Para-Clinical Pathology Syllabus

Describe the three steps of phagocytosis.

(1) Recognition and attachment (aided by opsonins: IgG, C3b, collectins), (2) Engulfment (forming a phagosome that fuses with a lysosome → phagolysosome), and (3) Killing/degradation (via ROS from the respiratory burst, reactive nitrogen species/NO, and lysosomal enzymes).

What generates the oxidative burst in neutrophil killing, and what is chronic granulomatous disease?

NADPH oxidase converts $\ce{O2}$ to superoxide, then $\ce{H2O2}$; myeloperoxidase (MPO) converts $\ce{H2O2 + Cl^{-}}$ to hypochlorite ($\ce{HOCl}$), the most potent bactericidal agent. Chronic granulomatous disease results from an inherited NADPH oxidase defect, causing recurrent infections with catalase-positive organisms.

Classify the chemical mediators of inflammation into cell-derived vs plasma-derived, with examples.

Cell-derived: histamine, serotonin (preformed); prostaglandins, leukotrienes, PAF, ROS, NO, cytokines (TNF, IL-1), chemokines (newly synthesized). Plasma-derived: complement system (C3a, C5a, MAC), kinin system (bradykinin), and coagulation/fibrinolytic systems.

Which arachidonic acid metabolites cause vasodilation, vasoconstriction, and chemotaxis? Name the two enzyme pathways.

Cyclooxygenase (COX) pathway → prostaglandins ($\ce{PGI2/PGE2}$ vasodilation; $\ce{TXA2}$ vasoconstriction + platelet aggregation). Lipoxygenase pathway → leukotrienes ($\ce{LTB4}$ chemotaxis; $\ce{LTC4/D4/E4}$ bronchoconstriction and increased permeability, the 'SRS-A').

Name the outcomes/sequelae of acute inflammation.

(1) Complete resolution, (2) Healing by fibrosis (scarring), (3) Abscess formation, or (4) Progression to chronic inflammation.

Define chronic inflammation and list its three histologic hallmarks.

Chronic inflammation is prolonged inflammation (weeks to years) in which active inflammation, tissue injury, and healing proceed simultaneously. Hallmarks: (1) infiltration by mononuclear cells (macrophages, lymphocytes, plasma cells), (2) tissue destruction, and (3) attempts at repair (angiogenesis and fibrosis).

What is a granuloma, and what are the two types?

A granuloma is a focal collection of activated (epithelioid) macrophages, often with multinucleated giant cells, surrounded by lymphocytes. Types: (1) Immune/foreign-body granulomas driven by T-cell responses (e.g., TB, sarcoidosis), and (2) Foreign-body granulomas around inert material. Caseating granulomas suggest TB.

Describe the two states of macrophage activation and their roles.

Classically activated (M1) — induced by IFN-$\gamma$ and microbial products; produce ROS, NO, IL-1, IL-12, TNF; microbicidal and pro-inflammatory. Alternatively activated (M2) — induced by IL-4/IL-13; produce TGF-$\beta$ and growth factors; anti-inflammatory, promote tissue repair and fibrosis.

List the main components of tissue repair by regeneration vs scarring, and define labile, stable, and permanent tissues.

Regeneration restores normal tissue; scarring replaces with connective tissue. Labile cells continuously divide (surface epithelium, bone marrow). Stable cells are quiescent but can divide when stimulated (hepatocytes, renal tubules). Permanent cells cannot divide (neurons, cardiac/skeletal muscle) and heal only by scar.

What is granulation tissue, and what are its components?

Granulation tissue is the hallmark of healing: soft pink granular tissue composed of proliferating fibroblasts, new capillaries (angiogenesis), and loose extracellular matrix, infiltrated by macrophages. It fills wounds and is later remodeled into a scar.

Name the key growth factor for angiogenesis and the key factor for fibrosis/scar deposition.

Angiogenesis: vascular endothelial growth factor (VEGF). Fibrosis (fibroblast proliferation and collagen deposition): transforming growth factor-beta (TGF-$\beta$), which also inhibits matrix degradation.

Contrast healing by first (primary) vs second (secondary) intention.

First intention: clean, sutured wounds with closely apposed edges; minimal tissue loss, little granulation tissue, small scar. Second intention: large wounds with tissue loss and open edges; abundant granulation tissue, wound contraction (myofibroblasts), and a larger scar.

Compare a keloid and a hypertrophic scar.

A hypertrophic scar has excess collagen but stays within the boundaries of the original wound and may regress. A keloid extends BEYOND the original wound margins, does not regress, and has a genetic predisposition (more common in darker-skinned individuals).

Give Starling's forces and state the two main mechanisms that cause edema.

Fluid movement is governed by hydrostatic vs oncotic pressure: net filtration $\propto (P_{c} - P_{i}) - \sigma(\pi_{c} - \pi_{i})$. Edema results mainly from increased capillary hydrostatic pressure and/or decreased plasma colloid osmotic (oncotic) pressure, plus lymphatic obstruction and sodium retention.

Differentiate transudate from exudate (protein content, specific gravity, cause).

Transudate: low protein, specific gravity $< 1.012$, few cells; from hydrostatic/oncotic imbalance (e.g., heart failure, hypoalbuminemia). Exudate: high protein, specific gravity $> 1.020$, many cells; from increased vascular permeability due to inflammation.

List four major categories of edema causes.

(1) Increased hydrostatic pressure (heart failure, venous obstruction), (2) Reduced plasma oncotic pressure (nephrotic syndrome, cirrhosis, malnutrition → hypoalbuminemia), (3) Lymphatic obstruction (lymphedema, e.g., filariasis, post-surgery), and (4) Sodium/water retention (renal disease, activation of RAAS).

Define hematoma, petechiae, purpura, and ecchymosis by size.

Hematoma — accumulation of blood in tissue. Petechiae — 1–2 mm hemorrhages (skin/mucosa), associated with thrombocytopenia. Purpura — $\geq 3$ mm hemorrhages. Ecchymosis — 1–2 cm subcutaneous hematoma ('bruise'). Bilirubin degradation causes the color change red-blue → green → gold-brown.

State the three components of Virchow's triad for thrombosis.

(1) Endothelial injury, (2) Abnormal blood flow (stasis or turbulence), and (3) Hypercoagulability of blood.

List inherited (primary) causes of hypercoagulability.

Factor V Leiden (resistance to activated protein C — most common), prothrombin G20210A mutation, deficiencies of antithrombin III, protein C, or protein S, and hyperhomocysteinemia (MTHFR).

What are the lines of Zahn, and what do they signify?

Lines of Zahn are alternating pale layers (platelets/fibrin) and dark layers (red cells) seen in a thrombus. Their presence indicates the thrombus formed in flowing blood ANTEMORTEM (before death), distinguishing true thrombi from postmortem clots.

List the possible fates of a thrombus.

(1) Propagation (enlargement), (2) Embolization (detachment and travel), (3) Dissolution (fibrinolysis), and (4) Organization and recanalization (ingrowth of endothelium, fibroblasts → new channels).

Define embolism and name the most common type.

An embolus is a detached intravascular solid, liquid, or gaseous mass carried by blood to a site distant from its origin. The most common type is thromboembolism (99%), usually a venous thrombus that lodges in the pulmonary circulation (pulmonary embolism).

Where do most pulmonary emboli originate, and what defines a saddle embolus?

About 95% of pulmonary emboli arise from deep vein thromboses of the lower extremities (popliteal, femoral, iliac veins). A saddle embolus is a large embolus that lodges at the bifurcation of the main pulmonary artery and can cause sudden death.

Describe fat embolism, amniotic fluid embolism, and air/gas embolism (decompression sickness).

Fat embolism: after long-bone fractures; triad of pulmonary insufficiency, neurologic symptoms, and petechial rash. Amniotic fluid embolism: during labor; can cause DIC and shock. Air embolism/decompression sickness ('the bends'): $\ce{N2}$ bubbles from rapid decompression; chronic form is caisson disease.

Define paradoxical embolism.

A paradoxical embolism occurs when an embolus from the venous circulation passes through a right-to-left shunt (e.g., patent foramen ovale or atrial/ventricular septal defect) into the systemic arterial circulation, bypassing the pulmonary filter.

Define shock and list its three major categories.

Shock is systemic hypoperfusion causing cellular hypoxia, from reduced cardiac output or reduced effective circulating blood volume. Categories: (1) Hypovolemic (blood/fluid loss), (2) Cardiogenic (pump failure, e.g., MI), and (3) Distributive (septic, anaphylactic, neurogenic — from vasodilation).

Describe the pathogenesis of septic shock.

Most often from gram-negative (endotoxin/LPS) or gram-positive infection. Microbial products activate innate immunity via TLRs, triggering massive cytokine release (TNF, IL-1), widespread vasodilation, endothelial activation, increased permeability, DIC, and metabolic derangements — leading to warm hypotension, then multiorgan failure.

Name the three progressive stages of shock.

(1) Nonprogressive (compensated) — reflex compensatory mechanisms (tachycardia, vasoconstriction, RAAS) maintain perfusion. (2) Progressive — tissue hypoperfusion with worsening metabolic (lactic) acidosis. (3) Irreversible — severe cellular/tissue injury making survival impossible even if hemodynamics are corrected.

Define Mendelian disorder and give the three basic patterns of single-gene inheritance.

Mendelian disorders result from mutations in a single gene of large effect. Patterns: autosomal dominant, autosomal recessive, and X-linked (recessive or dominant).

Contrast autosomal dominant and autosomal recessive disorders (enzymes, onset, examples).

Autosomal dominant: often affect structural/receptor proteins, appear in every generation, variable expressivity/reduced penetrance (e.g., Marfan, familial hypercholesterolemia, Huntington). Autosomal recessive: usually enzyme deficiencies, skip generations, more uniform expression, often early onset (e.g., cystic fibrosis, phenylketonuria, most storage diseases).

State the key features of X-linked recessive inheritance.

Genes on the X chromosome; affected mainly males (hemizygous), transmitted by heterozygous carrier females. No male-to-male transmission; all daughters of an affected male are carriers. Examples: hemophilia A/B, Duchenne muscular dystrophy, G6PD deficiency, color blindness.

Explain penetrance and expressivity.

Penetrance is the percentage of individuals carrying a mutant gene who actually express the trait (incomplete penetrance = some carriers are phenotypically normal). Expressivity is the DEGREE to which the trait is expressed among those who show it (variable expressivity = same genotype, different severity).

Compare Marfan syndrome and Ehlers-Danlos syndrome by defective protein.

Marfan syndrome: autosomal dominant defect in FBN1 (fibrillin-1), a glycoprotein of elastic microfibrils; skeletal, ocular (lens dislocation), and cardiovascular (aortic aneurysm) features. Ehlers-Danlos: heterogeneous defects in collagen synthesis/structure; hyperextensible skin, hypermobile joints, and fragile tissues.

What is the normal human karyotype, and how are numerical vs structural chromosomal abnormalities defined?

Normal karyotype is 46,XX (female) or 46,XY (male) — 46 chromosomes total. Numerical abnormalities are gains/losses of whole chromosomes (aneuploidy, e.g., trisomy/monosomy, usually from nondisjunction; or polyploidy). Structural abnormalities involve breaks: deletions, translocations, inversions, isochromosomes, and ring chromosomes.

Give the karyotypes and key features of Down, Klinefelter, and Turner syndromes.

Down syndrome: trisomy 21 (47,XX or XY,+21); intellectual disability, flat facies, congenital heart defects. Klinefelter: 47,XXY; tall male, hypogonadism, gynecomastia, infertility. Turner: 45,X (monosomy X); short female, webbed neck, ovarian dysgenesis (streak gonads), coarctation of the aorta.

What is Robertsonian translocation and its clinical importance in Down syndrome?

A Robertsonian translocation is fusion of the long arms of two acrocentric chromosomes (e.g., 13, 14, 15, 21, 22) with loss of the short arms. In Down syndrome, translocation of extra chromosome 21 material (e.g., der(14;21)) means a phenotypically normal carrier parent has a high recurrence risk in offspring.

Define multifactorial (polygenic) inheritance and its characteristics.

Multifactorial disorders result from the combined effects of MULTIPLE genes (each of small effect) plus environmental factors. Characteristics: familial clustering without a Mendelian pattern, risk increases with number of affected relatives and severity, and there is a threshold effect. Examples: hypertension, diabetes mellitus, cleft lip/palate, neural tube defects, coronary artery disease.

Explain trinucleotide (triplet) repeat mutations and give two examples.

Trinucleotide repeat disorders arise from amplification of a repeating 3-nucleotide sequence, showing ANTICIPATION (worsening severity/earlier onset in successive generations). Examples: Fragile X syndrome ($\ce{CGG}$ repeats in FMR1), Huntington disease ($\ce{CAG}$ repeats in HTT), and myotonic dystrophy ($\ce{CTG}$).

What are the key features of mitochondrial (maternal) inheritance?

Mitochondrial DNA is inherited exclusively from the mother (maternal inheritance); an affected mother transmits to ALL children, but only daughters pass it on. Features heteroplasmy (variable mutant mtDNA proportion) and affects high-energy tissues. Example: Leber hereditary optic neuropathy (LHON).

Explain genomic imprinting with the classic example of Prader-Willi vs Angelman syndrome.

Genomic imprinting is parent-of-origin-specific silencing of a gene. Both map to chromosome 15q. Prader-Willi syndrome results from loss of the PATERNAL gene copy (hyperphagia, obesity, hypotonia). Angelman syndrome results from loss of the MATERNAL copy (ataxia, seizures, inappropriate laughter — 'happy puppet').

Distinguish oncogenes, tumor suppressor genes, and their mechanisms of activation/inactivation.

Oncogenes are mutated/overexpressed proto-oncogenes that promote autonomous growth; a single (dominant) allele activation suffices (gain of function). Tumor suppressor genes normally inhibit proliferation; BOTH alleles must be inactivated (Knudson two-hit hypothesis, loss of function) — e.g., RB, TP53, APC.

State the six classic hallmarks of cancer (Hanahan and Weinberg).

(1) Self-sufficiency in growth signals, (2) Insensitivity to growth-inhibitory (antigrowth) signals, (3) Evasion of apoptosis, (4) Limitless replicative potential (immortality, telomerase), (5) Sustained angiogenesis, and (6) Ability to invade and metastasize. (Later additions: reprogrammed metabolism and immune evasion.)

Differentiate benign and malignant neoplasms on differentiation, growth rate, invasion, and metastasis.

Benign: well differentiated, slow growth, encapsulated/non-invasive, no metastasis (e.g., adenoma). Malignant: variable differentiation (may be anaplastic), rapid/erratic growth with many mitoses, locally invasive with irregular margins, and can metastasize (e.g., carcinoma).

Define anaplasia and list its cytologic features.

Anaplasia means 'lack of differentiation' and is a hallmark of malignancy. Features: pleomorphism (variation in cell/nuclear size and shape), hyperchromatic nuclei with a high nuclear-to-cytoplasmic ratio (approaching $1:1$ vs the normal $1:4$–$1:6$), prominent nucleoli, abnormal/atypical mitoses, and loss of polarity.

Give the nomenclature rules: adenoma, carcinoma, sarcoma, -oma exceptions.

Benign epithelial or mesenchymal tumors end in '-oma' (adenoma, lipoma). Malignant epithelial tumors = carcinomas; malignant mesenchymal tumors = sarcomas. Misleading '-oma' malignancies: lymphoma, melanoma, seminoma, mesothelioma, glioma. Teratoma arises from more than one germ layer; hamartoma and choristoma are non-neoplastic.

Compare the three main routes of metastatic spread and the typical tumors using each.

(1) Lymphatic spread — typical of carcinomas (to regional lymph nodes). (2) Hematogenous spread — typical of sarcomas (and some carcinomas); liver and lungs are common sites via portal/caval drainage. (3) Seeding of body cavities — e.g., ovarian carcinoma spreading transcoelomically across the peritoneum.

Explain the multistep model of carcinogenesis and the role of driver vs passenger mutations.

Carcinogenesis is a multistep accumulation of mutations: initiation (permanent DNA damage), promotion (clonal expansion), and progression (acquisition of additional malignant traits). Driver mutations confer selective growth advantage and drive cancer; passenger mutations are neutral bystanders that accumulate but do not contribute to the malignant phenotype.

Describe the RB gene and the cell cycle checkpoint it controls.

RB is a tumor suppressor that governs the $G_1 \to S$ checkpoint. Hypophosphorylated (active) RB binds E2F, blocking transcription of S-phase genes. Growth signals activate cyclin D–CDK4/6 to phosphorylate RB, releasing E2F and allowing progression. Loss of RB (or of p16/INK4a) removes this brake, causing uncontrolled proliferation.

Why is TP53 called 'the guardian of the genome,' and what does it do after DNA damage?

p53 senses DNA damage and either arrests the cell cycle at $G_1/S$ (via transcription of p21, a CDK inhibitor) to allow DNA repair, or triggers apoptosis (via BAX/PUMA) if damage is irreparable. It also induces senescence. TP53 is the most commonly mutated gene in human cancers; germline loss causes Li-Fraumeni syndrome.

Define oncogene addiction and give an example of a targeted therapy exploiting it.

Oncogene addiction is the dependence of a tumor on the continued activity of a single driver oncogene for survival, making that oncogene a therapeutic target. Example: imatinib inhibits the BCR-ABL fusion tyrosine kinase (t(9;22), Philadelphia chromosome) in chronic myeloid leukemia; trastuzumab targets HER2 in breast cancer.

What is the Warburg effect in cancer metabolism?

The Warburg effect is the tendency of cancer cells to rely on aerobic glycolysis — metabolizing glucose to lactate even in the presence of oxygen ($\ce{glucose -> 2\, lactate}$) — rather than oxidative phosphorylation. This provides rapid ATP and biosynthetic intermediates for proliferation and is the basis of FDG-PET tumor imaging.

List the major DNA repair systems and a cancer syndrome linked to each defect.

Mismatch repair defect → hereditary nonpolyposis colorectal cancer (Lynch syndrome, microsatellite instability). Nucleotide excision repair defect → xeroderma pigmentosum (UV sensitivity, skin cancers). Homologous recombination defect → BRCA1/BRCA2 mutations (breast/ovarian cancer) and Fanconi anemia.

Define paraneoplastic syndrome and give two classic hormone examples.

A paraneoplastic syndrome is a tumor-associated symptom complex not explained by local tumor spread or hormones normal to the tissue. Examples: small cell lung carcinoma producing ACTH (Cushing syndrome) or ADH (SIADH); squamous cell lung carcinoma producing PTHrP (hypercalcemia).

What are tumor grading and staging, and which better predicts prognosis?

Grading assesses the degree of differentiation/anaplasia and mitotic activity (how the tumor LOOKS). Staging assesses the extent of spread using the TNM system — Tumor size/extent, regional lymph Nodes, distant Metastasis. Staging has greater prognostic value than grading.

Explain the adenoma-carcinoma sequence in colorectal cancer with key gene changes.

Normal epithelium → (APC loss on 5q) → hyperproliferative epithelium/adenoma → (KRAS activation) → adenoma growth → (loss of tumor suppressors on 18q, e.g., SMAD4) → (TP53 loss on 17p) → carcinoma. Accumulation of these sequential mutations, not their order alone, drives malignant transformation.

Define telomeres and telomerase and their role in cancer immortality.

Telomeres are repetitive $\ce{TTAGGG}$ sequences capping chromosome ends that shorten with each division, eventually triggering senescence. Telomerase, a reverse transcriptase, rebuilds telomeres. It is silent in most somatic cells but reactivated in ~90% of cancers, granting limitless replicative potential (immortality).

Name the major chemical, radiation, and microbial (viral) carcinogens with an associated cancer.

Chemical: aflatoxin B1 (hepatocellular carcinoma, TP53 mutation), vinyl chloride (hepatic angiosarcoma), benzene (leukemia). Radiation: UV (skin cancers), ionizing radiation (leukemia, thyroid). Viral: HPV (cervical cancer, E6/E7 inactivate p53/RB), HBV/HCV (liver), EBV (Burkitt lymphoma, nasopharyngeal carcinoma), HTLV-1 (adult T-cell leukemia).