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COMPLETE PATHOLOGY SHORT-ANSWER GUIDE

Based on Robbins & Cotran + Zillur Rahman Pathology

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TOPIC 1: NEOPLASIA (TUMORS & CANCER)

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DEFINITIONS

• Abnormal mass of tissue with uncoordinated, excessive growth that persists after the initiating stimulus is removed
• Growth is autonomous, serving no physiological function
• May be benign or malignant

• Literally means "swelling"; now used synonymously with neoplasm
• Can refer to any benign or malignant new growth

• Malignant neoplasm arising from epithelial cells
• Subtypes: adenocarcinoma (glandular), squamous cell carcinoma, transitional cell carcinoma
• Most common type of cancer in adults

• Malignant neoplasm arising from mesenchymal (connective tissue) cells
• Examples: osteosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma
• Less common than carcinoma; tend to spread hematogenously

• Severe dysplastic changes involving the full thickness of epithelium without breaching the basement membrane
• Pre-invasive stage; 100% curable if detected
• Examples: CIN III (cervix), DCIS (breast), Bowen's disease (skin)

• Malignant epithelial tumor that has breached the basement membrane
• Cells invade surrounding stroma; risk of metastasis is present
• Defined by basement membrane disruption

• Spread of tumor cells from the primary site to a distant, non-contiguous site
• Hallmark of malignancy; absent in benign tumors
• Routes: lymphatic, hematogenous, transcoelomic, perineural

• Disordered, abnormal cellular differentiation and maturation within a tissue
• Changes are reversible if the stimulus is removed
• Features: pleomorphism, increased N:C ratio, loss of polarity, abnormal mitoses

• Loss of structural and functional differentiation of cells (extreme dedifferentiation)
• Hallmark of malignancy; cells resemble no normal tissue
• Features: marked pleomorphism, giant cells, atypical mitoses, prominent nucleoli

• Active penetration of tumor cells through the basement membrane and into surrounding tissue
• Requires: enzymes (MMPs, collagenases), cell motility, loss of cell adhesion
• Essential step before hematogenous or lymphatic metastasis

• Any agent capable of causing or initiating malignant transformation
• Types: chemical (PAHs, aflatoxin), physical (UV, ionizing radiation), biological (viruses)
• Acts by causing irreversible DNA mutations in proto-oncogenes/tumor suppressor genes

• Substance (protein, hormone, enzyme) produced by a tumor or in response to it
• Found in blood, urine, or tissue
• Examples: PSA (prostate), AFP (hepatocellular/germ cell), CEA (colon/lung), CA-125 (ovary)

• Clinical manifestations not caused by direct tumor invasion or metastasis
• Caused by: hormones/cytokines secreted by tumor, or immune response cross-reacting with normal tissue
• Examples: Cushing's (ACTH by small cell lung cancer), hypercalcemia (PTHrP)

• Neoplasm containing tissue from all three germ layers (ectoderm, mesoderm, endoderm)
• Arises from totipotent cells; most common in gonads
• Mature (benign) vs. immature (malignant)

• Disorganized but non-neoplastic overgrowth of tissue elements normally present in that organ
• Example: pulmonary hamartoma (cartilage, smooth muscle, fat in lung)
• Not a true neoplasm; does not recur after excision

• Ectopic rest of normal tissue in an abnormal location
• Example: gastric mucosa in Meckel's diverticulum; pancreatic tissue in stomach wall
• Non-neoplastic; a developmental anomaly

• Neoplasm showing differentiation along two or more cell lines
• Example: pleomorphic adenoma of salivary gland (epithelial + mesenchymal elements)
• Most are benign; malignant transformation possible

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BENIGN & MALIGNANT TUMORS

• Anaplasia (loss of differentiation)
• Rapid, uncontrolled growth
• Local invasion through basement membrane
• Ability to metastasize
• Abnormal mitoses, nuclear pleomorphism
• Necrosis due to outgrowing blood supply

• Hemangioma (most common benign tumor in infancy)
• Medulloblastoma, astrocytoma (CNS)
• Wilms tumor (nephroblastoma)
• Neuroblastoma
• Retinoblastoma
• Acute lymphoblastic leukemia (ALL)
• Rhabdomyosarcoma

• Neuroblastoma (most common solid tumor <4 yrs)
• Wilms tumor (nephroblastoma)
• Retinoblastoma
• Hepatoblastoma
• Acute leukemia (ALL)

• Ewing's sarcoma
• Neuroblastoma
• Rhabdomyosarcoma
• Wilms tumor (blastemal component)
• Lymphoma/leukemia
• Medulloblastoma
• Small cell carcinoma of lung
• Mnemonic: "LEMON" - Lymphoma, Ewing's, Medulloblastoma, Others, Neuroblastoma

• Tumors that invade locally but rarely metastasize
• Examples: Basal cell carcinoma of skin, Giant cell tumor of bone (locally aggressive), Craniopharyngioma
• Treatment is wide local excision

• Benign tumor composed of blood vessels, smooth muscle, and mature fat
• Most common in kidney; associated with tuberous sclerosis
• Can cause spontaneous hemorrhage if >4 cm

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METASTASIS & TUMOR SPREAD

1. Lymphatic - Most common route for carcinomas; spreads to regional nodes first
2. Hematogenous - Most common for sarcomas; spreads via blood to liver, lung, bone, brain
3. Transcoelomic - Spread across body cavities (pleural, peritoneal, pericardial)
4. Direct/contiguous - Direct invasion into adjacent organs
5. Perineural - Along nerve sheaths (prostate, pancreas cancers)
6. Iatrogenic - During surgery or biopsy

• Tumor cells enter lymphatics, travel to regional lymph nodes
• First nodes involved = sentinel lymph nodes
• Carcinomas favor this route
• Can result in "skip metastases" (bypass nearest node)

• Tumor cells invade veins (thin-walled), enter systemic circulation
• Preferred organs: liver (portal drainage), lung (all venous drainage), bone, brain
• Sarcomas, renal cell carcinoma, hepatocellular carcinoma favor this route

1. Local invasion through basement membrane
2. Intravasation into blood vessels
3. Survival in circulation (evading NK cells/immune system)
4. Arrest at distant capillary bed
5. Extravasation into distant tissue
6. Formation of micrometastasis
7. Colonization and angiogenesis → macrometastasis

• Active process requiring loss of cell adhesion, degradation of ECM, and cell motility
• Loss of E-cadherin reduces cell-cell adhesion
• MMPs (matrix metalloproteinases) degrade basement membrane and ECM
• Epithelial-mesenchymal transition (EMT) promotes invasiveness

1. Loss of cell-cell adhesion (downregulation of E-cadherin)
2. Attachment to ECM components via integrins
3. Degradation of ECM by proteases (MMPs, cathepsins)
4. Migration of tumor cells through degraded ECM

• First lymph node to receive lymphatic drainage from a primary tumor
• Identified by injection of blue dye or radioactive tracer
• If sentinel node is negative → remaining nodes likely negative (avoids full dissection)
• Used in breast cancer, melanoma staging

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CARCINOGENESIS

• Chemical carcinogens cause DNA mutations → activation of oncogenes or inactivation of tumor suppressors
• Initiation (irreversible mutation) + Promotion (clonal expansion) = carcinogenesis
• Two-stage model: initiation then promotion

• React directly with DNA without metabolic activation
• Examples: alkylating agents (cyclophosphamide), acylating agents, nitrogen mustard
• Used as chemotherapy drugs but are themselves carcinogenic

• Require metabolic activation (by CYP450 enzymes) to become ultimate carcinogens
• Examples: Benzo[a]pyrene (in cigarette smoke) → epoxide; Aflatoxin B1 (from Aspergillus in food) → epoxide

• Tobacco smoke: lung, oral, esophageal, bladder cancer
• Alcohol: oral, esophageal, liver, breast cancer
• Dietary fat: colorectal, breast, prostate
• H. pylori: gastric cancer, MALT lymphoma
• Aflatoxin (contaminated grains): hepatocellular carcinoma

• Asbestos → Mesothelioma, lung cancer
• Vinyl chloride → Angiosarcoma of liver
• Benzene → Leukemia
• 2-Naphthylamine → Bladder cancer
• Chromium, nickel → Lung cancer
• Arsenic → Skin, lung cancer

• UVB (290-320 nm) is most carcinogenic
• Causes pyrimidine dimers (thymidine-thymidine dimers) in DNA
• Causes: Squamous cell carcinoma, basal cell carcinoma, melanoma
• Xeroderma pigmentosum: defective nucleotide excision repair → high skin cancer risk

• X-rays, gamma rays, alpha/beta particles cause DNA strand breaks
• Causes: leukemia (especially CML, ALL), thyroid cancer, breast cancer, osteosarcoma
• Hiroshima survivors: peak leukemia at 5-7 years post-exposure
• Radiologists historically had increased cancer risk

• H. pylori → Gastric adenocarcinoma, MALT lymphoma
• Ulcerative colitis → Colorectal carcinoma
• Primary sclerosing cholangitis → Cholangiocarcinoma
• Chronic hepatitis (HBV/HCV) → Hepatocellular carcinoma
• Asbestosis → Mesothelioma
• Plummer-Vinson syndrome → Squamous cell carcinoma of esophagus

• Proto-oncogenes → Oncogenes (gain-of-function mutations): drive cell proliferation
• Tumor suppressor genes (loss-of-function): inhibit proliferation (RB, TP53)
• DNA repair genes: maintain genomic integrity
• Apoptosis regulators: BCL-2 overexpression prevents apoptosis
• Telomerase: reactivated in cancer → unlimited replication

• Genetic: point mutations, deletions, amplifications, translocations (e.g., BCR-ABL in CML)
• Epigenetic: DNA methylation (silences tumor suppressors), histone modification
• Promoter hypermethylation of CDKN2A (p16) silences cell cycle inhibitor
• Both are reversible targets for therapy (e.g., 5-azacytidine for methylation)

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TUMOR DIAGNOSIS

1. Clinical examination (history, physical)
2. Imaging (X-ray, CT, MRI, PET)
3. Laboratory: tumor markers, CBC, LFT
4. Histopathology (gold standard)
5. Cytology (FNAC, exfoliative)
6. Immunohistochemistry
7. Molecular/genetic tests (PCR, FISH, next-gen sequencing)

• Removal of tissue for histological examination
• Gold standard for definitive cancer diagnosis
• Must include representative, viable tissue

• Incisional: portion of tumor removed (for large tumors)
• Excisional: entire tumor removed (for small, accessible tumors)
• Core needle: large needle removes tissue core (breast, prostate)
• Tru-cut: type of core needle biopsy
• Punch biopsy: for skin lesions
• Endoscopic biopsy: via endoscope (GI tract)
• Stereotactic biopsy: image-guided (brain)

• 22-25 gauge needle aspirates cells from a lump
• Provides cytological (not histological) diagnosis
• Quick, cheap, minimally invasive, no anesthesia
• Cannot assess tissue architecture or invasion
• Used for: thyroid, lymph nodes, breast, salivary gland

• Study of individual cells or cell groups (not tissue architecture)
• Types: exfoliative (Pap smear, sputum, urine), aspiration (FNAC), imprint/touch prep
• Can detect malignant cells but cannot determine invasiveness

• Study of tissue sections under microscope
• Gold standard - assesses architecture, invasion, grade
• Requires tissue processing: fixation → embedding → sectioning → staining (H&E)

• Uses antibodies to detect specific antigens in tissue sections
• Identifies cell lineage, differentiation markers, hormone receptors
• Examples: ER/PR/HER2 in breast cancer; CK for carcinoma; CD markers for lymphoma; PSA for prostate
• Helps determine tumor origin in metastatic disease

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TUMOR GRADING & STAGING

• Assessment of degree of differentiation based on histological appearance
• Grade I: well differentiated; Grade II: moderately; Grade III: poorly; Grade IV: undifferentiated/anaplastic
• Higher grade = more aggressive, worse prognosis

• Assessment of extent of tumor spread (clinical + pathological)
• Based on size of primary tumor, nodal involvement, and distant metastasis
• More important than grading for prognosis and treatment

• T = Primary Tumor size/invasion (T0-T4)
• N = Regional lymph Node involvement (N0-N3)
• M = distant Metastasis (M0 = absent, M1 = present)
• Combined into Stage I-IV: Stage IV = distant metastasis

• Based on: degree of differentiation, mitotic index, nuclear pleomorphism, necrosis
• Nottingham grading for breast cancer; Gleason score for prostate
• Grade correlates with biological behavior

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PARANEOPLASTIC SYNDROME

1. Endocrine/hormonal: ectopic hormone production
2. Neuromuscular: Eaton-Lambert syndrome, peripheral neuropathy
3. Dermatological: acanthosis nigricans, dermatomyositis
4. Vascular/hematological: Trousseau's syndrome (migratory thrombophlebitis), DIC
5. Renal: membranous nephropathy, SIADH

• Cell-mediated immunity (CD8+ CTLs) is primary defense
• NK cells kill tumor cells without prior sensitization
• Tumors evade immunity via: downregulation of MHC I, PD-L1 expression, immunosuppressive cytokines (TGF-β, IL-10)
• Basis for checkpoint inhibitor therapy (anti-PD-1, anti-CTLA-4)

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EPIDEMIOLOGY

• Age: most cancers increase with age; childhood cancers are exceptions
• Sex: some cancers sex-specific (breast, prostate, cervical)
• Geography: gastric cancer in Japan; liver cancer in Africa/Asia; colon in Western world
• Genetic predisposition: BRCA1/2, APC, RB1
• Environmental: tobacco, diet, infections, radiation

1. Lung
2. Prostate
3. Colorectal
4. Stomach
5. Liver

1. Breast (most common)
2. Cervix
3. Colorectal
4. Lung
5. Ovary

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TOPIC 2: HEMODYNAMIC DISORDERS

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EDEMA

• Accumulation of excess fluid in interstitial tissue spaces or body cavities
• Caused by: increased capillary hydrostatic pressure, decreased plasma oncotic pressure, lymphatic obstruction, sodium/water retention, increased vascular permeability

• Confined to a specific organ or region
• Causes: local venous/lymphatic obstruction, inflammation
• Examples: DVT (leg edema), lymphedema post-mastectomy, pulmonary edema, cerebral edema

• Widespread subcutaneous edema involving the whole body
• Causes: congestive heart failure, nephrotic syndrome, cirrhosis, severe malnutrition (kwashiorkor)
• Pitting edema - indentation remains after pressure

• Transudative: low protein, due to hydrostatic/oncotic imbalance (CHF, cirrhosis, nephrotic)
• Exudative: high protein, due to inflammation/infection (cellulitis, peritonitis)
• Localized vs generalized
• Intracellular vs extracellular

• Due to increased venous hydrostatic pressure from right heart failure
• Distribution: dependent edema (ankles, sacrum)
• Also: ascites, pleural effusion, raised JVP

• Cirrhosis → decreased albumin synthesis → reduced oncotic pressure + portal hypertension
• Results in ascites (most prominent) and pedal edema
• Also due to increased ADH/aldosterone (sodium retention)

• Nephrotic syndrome → massive proteinuria → hypoalbuminemia → decreased oncotic pressure
• Periorbital edema (early morning, characteristic)
• Also: generalized edema, ascites

• Accumulation of fluid in alveolar spaces and interstitium
• Causes: left heart failure (most common), ARDS, pneumonia, high altitude
• Features: pink frothy sputum, breathlessness, crepitations
• Heart failure cells (hemosiderin-laden macrophages) seen in chronic cases

• Exudate due to increased vascular permeability from chemical mediators (histamine, bradykinin)
• High protein content, often with neutrophils
• Part of acute inflammation response

• Severe, generalized edema with fluid accumulation in all body compartments
• Includes: subcutaneous tissue, pleural cavity, peritoneum, pericardium
• Causes: CHF, nephrotic syndrome, cirrhosis, severe malnutrition

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HYPEREMIA & CONGESTION

• Increased blood in a tissue or organ
• Active hyperemia: arteriolar dilation → increased blood flow (physiological: exercise, emotion; pathological: inflammation)
• Passive hyperemia (congestion): impaired venous outflow → blood accumulation

• Arterioles dilate due to autonomic stimulation or local metabolites
• Tissue appears red and warm
• Examples: exercising muscle, blushing, inflammation

• Passive accumulation of blood due to impaired venous drainage
• Tissue appears blue-red (cyanotic), cool, congested
• Causes: right heart failure (systemic), left heart failure (pulmonary), local venous obstruction

• Chronic passive congestion of lung (long-standing left heart failure)
• Alveoli filled with hemosiderin-laden macrophages (heart failure cells/siderophages)
• Fibrous thickening of alveolar walls → firm, brown lung tissue
• Prussian blue stain identifies hemosiderin

• Gross appearance of chronic passive congestion of liver
• Cut surface shows alternating dark (congested central veins) and pale (fatty peripheral hepatocytes)
• Resembles cross-section of nutmeg
• Due to right heart failure or hepatic vein obstruction (Budd-Chiari)

• Hemosiderin-laden macrophages in alveoli
• Result from chronic pulmonary congestion (left heart failure)
• Phagocytose red blood cells that leaked into alveoli → convert Hb to hemosiderin
• Seen in sputum or BAL; stain positive with Prussian blue

• Due to right heart failure or cardiac tamponade
• Central veins and sinusoids are engorged → central hemorrhagic necrosis
• Periportal hepatocytes are spared (better oxygenated)
• Gross: nutmeg liver; microscopic: centrilobular congestion and necrosis

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HEMORRHAGE

• Extravasation of blood from vessels into tissues or spaces
• Due to: vessel wall damage, increased pressure, coagulation disorders

• By size: Petechiae (<3mm), Purpura (3-10mm), Ecchymosis (>10mm), Hematoma (collection)
• By site: Hemothorax, hemopericardium, hemarthrosis, retroperitoneal
• By mechanism: traumatic, spontaneous, diapedetic
• By speed: acute vs. chronic

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THROMBOSIS

• Formation of a solid mass (thrombus) from blood components within the vasculature during life
• Composed of platelets, fibrin, RBCs, WBCs
• Distinguished from post-mortem clot by attachment to vessel wall and Lines of Zahn

1. Endothelial injury - most important; exposes subendothelial collagen → platelet activation
2. Altered blood flow - stasis or turbulence disrupts laminar flow
3. Hypercoagulability - inherited (factor V Leiden, protein C/S deficiency) or acquired (malignancy, pregnancy, OCP)

• Exposes subendothelial matrix (collagen, vWF, tissue factor)
• Triggers platelet adhesion and aggregation
• Activates coagulation cascade
• Most important in arterial thrombosis

• Stasis (venous thrombosis in bedridden patients, atrial fibrillation)
• Turbulence (arterial bifurcations, aneurysms) causes endothelial injury
• Both disrupt laminar flow and allow platelet-vessel wall contact

• Immobility, postoperative state
• Malignancy (Trousseau's syndrome)
• OCP/hormone therapy
• Pregnancy
• Antiphospholipid syndrome
• Factor V Leiden mutation
• Protein C/S deficiency, antithrombin III deficiency
• Polycythemia, hyperviscosity

• Alternating pale (platelet/fibrin-rich) and dark (RBC-rich) layers in a thrombus
• Indicate formation during life with flowing blood
• Distinguish antemortem thrombus from postmortem clot

• Occlusive: completely blocks the lumen (more common in small vessels, veins)
• Mural: partially occludes lumen, adherent to wall (more common in heart chambers, aorta)

• Thrombosis in a vein without primary vein inflammation
• Due to stasis + hypercoagulability
• Common in deep leg veins (DVT)
• Risk of pulmonary embolism

• Thrombosis occurring secondary to inflammation of the vein wall
• Superficial veins commonly affected
• Tender, red, cord-like vein
• Less likely to embolize than deep vein thrombosis

1. Propagation: thrombus grows larger
2. Embolization: part breaks off → pulmonary embolism
3. Dissolution (fibrinolysis): plasmin degrades fibrin (if small)
4. Organization and recanalization: thrombus is replaced by fibroblasts; new channels form
5. Canalization: new blood flow through organized thrombus

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EMBOLISM

• Lodging of a detached intravascular mass (embolus) in a vessel, occluding it
• 99% are thromboemboli

• Thromboembolus (most common)
• Fat embolus
• Air/gas embolus
• Amniotic fluid embolus
• Tumor embolus
• Cholesterol embolus (atherosclerotic plaque)
• Septic embolus (infected thrombus)

• 95% originate from deep leg vein thrombi (DVT)

• Large emboli → saddle embolus at pulmonary artery bifurcation → sudden death
• Medium emboli → pulmonary infarction (hemorrhagic), pleuritic chest pain, hemoptysis
• Small emboli → pulmonary hypertension if recurrent

• Sudden death (massive embolism, >60% obstruction)
• Acute cor pulmonale (right heart strain)
• Pulmonary infarction (hemorrhagic, wedge-shaped, pleura-based)
• Pulmonary hypertension (recurrent small emboli)

• Gas bubbles obstruct vessels
• Causes: IV line disconnection, surgery (neurosurgical sitting position), central line placement, scuba diving

• 150 mL air can be fatal

• Churning sound (mill wheel murmur) over heart

• Release of fat globules into circulation after long bone fractures, liposuction
• Features (triad): respiratory distress, neurological symptoms, petechial rash (chest, axilla)
• Occurs 24-72 hours post-injury
• Mechanism: mechanical obstruction + free fatty acid-mediated endothelial injury

• Amniotic fluid enters maternal circulation during labor/delivery
• Features: sudden dyspnea, cyanosis, hypotension, DIC, coma
• Very rare but mortality >80%
• DIC caused by thromboplastin-rich amniotic fluid

• Emboli from left side of heart (mural thrombi, atrial fibrillation) or aortic atherosclerosis
• Travel to: brain (stroke), kidney, spleen, intestines, limbs
• Cause ischemic infarcts in target organs

• Venous thrombus crosses to arterial side through a cardiac defect (ASD, VSD, PFO)
• Causes arterial embolism from a venous source
• Consider in young stroke patients with DVT and PFO

• Rapid ascent from high-pressure (deep water diving) → dissolved N₂ comes out of solution as bubbles
• Bubbles obstruct small vessels in joints, muscles, CNS, lungs

• Acute musculoskeletal pain in joints/muscles in caisson disease
• Due to N₂ bubble formation in periarticular tissues

• Respiratory symptoms in caisson disease (pulmonary emboli from N₂ bubbles)
• Cough, dyspnea, substernal pain
• Can progress to ARDS

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INFARCTION

• Area of ischemic necrosis caused by occlusion of arterial supply or venous drainage

• Occurs in: loose/spongy tissues (lung, intestine), dual blood supply (liver, lung), reperfused areas, venous occlusion
• Blood re-enters necrotic tissue → hemorrhagic appearance
• Examples: lung infarct, intestinal infarct, testicular torsion

• Loose tissue (allows blood accumulation)
• Dual blood supply (one vessel occlusion allows hemorrhage from the other)
• Venous occlusion (retrograde hemorrhage)
• Reperfusion after ischemia

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SHOCK

• Systemic hypoperfusion leading to inadequate tissue oxygenation and organ dysfunction
• A state of cardiovascular collapse

1. Hypovolemic: blood/fluid loss (hemorrhage, burns, dehydration)
2. Cardiogenic: pump failure (MI, cardiac tamponade, arrhythmia)
3. Distributive: inappropriate vasodilation
   • Septic shock (most common distributive)
   • Anaphylactic shock (IgE-mediated)
   • Neurogenic shock (loss of vascular tone)
4. Obstructive: outflow obstruction (massive PTE, tension pneumothorax)

• Most common cause of death in ICUs
• Gram-negative bacteria (LPS/endotoxin) or gram-positive (lipoteichoic acid) → massive cytokine release (TNF, IL-1, IL-6)
• Features: hypotension, fever, warm skin (early), tachycardia, multi-organ failure
• Warm shock (early, high output) → Cold shock (late, low output)

1. Compensated (non-progressive): compensatory mechanisms maintain perfusion; tachycardia, vasoconstriction
2. Progressive (decompensated): compensatory mechanisms fail; metabolic acidosis, oliguria, confusion
3. Irreversible: widespread cell death, multi-organ failure, death inevitable even with treatment

• Endotoxin → macrophage activation → TNF-α, IL-1, IL-6 release
• Endothelial activation → NO synthesis (vasodilation), coagulopathy
• Neutrophil-mediated organ damage
• DIC, ARDS, acute tubular necrosis

• Baroreceptor reflex → tachycardia, vasoconstriction
• RAAS activation → sodium/water retention
• ADH release → water retention
• Cortisol release → gluconeogenesis
• Redistribution of blood to vital organs (brain, heart)

• Brain: ischemic encephalopathy, watershed infarcts
• Heart: subendocardial hemorrhage, coagulative necrosis
• Kidney: acute tubular necrosis (ATN), cortical pallor
• Lung: ARDS (diffuse alveolar damage), hyaline membranes
• GI: hemorrhagic enteropathy, mucosal necrosis
• Adrenal: cortical lipid depletion

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GANGRENE

• Macroscopic necrosis of tissue, usually with putrefaction (bacterial decomposition)

1. Dry gangrene: arterial occlusion; mummified, black, dry; line of demarcation present
2. Wet gangrene: venous occlusion/infection; swollen, foul-smelling, no demarcation; spreads rapidly
3. Gas gangrene: Clostridium perfringens infection; gas in tissues; crepitus on palpation; very rapid; surgical emergency
4. Hospital gangrene (necrotizing fasciitis): mixed bacterial infection

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AMYLOIDOSIS

• Extracellular deposition of abnormal fibrillar proteins (amyloid) in various tissues and organs
• Staining: Congo red → apple-green birefringence under polarized light
• AL amyloid (plasma cell disorders), AA amyloid (chronic inflammation), AH amyloid (hemodialysis)

• Kidney (most common and most serious)
• Liver (hepatomegaly, "lardaceous liver")
• Spleen (sago spleen or lardaceous spleen)
• Heart (restrictive cardiomyopathy)
• Tongue (macroglossia)
• Nerves (peripheral neuropathy)

• Gross: enlarged, waxy, pale kidneys early; shrunken in late disease
• Micro: amyloid deposits first in mesangium, then glomerular capillary walls, then tubular basement membranes
• Congo red staining: salmon-pink deposits → apple-green birefringence on polarized light
• Presents as nephrotic syndrome (massive proteinuria)

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ELECTROLYTES & ACID-BASE

• Causes: water deficit (diabetes insipidus, excess sweating), Na+ gain
• Features: thirst, confusion, seizures, coma
• Cells shrink (water moves out osmotically)

• Most common electrolyte disorder
• Causes: SIADH, CHF, cirrhosis, hypothyroidism, diuretics
• Features: nausea, headache, seizures, coma
• Cells swell (water moves in)

• Causes: renal failure, Addison's disease, ACE inhibitors, hemolysis, acidosis
• Features: muscle weakness, peaked T waves, widened QRS, cardiac arrest
• ECG changes: peaked T waves → wide QRS → sine wave → VF

• Causes: vomiting, diarrhea, diuretics, hyperaldosteronism, alkalosis
• Features: muscle weakness, cramps, paralytic ileus, U waves on ECG, arrhythmias

• pH <7.35
• Metabolic acidosis: increased acid (DKA, lactic acidosis, renal failure) or bicarbonate loss (diarrhea)
• Respiratory acidosis: hypoventilation (COPD, narcotic overdose) → CO₂ accumulation

• pH >7.45
• Metabolic alkalosis: vomiting, antacids, diuretics, hyperaldosteronism
• Respiratory alkalosis: hyperventilation (anxiety, high altitude, pregnancy)

• Na+: 135-145 mEq/L
• K+: 3.5-5.0 mEq/L
• Cl-: 98-106 mEq/L
• HCO₃-: 22-26 mEq/L
• Ca²+: 8.5-10.5 mg/dL
• pH: 7.35-7.45
• PaCO₂: 35-45 mmHg

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PLEURAL DISORDERS

• Transudative pleural effusion (non-inflammatory fluid)
• Causes: CHF (most common), nephrotic syndrome, cirrhosis

• Blood in pleural cavity
• Causes: trauma, aortic aneurysm rupture, bleeding disorders

• Lymphatic (chyle) fluid in pleural cavity; milky appearance
• Causes: thoracic duct trauma/obstruction, lymphoma, surgery

• Pus in pleural cavity (pyothorax)
• Causes: pneumonia (most common), lung abscess, thoracic surgery
• Features: fever, pleuritic pain, dullness on percussion
• Requires drainage

• Color: straw (transudate), turbid (exudate), bloody, milky (chyle)
• Protein, LDH (Light's criteria for exudate vs transudate)
• Cell count (neutrophils in bacterial, lymphocytes in TB/malignancy)
• Glucose, pH, culture, cytology

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TOPIC 3: CELL INJURY, ADAPTATION & CALCIFICATION

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CELL INJURY

• Result of stress exceeding the cell's adaptive capacity
• Reversible if stimulus is removed before cell death; irreversible leads to cell death

• Hypoxia/ischemia (most common)
• Infections (bacteria, viruses, parasites)
• Immune reactions (hypersensitivity, autoimmunity)
• Nutritional deficiency or excess
• Physical agents (trauma, temperature extremes, radiation)
• Chemical agents/drugs/toxins
• Genetic defects

• ATP depletion → Na/K pump failure → cell swelling
• Mitochondrial dysfunction → decreased ATP, ROS generation
• Ca²+ influx → activates destructive enzymes (phospholipases, proteases, endonucleases)
• Oxidative stress (free radicals) → lipid peroxidation, protein oxidation, DNA damage
• Membrane damage → lysosomal enzyme release

• Cell swelling (cloudy swelling, hydropic change)
• Fatty change (steatosis)
• Membrane blebbing
• ER dilation
• Mitochondrial swelling

• ↓ ATP
• ↑ Intracellular Ca²+
• ↑ ROS
• Acidosis (anaerobic glycolysis)
• Membrane phospholipid breakdown

• Causes: ischemia, toxins, ROS
• Effects: ATP depletion → cell swelling; cytochrome c release → apoptosis; mitochondrial permeability transition (MPT)
• MPT = opening of pores in inner mitochondrial membrane → irreversible injury

• Normally Ca²+ is low in cytoplasm (10⁻⁷ mol/L)
• Injury → Ca²+ enters → activates:
  • Phospholipases → membrane damage
  • Proteases → cytoskeletal damage
  • Endonucleases → DNA damage
  • ATPases → ATP depletion
• Ca²+ overload is a final common pathway of cell death

• Reduced blood supply → hypoxia + loss of metabolic substrates
• Worse than pure hypoxia (no removal of metabolites)
• Rapid ATP depletion → reversible changes → irreversible necrosis
• Neurons: 3-5 min; Cardiomyocytes: 20-40 min; Skeletal muscle: hours

• Re-establishing blood flow after ischemia paradoxically causes additional injury
• Mechanism: burst of ROS from mitochondria + neutrophil activation + Ca²+ overload + MPT opening
• Clinical relevance: post-MI reperfusion, organ transplantation

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CELLULAR ADAPTATION

• Reversible changes in size, number, phenotype, metabolic activity, or function of cells in response to stress

1. Atrophy
2. Hypertrophy
3. Hyperplasia
4. Metaplasia
5. Dysplasia (maladaptive)

• Decrease in cell size (and possibly number)
• Causes: disuse (immobilization), denervation, ischemia, nutritional deprivation, loss of endocrine stimulation, aging, pressure
• Mechanism: ubiquitin-proteasome pathway, autophagy

• Increase in cell size without increase in cell number
• Occurs in cells unable to divide (cardiomyocytes, neurons)
• Physiological: pregnancy uterus, exercise skeletal muscle
• Pathological: cardiac hypertrophy (hypertension, valvular disease)
• Triggered by: mechanical stress, growth factors, hormones

• Increase in cell number (with or without size increase)
• Occurs in cells capable of division (epithelial, stromal)
• Physiological: endometrial hyperplasia, lactating breast
• Pathological: BPH, endometrial hyperplasia from excess estrogen
• Controlled (responds to growth factor removal)

• Reversible replacement of one differentiated cell type by another
• Usually squamous replaces columnar (or vice versa)
• Examples: Barrett's esophagus (squamous → columnar), bronchial metaplasia (columnar → squamous from smoking)
• May progress to dysplasia → carcinoma if stimulus persists

• Cellular self-digestion of damaged organelles and proteins via lysosomes
• Protective in starvation (recycles intracellular components for energy)
• Can lead to cell death if excessive (autophagic cell death)
• Mechanism: double-membrane autophagosomes fuse with lysosomes

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INTRACELLULAR ACCUMULATIONS

• Lipids (fatty change/steatosis, cholesterol)
• Proteins (Russell bodies, α1-antitrypsin)
• Glycogen (diabetes, glycogen storage diseases)
• Pigments: hemosiderin, lipofuscin, melanin, bilirubin

• Intracellular: foam cells in atherosclerosis, xanthomas
• Extracellular: cholesterol crystals in gallstones, atherosclerotic plaques
• Macrophages engulf oxidized LDL → foam cells

• Iron-storage protein; golden-brown granular pigment
• Derived from degradation of ferritin
• Prussian blue stain positive
• Accumulates in: hemolysis, hemochromatosis, chronic hemorrhage, pulmonary congestion

• Primary (hereditary hemochromatosis): HFE gene mutation → excessive intestinal iron absorption
• Secondary: multiple blood transfusions, excessive dietary iron
• Organs affected: liver (cirrhosis), pancreas (diabetes), heart (cardiomyopathy), skin (bronzing), joints
• "Bronze diabetes" = hemochromatosis

• AR disorder; ATP7B gene mutation → defective copper excretion
• Copper accumulates in: liver (cirrhosis), brain (neuropsychiatric symptoms), eye (Kayser-Fleischer rings), kidney
• Lab: decreased ceruloplasmin, increased urinary copper
• Orcein stain for copper in liver

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NECROSIS

• Pathological cell death with cell membrane disruption, cytoplasmic content release, and inflammation
• Always pathological (unlike apoptosis which can be physiological)

1. Coagulative - most common; protein denaturation preserves cell outline; ischemic organs
2. Liquefactive - enzymatic digestion; brain infarcts, abscesses
3. Caseous - cheese-like; TB (granulomatous necrosis)
4. Fat necrosis - lipase action; acute pancreatitis, breast trauma
5. Gangrenous - coagulative + putrefaction; limb ischemia + infection
6. Fibrinoid - immune complexes + plasma proteins in vessel walls; vasculitis, malignant hypertension

• Cell cytoplasm becomes eosinophilic, nuclei disappear, cell outlines preserved (ghost cells)
• Due to denaturation of structural and enzymatic proteins
• Seen in: heart, kidney, spleen infarcts
• Except brain: liquefactive necrosis

• Enzymatic digestion of dead cells; no ghost cells; liquefied, creamy contents
• Seen in: brain (limited stroma, rich in proteolytic enzymes), bacterial abscesses
• Abscess = localized collection of pus (liquefactive necrosis + neutrophils)

• Caseous: central cheesy necrosis + granuloma rim (TB)
• Fat: chalky white deposits (calcium soaps from saponification of fat)
• Fibrinoid: pink, amorphous, necrotic vessel walls

• Pyknosis: nuclear condensation/shrinkage (dark, small nucleus)
• Karyorrhexis: fragmentation of pyknotic nucleus
• Karyolysis: dissolution/fading of nucleus due to DNase activity

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APOPTOSIS

• Programmed cell death; energy-dependent, controlled elimination of individual cells without triggering inflammation
• Characterized by: cell shrinkage, chromatin condensation, membrane blebbing, apoptotic bodies

• Physiological: embryogenesis, menstrual cycle, thymus selection, turnover of intestinal epithelium
• Pathological: DNA damage (radiation, chemotherapy), viral infection, immune-mediated killing, growth factor withdrawal

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CALCIFICATION

• Abnormal deposition of calcium salts in tissues
• Two types: dystrophic and metastatic

• Calcium deposition in dead or dying tissue
• Serum calcium is NORMAL
• Examples: atherosclerotic plaques, old TB foci (caseous necrosis), dead parasites, psammoma bodies
• Mechanism: cell death → mitochondria accumulate Ca²+ → crystallize

• Calcium deposition in normal tissues due to hypercalcemia
• Serum calcium is ELEVATED
• Causes: hyperparathyroidism, vitamin D toxicity, multiple myeloma, bone metastases, sarcoidosis
• Sites: lungs (most common), kidney, gastric mucosa, blood vessel walls, cornea

• Laminated, concentric calcified spherules (dystrophic calcification)
• Seen in: Papillary thyroid carcinoma, Papillary serous carcinoma of ovary, Meningioma, Mesothelioma
• Mnemonic: "Pam's tumors" - Papillary thyroid, Ovary serous, Meningioma, Mesothelioma

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FREE RADICALS

• Highly reactive molecules with unpaired electrons
• Main types: superoxide (O₂•⁻), hydrogen peroxide (H₂O₂), hydroxyl radical (•OH) - most dangerous

• Normal metabolism (mitochondrial electron transport)
• Reperfusion after ischemia (major source)
• Phagocyte NADPH oxidase (respiratory burst in neutrophils)
• Ionizing radiation, drugs, toxins
• Fenton reaction: Fe²+ + H₂O₂ → Fe³+ + •OH

• Lipid peroxidation: damage to cell membranes
• Protein oxidation: enzyme inactivation, structural protein damage
• DNA damage: strand breaks, base modifications → mutations

• Superoxide dismutase (SOD): O₂•⁻ → H₂O₂
• Catalase: H₂O₂ → H₂O + O₂
• Glutathione peroxidase: reduces H₂O₂ and lipid peroxides
• Vitamins C, E, beta-carotene
• Ceruloplasmin, transferrin (sequester Fe/Cu)

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TOPIC 4: ACUTE INFLAMMATION

• Protective response of vascularized tissue to injury, infection, or foreign material
• Goal: destroy/dilute the injurious agent and prepare for healing
• Components: vascular, cellular, chemical mediator phases

• Acute: rapid onset, short duration, neutrophils predominate, exudate formation
• Chronic: slow onset, long duration, lymphocytes/macrophages predominate, fibrosis

• Immediate response to injury
• Duration: hours to days
• Key cells: neutrophils (first 24-48 hrs)
• Outcomes: resolution, abscess, chronic inflammation, fibrosis

• Infections (bacteria, viruses, fungi, parasites)
• Tissue necrosis (ischemia, trauma)
• Foreign bodies
• Immune reactions (hypersensitivity)

1. Rubor (redness) - vasodilation
2. Calor (heat) - increased blood flow
3. Tumor (swelling) - edema
4. Dolor (pain) - bradykinin, prostaglandins
5. Functio laesa (loss of function) - Virchow's addition

• Transient vasoconstriction (seconds)
• Vasodilation (arterioles) → increased blood flow → redness/heat
• Increased vascular permeability → protein-rich exudate leaks out → edema
• Mediators: histamine, bradykinin, NO, leukotrienes

1. Margination (neutrophils move to periphery)
2. Rolling (selectin-mediated)
3. Adhesion/Pavementing (integrin-mediated, ICAM-1)
4. Transmigration/Diapedesis (through vessel wall)
5. Chemotaxis (movement toward chemotactic agents)
6. Phagocytosis

• Slowing of blood flow (stasis) allows neutrophils to move to vessel periphery
• Erythrocytes stack in center (rouleaux formation)
• Precedes rolling and adhesion

• Neutrophils firmly adhere to endothelial surface
• Mediated by integrins (LFA-1, Mac-1) binding ICAM-1 on endothelium
• Requires activation by chemokines

• Leukocytes squeeze between endothelial cells (paracellular)
• Guided by PECAM-1 (CD31) at cell junctions
• Enter interstitial tissue, then follow chemotactic gradient

• Directional movement of leukocytes along a chemical gradient
• Major chemotactic agents: C5a, LTB4, IL-8, bacterial products (fMLP)
• Requires G-protein coupled receptors on leukocytes

• Steps: Recognition/attachment → Engulfment → Killing
• Recognition enhanced by opsonins (IgG, C3b)
• Killing: oxidative (NADPH oxidase → ROS; MPO → hypochlorous acid) + non-oxidative (lysozyme, defensins)
• Myeloperoxidase deficiency → recurrent Candida infections

• Protein-rich fluid (>3 g/dL) that escapes from vessels during inflammation
• Contains fibrin, inflammatory cells
• Indicates increased vascular permeability (inflammatory)

• Protein-poor fluid (<3 g/dL) due to hydrostatic/oncotic imbalance
• No inflammatory cells; ultrafiltrate of plasma
• Seen in: CHF, nephrotic syndrome, cirrhosis

• Cell-derived: histamine, serotonin, prostaglandins, leukotrienes, platelet-activating factor, cytokines
• Plasma-derived: complement (C3a, C5a), kinin system (bradykinin), clotting cascade

• Stored in mast cells, basophils, platelets
• Released by: trauma, IgE-mediated reaction, C3a, C5a
• Effects: vasodilation, increased vascular permeability, bronchoconstriction
• H1 receptors mediate most inflammatory effects

• Found in platelets and GI enterochromaffin cells
• Released during platelet aggregation
• Effects: similar to histamine; vasoconstriction/dilation depending on vessel
• Less important than histamine in human inflammation

• Derived from arachidonic acid via COX-1 and COX-2
• PGE₂, PGI₂: vasodilation, increased vascular permeability, fever (hypothalamic), pain sensitization
• TXA₂: vasoconstriction, platelet aggregation
• Blocked by NSAIDs (COX inhibitors), aspirin

• Derived from arachidonic acid via 5-lipoxygenase pathway
• LTB4: potent chemotactic agent for neutrophils
• LTC4, LTD4, LTE4 (slow-reacting substances): bronchoconstriction, increased permeability, vasoconstriction
• Blocked by zileuton (5-LOX inhibitor), montelukast (LT receptor antagonist)

• Caused by exogenous pyrogens (LPS) → stimulate macrophages → endogenous pyrogens (IL-1, TNF, IL-6)
• Endogenous pyrogens → COX-2 → PGE₂ in hypothalamus → raise set point
• Aspirin/NSAIDs → inhibit COX → reduce PGE₂ → reduce fever

• Fever (IL-1, TNF, IL-6, PGE₂)
• Leukocytosis (bacterial = neutrophilia; viral = lymphocytosis; parasitic/allergic = eosinophilia)
• Acute phase response: ↑ CRP, fibrinogen, serum amyloid A, ferritin; ↓ albumin, transferrin
• Increased ESR (↑ fibrinogen → rouleaux formation)

1. Resolution: complete restoration (most common if minor)
2. Fibrosis (scarring): extensive damage; fibrous repair
3. Abscess formation: walled-off collection of pus
4. Progression to chronic inflammation: persistent injury

• Localized collection of pus surrounded by a fibrous capsule (pyogenic membrane)
• Contents: dead and dying neutrophils, liquefied necrotic tissue, bacteria
• Requires surgical drainage; antibiotics alone insufficient
• Common organisms: Staphylococcus aureus

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TOPIC 5: CHRONIC INFLAMMATION & WOUND HEALING

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CHRONIC INFLAMMATION

• Inflammation of prolonged duration (weeks to months) where ongoing injury and attempted healing occur simultaneously

• Persistent infections (TB, syphilis, fungi, helminths)
• Autoimmune diseases (RA, SLE, IBD)
• Prolonged toxic exposure (silicosis, berylliosis)
• Follows unresolved acute inflammation

• Specialized form of chronic inflammation
• Hallmark: granuloma - aggregate of activated macrophages (epithelioid cells) + lymphocytes + giant cells
• Types: caseating (TB, fungi) and non-caseating (sarcoidosis, Crohn's, berylliosis, foreign body)
• Giant cells: Langhans type (TB), foreign body type
• Mechanism: Th1 response, IL-12, IFN-γ → macrophage activation

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WOUND HEALING

• Restoration of tissue architecture and function after injury
• Involves: regeneration (replacement by same cell type) + repair (replacement by fibrous scar)

• Replacement of lost tissue with identical cells
• Requires: viable tissue framework (ECM intact), labile/stable cells
• Labile cells (continuous division): skin, GI epithelium, hematopoietic cells
• Stable cells (division when stimulated): hepatocytes, renal tubular cells, smooth muscle
• Permanent cells (no division): neurons, cardiomyocytes, skeletal muscle

• Occurs when ECM is damaged or when tissue cannot regenerate
• Fibrous connective tissue replaces parenchymal cells
• Steps: granulation tissue → collagen deposition → remodeling → scar

1. Inflammatory phase (0-3 days): hemostasis, neutrophil influx, macrophage activation
2. Proliferative phase (3-21 days): angiogenesis, fibroblast proliferation, granulation tissue, re-epithelialization
3. Remodeling phase (21 days-2 years): collagen remodeling, scar maturation, wound contraction

• Clean, apposed wound edges (surgical incision)
• Minimal tissue loss, no infection
• Rapid healing, minimal scar

• Large, gaping wound; edges cannot be apposed
• Significant tissue loss, infection common
• Requires more granulation tissue, more collagen, more contraction
• More scar formation

• Hallmark of repair
• Appears 3-5 days after injury
• Components: new capillaries (angiogenesis), fibroblasts, myofibroblasts, inflammatory cells
• Pink, granular appearance
• Replaces fibrin clot; later replaced by collagen scar

• Formation of new blood vessels from pre-existing vessels
• Stimulated by: VEGF (vascular endothelial growth factor), FGF, hypoxia
• Steps: endothelial activation → proteolysis of basement membrane → migration → proliferation → tube formation

• Replacement of type III collagen with type I collagen (stronger)
• Mediated by MMPs (collagenase, gelatinase) balanced by TIMPs
• Scar reaches ~70% of original tensile strength (never 100%)
• Can continue for up to 2 years

• Systemic: malnutrition (protein, vitamin C, zinc), diabetes (↓ angiogenesis, ↑ infection), corticosteroids (↓ inflammation/collagen), anemia, advanced age
• Local: infection (most common cause of delayed healing), poor blood supply, foreign body, wound size, radiation

• Keloid
• Hypertrophic scar
• Wound dehiscence
• Contracture (excessive contraction)
• Incisional hernia
• Wound infection

• Excessive collagen deposition beyond the wound margins; irregular, raised scar
• Does NOT regress spontaneously
• More common in dark-skinned individuals
• Recurs after excision
• Type III collagen > Type I collagen

• Raised, red scar confined within wound margins
• May regress over time
• Does not recur if excised properly
• Distinguished from keloid by staying within wound boundaries

• Impaired due to: microangiopathy (poor vascularity), neuropathy, ↓ growth factor activity, ↑ infection risk, reduced neutrophil function, advanced glycation end-products (AGEs) impairing collagen formation

• Rupture of wound edges, usually within first 2 weeks
• Causes: infection, poor nutrition, obesity, steroids, technical failure
• Most common after abdominal surgery

• Essential for collagen synthesis (hydroxylation of proline and lysine residues)
• Deficiency (scurvy) → impaired collagen synthesis → poor wound healing, perifollicular hemorrhages, bleeding gums

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TOPIC 6: HEMATOLOGY

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ANEMIA

• Reduction in the oxygen-carrying capacity of blood
• Defined as Hb <13.5 g/dL in males, <12 g/dL in females (WHO)

• Morphological: microcytic (IDA, thalassemia), normocytic (aplastic, hemolytic, ACD), macrocytic (megaloblastic)
• Pathophysiological: blood loss, decreased production, increased destruction (hemolysis)
• By MCV: microcytic (<80 fL), normocytic (80-100 fL), macrocytic (>100 fL)

• Most common anemia worldwide
• Causes: chronic blood loss (most common in adults), poor intake, malabsorption
• Blood picture: microcytic hypochromic anemia; target cells, pencil cells
• Lab: ↓ serum iron, ↓ ferritin, ↑ TIBC, ↓ serum transferrin saturation

• Deficiency of B12 or folate → impaired DNA synthesis → nuclear maturation lag
• Blood picture: macrocytic anemia; hypersegmented neutrophils (≥5 lobes)
• Megaloblasts in bone marrow
• B12 deficiency also causes subacute combined degeneration of spinal cord
• Causes: pernicious anemia (lack of intrinsic factor), malabsorption, dietary deficiency

• Bone marrow failure → pancytopenia (↓ RBC, ↓ WBC, ↓ platelets)
• Causes: autoimmune (most common), radiation, drugs (chloramphenicol, benzene), hepatitis (non-A, non-B, non-C)
• Bone marrow biopsy: hypocellular marrow replaced by fat
• Treatment: immunosuppression + bone marrow transplant

• Premature destruction of RBCs (intravascular or extravascular)
• Lab: ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes, Hb in urine (intravascular)
• Types: immune (AIHA, transfusion reaction), non-immune (G6PD, sickle cell, thalassemia, TTP, malaria)

• Autosomal recessive; HbS (βGlu6Val mutation)
• RBCs sickle under hypoxia, acidosis, dehydration
• Complications: vaso-occlusive crises, dactylitis, acute chest syndrome, stroke, splenic sequestration, avascular necrosis
• Hemoglobin electrophoresis: HbS
• Protective against P. falciparum malaria

• Group of inherited hemoglobin disorders with reduced synthesis of α or β chains
• β-thalassemia major: severe; HbF elevated, transfusion-dependent; Cooley's anemia; crew-cut skull X-ray
• α-thalassemia: gene deletions; Hb Barts (4 gene deletion = hydrops fetalis)
• Treatment: regular transfusions, chelation therapy, BMT

• Increased RBC mass (Hb >17 g/dL males, >15 g/dL females)
• Primary (PV): JAK2 V617F mutation; all cell lines increased; low EPO
• Secondary: hypoxia (COPD, high altitude) or EPO-producing tumors → increased EPO
• Features of PV: splenomegaly, pruritis after bathing, Budd-Chiari, thrombosis

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LEUKEMIA

• Malignant clonal proliferation of hematopoietic cells in the bone marrow with spillover into blood

• By cell of origin: lymphoid (ALL, CLL) vs. myeloid (AML, CML)
• By course: acute (blasts >20%) vs. chronic (mature cells, slower course)

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LYMPHOMA

• Malignant neoplasm of lymphoid cells that typically presents as a solid tumor in lymph nodes or extranodal sites

• Hodgkin lymphoma (HL): Reed-Sternberg cells; bimodal age distribution; good prognosis
  • Classical HL, lymphocyte-rich HL, nodular lymphocyte-predominant HL
  • Ann Arbor staging
• Non-Hodgkin lymphoma (NHL): diverse group; more common than HL; spread to extranodal sites
  • Follicular (indolent), DLBCL (aggressive), Burkitt's (EBV, t(8;14))

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MULTIPLE MYELOMA

• Malignant proliferation of plasma cells in bone marrow producing monoclonal immunoglobulin (M protein)
• Most common primary bone marrow malignancy in adults

• CRAB criteria: Calcium elevated (hypercalcemia), Renal failure, Anemia, Bone lesions (punched-out lytic lesions)
• Recurrent bacterial infections (↓ normal immunoglobulins)
• Amyloidosis (AL type)

• Serum electrophoresis: M-protein spike (monoclonal band)
• Urine: Bence-Jones protein (free light chains κ or λ)
• Bone marrow biopsy: >10% plasma cells
• X-ray skull: punched-out lesions ("rain drop skull")
• ↑ serum calcium, ↑ total protein, ↑ ESR (very high), ↓ albumin
• Rouleaux formation on peripheral blood smear

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TOPIC 7: HEMOSTASIS & BLEEDING DISORDERS

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• Process that prevents blood loss after vascular injury while maintaining blood fluidity within intact vessels
• Involves: vascular spasm, platelet plug formation, coagulation cascade, fibrinolysis

1. Vascular spasm (immediate, transient)
2. Primary hemostasis: platelet plug formation (1-3 min): adhesion (vWF-GP Ib) → activation → aggregation (fibrinogen-GP IIb/IIIa)
3. Secondary hemostasis: coagulation cascade → fibrin clot
4. Fibrinolysis: plasmin degrades clot (tPA → plasminogen → plasmin)

• Due to: platelet defects (↓ number or function), coagulation factor defects, vascular defects
• Platelet disorders → immediate bleeding (petechiae, purpura, mucosal)
• Coagulation disorders → delayed deep bleeding (hemarthrosis, muscle hematomas)

• Platelet count <150,000/µL
• Causes: decreased production (aplastic anemia, chemotherapy), increased destruction (ITP, TTP, HIT), sequestration (hypersplenism)
• Features: petechiae, purpura, mucosal bleeding, menorrhagia

• Autoimmune destruction of platelets by IgG antibodies (anti-GP IIb/IIIa)
• Acute ITP: children post-viral infection; self-limiting
• Chronic ITP: adults, especially women; requires treatment
• Lab: ↓ platelets, normal PT/APTT, normal/↑ megakaryocytes in bone marrow
• Treatment: steroids, IVIG, splenectomy, rituximab

• Systemic activation of coagulation → microthrombi + consumption of clotting factors + bleeding
• Causes: sepsis (most common), obstetric emergencies (abruptio placentae, amniotic fluid embolism), malignancy, massive trauma, snake venom
• Lab: ↓ platelets, ↑ PT, ↑ APTT, ↑ D-dimer, ↓ fibrinogen, fragmented RBCs (schistocytes)
• Paradox: simultaneous thrombosis AND hemorrhage

• X-linked recessive; Factor VIII deficiency
• Features: hemarthrosis (joints), deep muscle hematomas, post-surgical bleeding
• Lab: ↑ APTT, normal PT, normal BT
• Treatment: Factor VIII concentrate, DDAVP (mild disease)

• X-linked recessive; Factor IX deficiency
• Clinically identical to Hemophilia A; distinguished by specific factor assay
• Treatment: Factor IX concentrate

• Most common inherited bleeding disorder
• Deficiency/dysfunction of vWF → impaired platelet adhesion + decreased Factor VIII stability
• Features: mucosal bleeding, menorrhagia, prolonged BT
• Lab: ↑ BT, ↑ APTT (decreased FVIII), normal PT, ristocetin aggregation test abnormal
• Treatment: DDAVP (releases vWF from endothelium), vWF concentrate

• Factor XII → XI → IX → VIII → X (common pathway)
• Tested by APTT
• Initiated by contact activation (exposed collagen, HMWK)
• Defects in VIII, IX, XI cause bleeding; XII deficiency does NOT cause bleeding

• Tissue factor (III) + Factor VII → X (common pathway)
• Tested by PT (Prothrombin Time)
• Initiated by tissue factor release after injury
• Faster than intrinsic pathway

• Hereditary or acquired predisposition to thrombosis
• Inherited: Factor V Leiden (most common), Prothrombin G20210A, Protein C/S deficiency, Antithrombin III deficiency
• Acquired: antiphospholipid syndrome, OCP, malignancy, immobility

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TOPIC 8: DIABETES MELLITUS

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• Metabolic disorder characterized by chronic hyperglycemia due to absolute or relative insulin deficiency, resistance, or both

1. Type 1 DM: autoimmune β-cell destruction; absolute insulin deficiency
2. Type 2 DM: insulin resistance + relative insulin deficiency; most common (90%)
3. Gestational DM: glucose intolerance first recognized in pregnancy
4. MODY: Maturity-onset diabetes of the young; monogenic defects

• Fasting plasma glucose ≥126 mg/dL (on 2 occasions)
• 2-hr OGTT ≥200 mg/dL
• Random plasma glucose ≥200 mg/dL + symptoms
• HbA1c ≥6.5%
• Pre-diabetes: FPG 100-125 mg/dL (IFG) or OGTT 140-199 mg/dL (IGT)

• Autoimmune destruction of β-cells (T-cell mediated)
• Association with HLA-DR3, HLA-DR4
• Autoantibodies: anti-GAD, anti-islet cell, anti-insulin
• Absolute insulin deficiency → ketosis prone
• Onset: typically childhood/adolescence
• Requires insulin therapy

• Peripheral insulin resistance + progressive β-cell failure
• Strong genetic predisposition; associated with obesity
• Amyloid deposition in islets (IAPP/amylin)
• Managed with lifestyle, oral hypoglycemics, insulin (later)

• DKA (Type 1): hyperglycemia + ketosis + metabolic acidosis
• HHS (Type 2): extreme hyperglycemia + hyperosmolarity, no ketosis
• Hypoglycemia (treatment-induced)
• Somogyi effect: rebound hyperglycemia after nighttime hypoglycemia

• Absolute insulin deficiency → lipolysis → FFA oxidation → ketone bodies (acetoacetate, β-hydroxybutyrate)
• Anion gap metabolic acidosis
• Features: polydipsia, polyuria, nausea, vomiting, Kussmaul breathing, fruity breath, dehydration
• Lab: ↑ glucose, ↑ ketones, ↓ pH, ↓ HCO₃, ↑ anion gap
• Treatment: IV fluids, insulin, potassium replacement

• Type 2 DM; glucose >600 mg/dL; serum osmolality >320 mOsm/kg; no ketosis
• Severe dehydration, mental status changes
• Higher mortality than DKA
• Treatment: aggressive fluid resuscitation, insulin

• Diabetic retinopathy: microaneurysms → hard exudates → cotton wool spots → neovascularization (proliferative DR); leading cause of blindness in working-age adults
• Diabetic nephropathy: glomerulosclerosis (Kimmelstiel-Wilson nodules) → proteinuria → nephrotic syndrome → ESRD; leading cause of ESRD
• Diabetic neuropathy: "stocking-glove" peripheral neuropathy; autonomic neuropathy (gastroparesis, erectile dysfunction, postural hypotension)

• Coronary artery disease (leading cause of death in DM)
• Peripheral arterial disease → gangrene, amputations
• Stroke

• Early: microalbuminuria (30-300 mg/day) → overt proteinuria → nephrotic syndrome
• Pathology: glomerular basement membrane thickening, diffuse or nodular glomerulosclerosis
• Kimmelstiel-Wilson nodules (nodular glomerulosclerosis): pathognomonic
• Leading cause of ESRD worldwide

• Background (non-proliferative): microaneurysms, dot/blot hemorrhages, hard exudates, macular edema
• Proliferative: new vessel formation (neovascularization) due to VEGF → vitreous hemorrhage, retinal detachment
• Screening: annual fundoscopy

• Glucose intolerance first recognized in pregnancy (usually 24-28 weeks)
• Caused by placental hormones (HPL, cortisol) increasing insulin resistance
• Risks: macrosomia, neonatal hypoglycemia, stillbirth, maternal type 2 DM later
• Screened with 50g GCT → confirmed with 100g OGTT
• Treatment: diet, insulin

• FPG, random glucose, OGTT
• HbA1c (reflects 2-3 month average glucose; not affected by recent meals)
• C-peptide (measures endogenous insulin secretion; low in T1DM)
• Urine: glucose, ketones, albumin/creatinine ratio
• Lipid profile, renal function, eye examination

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TOPIC 9: RENAL PATHOLOGY

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GLOMERULAR DISEASES

• Inflammation of glomeruli, usually immune-mediated
• Mechanisms: immune complex deposition (most common), anti-GBM antibodies (Goodpasture's), ANCA-mediated

• By clinical presentation: nephritic vs. nephrotic syndrome
• By distribution: diffuse, focal, segmental, global
• By histology: proliferative, sclerosing, membranous

• Follows Group A β-hemolytic streptococcal throat/skin infection
• Type III hypersensitivity; immune complexes deposit in glomeruli → complement activation
• Onset: 1-3 weeks after throat infection, 3-6 weeks after skin infection
• Features: hematuria (cola-colored urine), edema (periorbital), hypertension, oliguria → nephritic syndrome
• Lab: ↑ ASO titer, ↓ C3, normal C4
• Biopsy: "lumpy-bumpy" subepithelial deposits on EM ("humps"), hypercellular glomeruli
• Prognosis: children - >95% recover; adults - higher risk of chronic GN

• Glomerular inflammation with: hematuria (RBC casts in urine), proteinuria (<3.5 g/day), hypertension, oliguria, azotemia (↑ creatinine, ↑ BUN)
• Causes: APSGN, IgA nephropathy, RPGN, Alport syndrome

• Massive protein loss from glomeruli: proteinuria >3.5 g/day, hypoalbuminemia, generalized edema, hyperlipidemia, lipiduria (fatty casts)
• Causes: Minimal change disease (children), Membranous nephropathy (adults), FSGS (African Americans), Diabetic nephropathy, Amyloidosis

• Most common nephrotic syndrome in children
• Light microscopy: normal glomeruli
• EM: effacement (fusion) of podocyte foot processes
• IF: negative (no deposits)
• Excellent response to steroids
• Associated with Hodgkin's lymphoma in adults

• Most common nephrotic syndrome in adults
• Immune complex deposition on sub-epithelial surface of GBM
• IF: granular IgG and C3 along GBM ("spike and dome" pattern on silver stain)
• Associated with: HBV, SLE, drugs (penicillamine, gold), autoantibodies (anti-PLA2R)
• Often progresses to CKD

• Clinical syndrome of rapid loss of renal function (weeks to months) with crescents on biopsy
• Three types:
  • Type I: Anti-GBM disease (Goodpasture's) - linear IgG on IF
  • Type II: Immune complex GN (lupus, APSGN) - granular on IF
  • Type III: Pauci-immune (ANCA-associated: Wegener's, microscopic polyangiitis) - no deposits on IF
• Crescents = proliferating parietal epithelial cells + monocytes filling Bowman's space
• Poor prognosis without treatment

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KIDNEY FAILURE

• Rapid decline in GFR over hours to days
• Criteria: ↑ serum creatinine ≥0.3 mg/dL in 48 hrs, or ↑ ≥1.5× baseline in 7 days, or UO <0.5 mL/kg/hr for ≥6 hrs
• Prerenal: hypovolemia, ↓ cardiac output (BUN:Cr ratio >20:1, fractional Na excretion <1%)
• Intrinsic renal: ATN (ischemia, nephrotoxins), GN, interstitial nephritis
• Postrenal: obstruction (BPH, stones, tumor)
• Most common cause of intrinsic AKI: acute tubular necrosis (ATN)

• Persistent kidney damage or GFR <60 mL/min/1.73m² for >3 months
• Stages 1-5 (Stage 5 = ESRD, GFR <15)
• Most common causes: Diabetic nephropathy, hypertension, GN

• Anemia: ↓ EPO production (normocytic, normochromic)
• Renal osteodystrophy: ↓ Vit D → ↓ Ca → ↑ PTH → osteitis fibrosa cystica; also osteomalacia
• Uremia: buildup of nitrogenous waste → encephalopathy, pericarditis, platelet dysfunction
• Hypertension: fluid overload + RAAS activation
• Hyperkalemia, Metabolic acidosis
• Cardiovascular disease: leading cause of death in CKD

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TUBULOINTERSTITIAL DISEASES

• Infection of the renal pelvis + parenchyma
• Most common organisms: E. coli (most common), Klebsiella, Proteus, Enterococcus
• Route: ascending (most common), hematogenous (rare)

• Acute pyelonephritis: fever, chills, flank pain (costovertebral angle tenderness), dysuria, frequency; pyuria, bacteriuria, WBC casts (pathognomonic)
• Chronic pyelonephritis: repeated infections → fibrosis → cortical scarring; irregular shrunken kidney; blunting of calyces on IVP

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RENAL TUMORS

• Most common primary renal malignancy in adults
• Originates from proximal tubular epithelium
• Subtypes: clear cell (most common, VHL gene), papillary, chromophobe, collecting duct
• Classic triad: flank pain + hematuria + palpable mass (late presentation, only 10%)
• Metastasizes early: lung ("cannonball" metastases), bone, liver, brain
• Paraneoplastic syndromes: erythrocytosis (EPO), hypercalcemia (PTHrP), Stauffer syndrome (hepatic dysfunction without metastasis)
• Spreads into renal vein → IVC ("tumor thrombus")
• Treatment: partial/radical nephrectomy

• Most common renal tumor of children (peak age 2-5 years)
• Associated with: WAGR syndrome (WT1 gene: Wilms, Aniridia, GU anomalies, Retardation), Beckwith-Wiedemann (WT2), Denys-Drash (WT1 mutation)
• Histology: triphasic - blastemal, stromal, epithelial components
• Presentation: large abdominal mass (often discovered incidentally), hematuria, hypertension
• Prognosis: excellent (>90% cure with surgery + chemo ± radiotherapy)

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QUICK REFERENCE SUMMARY

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