BDS General Pathology Syllabus

Name four important chemotactic agents for neutrophils.

$\ce{C5a}$, leukotriene $\ce{B4}$ (LTB4), bacterial N-formyl-methionyl peptides, and chemokines (e.g., IL-8/CXCL8).

Distinguish exudate from transudate using specific gravity and protein content.

Exudate: inflammatory, protein-rich fluid, specific gravity $> 1.020$, high protein/LDH, often cellular (from increased vascular permeability). Transudate: ultrafiltrate, protein-poor, specific gravity $< 1.012$, low protein, few cells (from hydrostatic/osmotic imbalance, not inflammation).

Which arachidonic acid metabolites derive from the cyclooxygenase versus the lipoxygenase pathway?

Cyclooxygenase (COX) → prostaglandins ($\ce{PGE2}$, $\ce{PGD2}$, $\ce{PGF2\alpha}$), prostacyclin ($\ce{PGI2}$), and thromboxane $\ce{A2}$. Lipoxygenase → leukotrienes ($\ce{LTB4}$ chemotactic; $\ce{LTC4}$, $\ce{LTD4}$, $\ce{LTE4}$ cause bronchospasm and vascular permeability) and lipoxins.

Name the four systemic plasma protein cascades activated in inflammation.

The complement system, the kinin system (producing bradykinin), the clotting/coagulation cascade, and the fibrinolytic system — all interlinked through activated Hageman factor (Factor XII).

What are the major functions of complement components C3a/C5a, C3b, and C5b-9?

C3a and C5a are anaphylatoxins (mast cell degranulation, increased permeability); C5a is also chemotactic. C3b is an opsonin promoting phagocytosis. C5b-9 forms the membrane attack complex (MAC) causing cell lysis.

Compare the four possible outcomes of acute inflammation.

(1) Complete resolution (return to normal), (2) healing by connective tissue replacement (fibrosis/scarring), (3) abscess formation, and (4) progression to chronic inflammation.

What cell types characterize chronic inflammation, and how does its infiltrate differ from acute inflammation?

Chronic inflammation is dominated by mononuclear cells — macrophages, lymphocytes, and plasma cells — with tissue destruction and repair (angiogenesis, fibrosis) occurring simultaneously. Acute inflammation is dominated by neutrophils and edema.

Define a granuloma and name its key cellular components.

A granuloma is a focal collection of activated (epithelioid) macrophages, often with a rim of lymphocytes and multinucleate giant cells (e.g., Langhans type). It forms in response to poorly digestible agents or T cell–mediated (type IV) immunity, as in TB and sarcoidosis.

Differentiate caseating from non-caseating granulomas with examples.

Caseating granulomas have central caseous (cheese-like) necrosis — classic of tuberculosis and some fungal infections. Non-caseating granulomas lack central necrosis — seen in sarcoidosis, Crohn disease, and foreign-body reactions.

Distinguish healing by primary intention from secondary intention.

Primary intention: clean, apposed wound (e.g., surgical incision) with minimal tissue loss, little granulation tissue, and a small scar. Secondary intention: large wound with tissue loss, healing by abundant granulation tissue, wound contraction (myofibroblasts), and a larger scar.

What is granulation tissue and what are its two defining components?

Granulation tissue is the specialized reparative tissue of healing, composed of (1) proliferating new blood vessels (angiogenesis) and (2) proliferating fibroblasts with loose connective/extracellular matrix. It appears soft, pink, and granular.

Classify cells by regenerative capacity: labile, stable, and permanent, with an example of each.

Labile: continuously dividing (surface epithelia, hematopoietic cells). Stable: quiescent in $\text{G}_0$ but can divide on stimulus (hepatocytes, renal tubular cells). Permanent: cannot regenerate (neurons, cardiac and skeletal muscle), healing only by scar.

Name three growth factors important in tissue repair and their principal actions.

VEGF — angiogenesis; PDGF — recruits and stimulates fibroblasts/smooth muscle and macrophages; TGF-$\beta$ — fibrogenic (stimulates collagen and ECM deposition, inhibits inflammation); FGF and EGF also drive proliferation and re-epithelialization.

List key local and systemic factors that impair wound healing.

Local: infection, foreign bodies, poor blood supply/ischemia, mechanical stress, wound size and location. Systemic: nutrition (protein, vitamin C deficiency), diabetes, glucocorticoids (inhibit collagen), old age, and metabolic status.

Write Starling's law of capillary fluid exchange and state which imbalances cause edema.

Net filtration $\propto (P_{c} - P_{i}) - \sigma(\pi_{c} - \pi_{i})$. Edema results from increased hydrostatic pressure ($P_c$), decreased plasma oncotic pressure ($\pi_c$, e.g., hypoalbuminemia), increased vascular permeability, lymphatic obstruction, or sodium/water retention.

List the five major pathophysiologic categories of edema.

(1) Increased hydrostatic pressure (heart failure, venous obstruction), (2) reduced plasma oncotic pressure (nephrotic syndrome, cirrhosis, malnutrition), (3) lymphatic obstruction (lymphedema), (4) sodium/water retention (renal disease), and (5) inflammation (increased permeability).

Define hemorrhage and distinguish petechiae, purpura, and ecchymoses by size.

Hemorrhage is extravasation of blood from vessels. Petechiae are 1–2 mm hemorrhages; purpura are $\geq 3$ mm (about 3–10 mm); ecchymoses are $> 1{-}2$ cm (larger subcutaneous 'bruises').

State the three components of Virchow's triad predisposing to thrombosis.

(1) Endothelial injury, (2) abnormal blood flow (stasis or turbulence), and (3) hypercoagulability of the blood.

How are arterial and venous thrombi different in composition and appearance?

Arterial (white) thrombi form under high flow at sites of endothelial injury, are platelet- and fibrin-rich with pale lines of Zahn, and grow retrograde. Venous (red) thrombi form in stasis, are rich in enmeshed red cells (occlusive), and propagate toward the heart.

What are lines of Zahn and what is their significance?

Lines of Zahn are alternating pale (platelet/fibrin) and dark (red cell) laminations within a thrombus. Their presence indicates the thrombus formed in flowing blood before death, distinguishing a true antemortem thrombus from a postmortem clot.

List the possible fates of a thrombus.

Propagation (enlargement), embolization, dissolution (fibrinolysis), and organization with recanalization (ingrowth of endothelium, fibroblasts forming new vascular channels).

Define an embolus 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 (>99%) is a thromboembolus, arising from a dislodged thrombus (e.g., deep vein thrombi causing pulmonary embolism).

Name four non-thrombotic types of embolism.

Fat embolism (long-bone fractures), air/gas embolism (decompression sickness — 'the bends'), amniotic fluid embolism (labor complication with DIC risk), and (tumor, atheromatous, or foreign-body emboli).

Contrast a red (hemorrhagic) infarct with a white (anemic) infarct.

Red infarcts occur in loose tissues with dual circulation or collateral flow, or with venous occlusion or reperfusion (e.g., lung, intestine). White infarcts occur with arterial occlusion in solid organs having end-arterial supply (e.g., heart, spleen, kidney).

Define shock and list its three major categories.

Shock is systemic hypoperfusion due to reduced cardiac output or effective circulating blood volume, causing cellular hypoxia. Major types: hypovolemic (blood/fluid loss), cardiogenic (pump failure, e.g., MI), and distributive — including septic, anaphylactic, and neurogenic shock.

Describe the three sequential stages in the progression of shock.

(1) Nonprogressive (compensated) — reflex mechanisms (baroreceptor, catecholamines, RAAS) maintain perfusion of vital organs; (2) Progressive — tissue hypoperfusion, worsening metabolic (lactic) acidosis; (3) Irreversible — cell and organ injury so severe that survival is impossible even if hemodynamics are corrected.

Explain the pathogenesis of septic shock.

Most often triggered by endotoxin (LPS) from gram-negative bacteria activating a massive cytokine cascade (TNF, IL-1, IL-6). This causes systemic vasodilation, increased vascular permeability, myocardial depression, DIC, and widespread endothelial activation, leading to hypotension and multi-organ failure.

Define the terms used in Mendelian pedigrees: penetrance, expressivity, and pleiotropy.

Penetrance = percentage of individuals with a mutant genotype who show the phenotype. Expressivity = degree/variability of phenotypic expression among affected individuals. Pleiotropy = a single gene producing multiple, often unrelated, phenotypic effects.

Compare the inheritance and recurrence risk of autosomal dominant versus autosomal recessive disorders.

Autosomal dominant: one mutant allele suffices; typically vertical transmission, affected in every generation, and a $50\%$ ($\frac{1}{2}$) risk to offspring of an affected parent. Autosomal recessive: two mutant alleles needed; horizontal pattern, carriers unaffected, and a $25\%$ ($\frac{1}{4}$) risk when both parents are carriers.

Give the classic example and molecular defect of an autosomal dominant structural-protein disorder.

Marfan syndrome — an autosomal dominant disorder caused by mutation in the FBN1 gene encoding fibrillin-1, weakening connective tissue and causing skeletal (tall, arachnodactyly), ocular (lens dislocation), and cardiovascular (aortic aneurysm/dissection) features.

Contrast the inheritance pattern of X-linked recessive disorders in males versus females.

X-linked recessive disorders (e.g., hemophilia A, Duchenne muscular dystrophy) affect hemizygous males fully; heterozygous females are usually asymptomatic carriers. There is no male-to-male transmission, and all daughters of an affected male are obligate carriers.

State the karyotype and key features of Down syndrome, and its most common cause.

Trisomy 21, karyotype $47,XY,+21$ (or $47,XX,+21$). Most cases (~95%) arise from meiotic nondisjunction, strongly correlated with advanced maternal age. Features: intellectual disability, flat facies, epicanthic folds, single palmar crease, congenital heart defects, and increased leukemia/Alzheimer risk.

Give the karyotypes and distinguishing features of Klinefelter and Turner syndromes.

Klinefelter: $47,XXY$ — hypogonadal male, tall, gynecomastia, small testes, infertility. Turner: $45,X$ — phenotypic female, short stature, webbed neck, streak (fibrous) ovaries with primary amenorrhea, and coarctation of the aorta.

Define a multifactorial (polygenic) disorder and list its characteristics.

A disorder caused by the combined action of multiple genes and environmental factors, producing a continuous (quantitative) trait. Examples: hypertension, diabetes mellitus, cleft lip/palate, neural tube defects. Recurrence risk rises with number of affected relatives and severity, and does not follow simple Mendelian ratios.

What are the three main mechanisms by which point mutations affect protein function?

(1) Missense mutation — single amino-acid substitution (e.g., sickle cell: $\text{Glu} \to \text{Val}$ at position 6 of $\beta$-globin); (2) Nonsense mutation — creates a premature stop codon and truncated protein; (3) Silent mutation — no amino-acid change. Frameshifts from insertions/deletions also disrupt the reading frame.

Explain trinucleotide repeat expansion as a molecular basis of genetic disease, with one example.

Amplification of a specific 3-nucleotide sequence beyond a normal threshold destabilizes gene function, often worsening in successive generations (anticipation). Example: Fragile X syndrome from $\ce{CGG}$ repeat expansion in FMR1; Huntington disease from $\ce{CAG}$ repeats in HTT.

Define anticipation and genomic imprinting in the context of genetic disease.

Anticipation: a disease appears at an earlier age and/or with increasing severity in successive generations (typical of trinucleotide-repeat disorders). Genomic imprinting: differential expression of a gene depending on parental origin, e.g., Prader-Willi (paternal deletion) versus Angelman (maternal deletion) of chromosome 15q.

Define neoplasia and distinguish the parenchyma from the stroma of a tumor.

Neoplasia is a new, abnormal, uncoordinated, and autonomous proliferation of cells that persists after the initiating stimulus ceases. Parenchyma = the proliferating neoplastic cells (determines the tumor's name/behavior); stroma = the supporting connective tissue and blood vessels (host-derived).

Give the general nomenclature rules for benign and malignant tumors of epithelial and mesenchymal origin.

Benign: add '-oma' to the cell of origin (e.g., adenoma, lipoma, chondroma). Malignant mesenchymal tumors: '-sarcoma' (e.g., osteosarcoma, liposarcoma). Malignant epithelial tumors: 'carcinoma' (e.g., adenocarcinoma, squamous cell carcinoma).

Compare benign and malignant tumors on differentiation, growth rate, invasion, and metastasis.

Benign: well differentiated, slow growth, expansile/encapsulated (no invasion), and no metastasis. Malignant: variable/poor differentiation (anaplasia), rapid growth with atypical mitoses, invasive infiltrative margins, and capacity to metastasize.

Define anaplasia and list its key cytologic features.

Anaplasia is lack of differentiation, the hallmark of malignancy. Features: pleomorphism (variation in cell/nuclear size and shape), hyperchromatic nuclei with a high nuclear:cytoplasmic ratio (approaching $1{:}1$), prominent nucleoli, abundant and atypical mitoses, and loss of normal polarity/architecture.

List the three principal routes by which malignant tumors metastasize.

(1) Lymphatic spread (typical of carcinomas, to regional lymph nodes), (2) hematogenous spread (typical of sarcomas, via veins to liver and lungs), and (3) seeding of body cavities/surfaces (transcoelomic, e.g., peritoneal spread of ovarian carcinoma).

Name the sequential steps of the metastatic cascade.

(1) Detachment (loss of E-cadherin/cell adhesion), (2) invasion of ECM/basement membrane (via proteases like matrix metalloproteinases), (3) intravasation into vessels, (4) survival and transport in circulation, (5) extravasation, and (6) colonization/growth at the distant site with angiogenesis.

State the classic two-step chemical carcinogenesis model of initiation and promotion.

Initiation: irreversible, mutation-causing DNA damage by a carcinogen (initiator). Promotion: reversible, non-mutagenic stimulation of proliferation of initiated cells by a promoter. Tumors arise only when initiation is followed by promotion; promotion alone or promotion before initiation does not cause tumors.

List the four classes of normal regulatory genes whose damage drives carcinogenesis.

(1) Proto-oncogenes (growth-promoting; gain-of-function → oncogenes), (2) tumor suppressor genes (growth-inhibiting; loss-of-function), (3) apoptosis-regulating genes, and (4) DNA-repair genes (caretaker genes).

Contrast oncogenes and tumor suppressor genes in terms of dominance and number of alleles that must be altered.

Oncogenes act in a dominant fashion — a single activated (mutated) allele is sufficient (gain of function). Tumor suppressor genes are typically recessive at the cellular level — BOTH alleles must be inactivated (loss of function), as described by Knudson's two-hit hypothesis.

Explain Knudson's two-hit hypothesis using retinoblastoma.

For a tumor suppressor gene like RB, both alleles must be inactivated ('two hits'). In hereditary retinoblastoma, one mutant RB allele is inherited (first hit in all cells), so a single somatic second hit causes bilateral, early tumors. In sporadic cases, both hits must occur somatically in the same cell, giving unilateral, later disease.

What is the function of the p53 gene and why is it called the 'guardian of the genome'?

$p53$ (TP53) is a tumor suppressor that senses DNA damage and arrests the cell cycle at the $\text{G}_1/\text{S}$ checkpoint to allow repair, or triggers apoptosis if damage is irreparable. Loss of both alleles allows damaged DNA to replicate, making $TP53$ the most commonly mutated gene in human cancers.

Name the major oncogene functional categories with one example each.

Growth factors (e.g., PDGF/SIS), growth factor receptors (e.g., ERBB2/HER2, RET), signal transducers (e.g., RAS — most common oncogene; ABL), nuclear transcription factors (e.g., MYC), and cell-cycle regulators (e.g., cyclin D/CDK4).

List the classic 'hallmarks of cancer' that malignant cells acquire.

Self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential (telomerase), sustained angiogenesis, tissue invasion and metastasis — plus enabling traits of genomic instability, tumor-promoting inflammation, altered metabolism (Warburg effect), and immune evasion.

What is the Warburg effect in cancer metabolism?

The Warburg effect is the tendency of tumor cells to rely on aerobic glycolysis — high glucose uptake and conversion to lactate even in the presence of oxygen — rather than oxidative phosphorylation, providing metabolic intermediates for rapid biosynthesis and growth. It underlies FDG-PET tumor imaging.

Define paraneoplastic syndrome and give two classic examples.

A paraneoplastic syndrome is a symptom complex in cancer patients not explained by local/metastatic tumor spread or by hormones native to the tissue. Examples: Cushing syndrome from ectopic ACTH (small cell lung carcinoma) and hypercalcemia from PTH-related peptide (squamous cell lung carcinoma).

Define grading versus staging of a malignant tumor.

Grading is based on histologic degree of differentiation and mitotic activity of tumor cells (how abnormal they look). Staging is based on anatomic extent — using the TNM system: T = size/extent of primary Tumor, N = regional lymph Node involvement, M = distant Metastasis. Staging is generally of greater clinical/prognostic value.