic (P/Q-type) Ca²⁺ channels at NMJ * small cell lung cancer

Lambert-Eaton Myasthenic Syndrome

Paraneoplastic Syndromes: * antibodies against postsynaptic ACh receptors at NMJ * thymoma

Myasthenia Gravis

Gain of function mutation converts proto-oncogene (normal gene) to _____ → ↑ cancer risk. Need damage to only one allele of a proto-oncogene.

Oncogene

Oncogenes: * receptor tyrosine kinase * lung adenocarcinoma

ALK (**A**denocarcinoma of the **L**ung **K**inase)

Oncogenes: * tyrosine kinase * CML * ALL

BCR-ABL

Oncogenes: * antiapoptotic molecule (inhibits apoptosis) * follicular and diffuse large B cell lymphomas

BCL-2

Oncogenes: * serine/threonine kinase * melanoma * non-Hodgkin lymphoma * papillary thyroid carcinoma

BRAF

Oncogenes: * cytokine receptor * gastrointestinal stromal tumor (GIST)

c-KIT

Oncogenes: * transcription factor * Burkitt lymphoma

c-MYC

Oncogenes: * receptor tyrosine kinase * breast and gastric carcinomas

HER2/neu (c-erbB2)

Oncogenes: * tyrosine kinase * chronic myeloproliferative disorders

JAK2

Oncogenes: * GTPase * colon cancer * lung cancer * pancreatic cancer

KRAS

Oncogenes: * transcription factor * lung tumor

MYCL1

Oncogenes: * transcription factor * neuroblastoma

N-myc (MYCN)

Oncogenes: * receptor tyrosine kinase * MEN 2A and 2B * papillary thyroid carcinoma

RET

Loss of function of _____ → ↑ cancer risk; both (two) alleles must be lost for expression of disease.

Tumor Suppressor Genes

Tumor Suppressor Genes: * negative regulator of β-catenin/WNT pathway * colorectal cancer (associated with FAP)

APC

Tumor Suppressor Genes: * DNA repair protein * breast, ovarian, and pancreatic cancer

BRCA1/BRCA2

Tumor Suppressor Genes: * p16, blocks G1 → S phase * melanoma * pancreatic cancer

CDKN2A

Tumor Suppressor Genes: colon cancer

DCC **D**eleted in **C**olon **C**ancer

Tumor Suppressor Genes: pancreatic cancer

SMAD4 (DPC4) **D**eleted in **P**ancreatic **C**ancer

Tumor Suppressor Genes: * menin * Multiple Endocrine Neoplasia 1

MEN1

Tumor Suppressor Genes: * neurofibromin (Ras GTPase activating protein) * Neurofibromatosis type 1

NF1

Tumor Suppressor Genes: * merlin (schwannomin) protein * Neurofibromatosis type 2

NF2

Tumor Suppressor Genes: * negatively regulates PI3k/AKT pathway * breast, prostate, and endometrial cancer

PTEN

Tumor Suppressor Genes: * inhibits E2F * blocks G1 → S phase * retinoblastoma * osteosarcoma

Tumor Suppressor Genes: * p53, activates p21, blocks G1 → S phase * most human cancers * Li-Fraumeni syndrome—multiple malignancies at early age, aka, SBLA cancer syndrome: Sarcoma, Breast, Leukemia, Adrenal gland

TP53

Tumor Suppressor Genes: * hamartin protein * tuberous sclerosis

TSC1

Tumor Suppressor Genes: * tuberin protein * tuberous sclerosis

TSC2

Tumor Suppressor Genes: * inhibits hypoxia inducible factor 1a * von Hippel-Lindau disease

VHL

Tumor Suppressor Genes: * transcription factor that regulates urogenital development * Wilms tumor (nephroblastoma)

WT1

Oncogenic Microbes: * Burkitt lymphoma * Hodgkin lymphoma * nasopharyngeal carcinoma * 1° CNS lymphoma (in immunocompromised patients)

EBV

Oncogenic Microbes: hepatocellular carcinoma

* HBV * HCV

Oncogenic Microbes: Kaposi sarcoma

HHV-8

Oncogenic Microbes: * cervical and penile/anal carcinoma (types 16, 18) * head and neck cancer

HPV

Oncogenic Microbes: * gastric adenocarcinoma * MALT lymphoma

*H. pylori*

Oncogenic Microbes: adult T-cell leukemia/lymphoma

HTLV-1

Oncogenic Microbes: cholangiocarcinoma

Liver Fluke (*Clonorchis sinensis*)

Oncogenic Microbes: bladder cancer (squamous cell)

*Schistosoma haematobium*

Carcinogens: * stored grains and nuts * hepatocellular carcinoma

Aflatoxins (*Aspergillus*)

Carcinogens: * oncologic chemotherapy * leukemia * lymphoma

Alkylating Agents

Carcinogens: * textile industry (dyes) * cigarette smoke (2-naphthylamine) * bladder—transitional cell carcinoma

Aromatic Amines * Benzidine * 2-Naphthylamine

Carcinogens: * herbicides (vineyard workers) * metal smelting * liver—angiosarcoma * lung—lung cancer * skin—squamous cell carcinoma

Arsenic

Carcinogens: * old roofing material * shipyard workers * lung—bronchogenic carcinoma \> mesothelioma

Asbestos

Carcinogens: * bladder—transitional cell carcinoma * cervix—squamous cell carcinoma * esophagus—squamous cell carcinoma/adenocarcinoma * kidney—renal cell carcinoma * larynx—squamous cell carcinoma * lung—squamous cell and small cellcarcinoma * pancreas—pancreatic adenocarcinoma

Cigarette Smoke

Carcinogens: * esophagus—squamous cell carcinoma * liver—hepatocellular carcinoma

Ethanol

Carcinogens: papillary thyroid carcinoma

Ionizing Radiation

Carcinogens: * smoked foods * gastric cancer

Nitrosamines

Carcinogens: * by-product of uranium decay * accumulates in basements * lung cancer (2nd leading cause after cigarette smoke)

Radon

Carcinogens: * used to make PVC pipes (plumbers) * liver—angiosarcoma

Vinyl Chloride

\_\_\_\_\_ are laminated, concentric spherules with dystrophic calcification.

Psammoma Bodies

Psammoma Bodies are seen in \_\_\_\_\_.

**PS**a**MM**oma Bodies: * **P**apillary Carcinoma of the Thyroid * **S**erous Papillary Cystadenocarcinoma of the Ovary * **M**eningioma * **M**alignant Mesothelioma

Serum Tumor Markers: * metastases to bone or liver * Paget disease of bone * seminoma (placental) * exclude hepatic origin by checking LFTs and GGT levels

Alkaline Phosphatase

Serum Tumor Markers: * hepatocellular carcinoma * endodermal sinus (yolk sac) tumor * mixed germ cell tumor * ataxia-telangiectasia * neural tube defects * normally made by fetus * transiently elevated in pregnancy * high levels associated with neural tube and abdominal wall defects * low levels associated with Down syndrome

α-Ftoprotein **HE-MAN** is the **alpha** male! * Hepatocellular Carcinoma * Endodermal Sinus (Yolk Sac) Tumor * Mixed Germ Cell Tumor * Ataxia-Telangiectasia * Neural Tube Defects

Serum Tumor Markers: * hydatidiform moles * choriocarcinomas * gestational trophoblastic disease * testicular cancer * mixed germ cell tumor * produced by syncytiotrophoblasts of the placenta

β-hCG **HCG**: * **H**ydatidiform Moles * **C**horiocarcinomas * **G**estational Trophoblastic Disease

Serum Tumor Markers: breast cancer

CA 15-3/CA 27-29

Serum Tumor Markers: pancreatic adenocarcinoma

CA 19-9

Serum Tumor Markers: ovarian cancer

CA 125

Serum Tumor Markers: * medullary thyroid carcinoma * MEN2A * MEN2B

Calcitonin

Serum Tumor Markers: * Major Associations: * colorectal cancer * pancreatic cancer * Minor Associations: * gastric carcinoma * breast carcinoma * medullary thyroid carcinoma * carcinoembryonic antigen * very nonspecific

CEA **C**arcino**E**mbryonic **A**ntigen

Serum Tumor Markers: neuroendocrine tumors

Chromogranin

Serum Tumor Markers: * testicular germ cell tumors * ovarian dysgerminoma * can be used as an indicator of tumor burden

LDH

Serum Tumor Markers: * prostate cancer. * can also be elevated in BPH and prostatitis * questionable risk/benefit for screening * surveillance marker for recurrent disease after prostatectomy

PSA **P**rostate-**S**pecific **a**ntigen

\_\_\_\_\_ determine primary site of origin for metastatic tumors and characterize tumors that are difficult to classify. Can have prognostic and predictive value

Immunohistochemical Stains

Immunohistochemical Stains: * mesenchymal tissue (eg. fibroblasts, endothelial cells, macrophages) * Mesenchymal tumors (eg. sarcoma) * many other tumors (eg. endometrial carcinoma, renal cell carcinoma, meningioma)

Vimentin

Immunohistochemical Stains: * neural crest cells * melanoma * schwannoma * Langerhans cell histiocytosis

S-100

Immunohistochemical Stains: muscle tumors (eg. rhabdomyosarcoma)

Desmin

Immunohistochemical Stains: epithelial tumors (eg. squamous cell carcinoma)

Cytokeratin

Immunohistochemical Stains: * neuroglia (eg. astrocytes, Schwann cells, oligodendrocytes) * astrocytoma * glioblastoma

GFAP

Immunohistochemical Stains: neuronal tumors (eg. neuroblastoma)

Neurofilament

Immunohistochemical Stains: * prostatic epithelium * prostate cancer

PSA

Immunohistochemical Stains: hairy cell leukemia

TRAP **T**artrate-**R**esistant **A**cid **P**hosphatase

Immunohistochemical Stains: * neuroendocrine cells * small cell carcinoma of the lung * carcinoid tumor

* Chromogranin * Synaptophysin

\_\_\_\_\_ is also known as multidrug resistance protein 1 (MDR1). Classically seen in adrenocortical carcinoma but also expressed by other cancer cells (eg. colon, liver). Used to pump out toxins, including chemotherapeutic agents (one mechanism of ↓ responsiveness or resistance to chemotherapy over time).

P-glycoprotein

\_\_\_\_\_ is weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg. cancer, AIDS, heart failure, COPD). Mediated by TNF, IFN-γ, IL-1, and IL-6.

Cachexia

\_\_\_\_\_ is the most common cancer.

Skin Cancer basal \> squamous \>\> melanoma

Cancer Incidence in Men

1. Prostate 2. Lung 3. Colon/Rectum

Cancer Incidence in Women

1. Breast 2. Lung 3. Colon/Rectum

Cancer Incidence in Children (0-14 yrs.)

1. Leukemia 2. CNS 3. Neuroblastoma

Cancer Mortality in Men

1. Lung 2. Prostate 3. Colon/Rectum

Cancer Mortality in Women

1. Lung 2. Breast 3. Colon/Rectum

Cancer Mortality in Children (0-14 yrs.)

1. Leukemia 2. CNS 3. Neuroblastoma

\_\_\_\_\_ is the 2nd leading cause of death in the United States (heart disease is 1st).

Cancer

Most sarcomas spread \_\_\_\_\_.

hematogenously

Most carcinomas spread via \_\_\_\_\_.

lymphatics

Hematogenously Spreading Carcinomas

**F**our **C**arcinomas **R**oute **H**ematogenously: * **F**ollicular Thyroid Carcinoma * **C**horiocarcinoma * **R**enal Cell Carcinoma * **H**epatocellular Carcinoma

Common Metastases: * lung \> breast \> melanoma, colon, kidney * 50% of _____ tumors are from metastases * commonly seen as multiple well-circumscribed tumors at gray/white matter junction

Brain

Common Metastases: * colon \>\> stomach \> pancreas * _____ and lung are the most common sites of metastasis after the regional lymph nodes

Liver

Common Metastases: * prostate, breast \> kidney, thyroid, lung * _____ metastasis \>\> 1° _____ tumors (eg. multiple myeloma, lytic) * Common Mets: * breast (mixed) * lung (lytic) * thyroid (lytic) * kidney (lytic) * prostate (blastic) * predilection for axial skeleton

Bone Lead (**PB**) **K**e**T**t**L**e **P**rostate, **B**reast \> **K**idney, **T**hyroid, Lung

Pathology - First Aid Flashcards

(261 cards)