Pathology General Pathology: Cell injury, Necrosis & Apoptosis Acute vs chronic inflammation Cytokines, complement & coagulation cascade Immunology: Innate vs acquired immunity Hypersensitivity reactions CD markers Transplant rejection & GVHD (Graft-versus-Host Disease) Amyloidosis Autoimmune & Immunodeficiency disorders Neoplasia: Carcinogens & Tumor markers Hematology: Anemia patterns & Iron profiles Hereditary spherocytosis, G6PD deficiency Sickle cell anemia & Thalassemia ALL, AML, CLL, CML Hodgkin vs Non-Hodgkin lymphoma DIC, Hemophilia & vWD (von Willebrand Disease) Renal Pathology: Nephrotic vs nephritic syndrome PSGN, RPGN, Berger disease Minimal change disease, FSGS, MPGN RCC & bladder carcinoma GIT & Respiratory: Barrett esophagus & Gastric carcinoma Colon carcinoma & Polyps Asthma, COPD, ARDS & Emphysema Lung cancer & Pneumoconiosis CVS, Endocrine & CNS: Vasculitis & ANCA patterns IHD (Ischemic Heart Disease) & Cardiomyopathies Thyroid disorders & Pheochromocytoma CNS tumors & Breast carcinoma classification

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COMPREHENSIVE PATHOLOGY NOTES

PART 1: GENERAL PATHOLOGY

1.1 Cell Injury, Necrosis & Apoptosis

Cell Injury

Definition: Cell injury occurs when cells are stressed beyond their adaptive capacity, resulting in structural and functional abnormalities.

Causes of cell injury:

Hypoxia/ischemia (most common) - cuts off oxidative phosphorylation
Physical agents: trauma, heat, cold, radiation
Chemical toxins: CCl4, acetaminophen, heavy metals
Infectious agents: bacteria, viruses, parasites
Immune/inflammatory reactions
Nutritional deficiencies

Sequence of events in reversible injury:

ATP depletion → failure of Na+/K+-ATPase → cellular swelling (most common morphologic change)
Anaerobic glycolysis → lactic acid → pH falls → chromatin clumping
Ribosomal detachment → reduced protein synthesis
Membrane pump failure → Ca²+ influx, K+ efflux

Hallmarks of reversible injury:

Cellular swelling (hydropic change)
Fatty change (steatosis) - especially in liver
Plasma membrane blebbing
Reversible by removal of the injurious stimulus

Irreversible injury threshold:

Persistent ATP depletion → massive Ca²+ influx
Mitochondrial permeability transition (MPT) pore opening
Loss of plasma membrane integrity
Key indicator of irreversibility: enzyme leak into blood (LDH, troponin, AST/ALT)

Necrosis

Definition: Necrosis is a form of cell death involving enzymatic digestion and protein denaturation, typically affecting groups of cells, with host inflammatory response.

Biochemical mechanisms:

ATP depletion → mitochondrial dysfunction
Membrane damage via:
- Reactive oxygen species (ROS)
- Intracellular Ca²+ activation of phospholipases, proteases, endonucleases
- Loss of membrane phospholipids

Morphologic patterns of necrosis:

Type	Mechanism	Key Feature	Classic Example
Coagulative	Denaturation of proteins; cell outlines preserved	Ghost cells with preserved architecture	Myocardial infarction (all solid organs except brain)
Liquefactive	Enzymatic digestion dominates; liquid pus	No tissue architecture preserved	Brain infarcts; bacterial abscesses
Caseous	Combined coagulative + liquefactive	Cheese-like, white; no architecture; surrounded by granuloma	Tuberculosis
Fat	Lipase-mediated destruction of adipocytes	Chalky-white deposits (Ca²+ soaps)	Acute pancreatitis, breast trauma
Fibrinoid	Immune complex + fibrin deposits in vessel walls	Pink, homogeneous deposits	Vasculitis, malignant hypertension, polyarteritis nodosa
Gangrenous	Coagulative + liquefactive	"Dry" vs. "wet" gangrene	Limb ischemia

Necroptosis: Programmed (regulated) necrosis. Triggered by TNF, involves RIPK1/RIPK3. Morphologically resembles necrosis but is mechanistically caspase-independent.

Apoptosis

Definition: Programmed, energy-dependent cell death - clean, no inflammation. Involves single cells, cell shrinkage, chromatin condensation, apoptotic bodies.

Key features vs. necrosis:

Feature	Apoptosis	Necrosis
Cell size	Shrinkage	Swelling
Nucleus	Condensation, fragmentation	Karyolysis, karyorrhexis, pyknosis
Membrane	Intact	Disrupted
Inflammation	None	Yes
DNA	Ladder pattern (180bp)	Random fragmentation
Energy	Required (ATP)	Not required

Mechanisms of apoptosis:

Intrinsic (mitochondrial) pathway:

Triggered by: DNA damage, hypoxia, radiation, oxidative stress
Pro-apoptotic: BAX, BAK → increase mitochondrial permeability → release cytochrome c
Anti-apoptotic: BCL-2, BCL-XL (mutated/overexpressed in follicular lymphoma - t(14;18))
Cytochrome c + APAF-1 + caspase-9 → apoptosome → activates caspase-3 (executioner)
p53 is the key trigger for intrinsic pathway in DNA damage

Extrinsic (death receptor) pathway:

Triggered by: FasL/Fas interaction, TNF-α/TNFR
FADD recruited → activates caspase-8 → activates caspase-3
Granzyme B (from CTLs/NK cells) enters via perforin pores → activates caspases

Physiologic apoptosis examples:

Embryogenesis (interdigital web removal)
Hormonal involution (endometrium shedding, lactating breast)
Negative selection of autoreactive T cells in thymus
B cell selection in germinal centers

Pathologic apoptosis:

Increased: viral cytopathic effect, DNA damage (radiation), Councilman bodies (hepatitis)
Decreased: cancer (BCL-2 overexpression), autoimmunity

1.2 Acute vs. Chronic Inflammation

Acute Inflammation

Triggers: Infection, tissue necrosis, foreign bodies, immune reactions Duration: Minutes to days Hallmarks (Cardinal signs): Rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function)

Vascular events:

Transient vasoconstriction (seconds)
Vasodilation → increased blood flow (redness, heat) - mediated by histamine, NO, prostaglandins
Increased vascular permeability → exudate formation (edema)

Mechanisms of increased permeability:

Endothelial cell contraction (most common) - gaps form in postcapillary venules; mediated by histamine, bradykinin, leukotrienes
Direct endothelial injury (burns, toxins)
Leukocyte-mediated injury

Exudate vs. Transudate:

Feature	Exudate (Inflammation)	Transudate (Hydrostatic/Oncotic)
Protein	High (>3 g/dL)	Low (<3 g/dL)
Specific gravity	>1.020	<1.012
Cells	Many leukocytes	Few cells
Cause	Inflammation	Heart failure, cirrhosis, nephrotic syndrome

Leukocyte events (cellular phase):

Margination - leukocytes move to periphery (stasis)
Rolling - mediated by selectins (P-selectin on platelets/endothelium; E-selectin on endothelium; L-selectin on leukocytes)
Adhesion (firm) - integrins (LFA-1, Mac-1) bind ICAM-1, VCAM-1; upregulated by TNF-α, IL-1
Transmigration (diapedesis) - through junctions; PECAM-1 (CD31) guides
Chemotaxis - movement toward C5a, LTB4, bacterial products (fMet-Leu-Phe), IL-8
Phagocytosis - opsonization by IgG (Fc receptor) and C3b (complement receptor)
Killing - O2-dependent (NADPH oxidase → superoxide, H2O2, HOCl via MPO) and O2-independent (defensins, lysozyme, lactoferrin)

Defects in leukocyte function:

Leukocyte adhesion deficiency (LAD): CD18 (β2 integrin) mutation → no firm adhesion; elevated blood neutrophils, recurrent bacterial infections, delayed cord separation
Chediak-Higashi: abnormal microtubule polymerization → defective lysosome fusion; giant granules in leukocytes
Chronic Granulomatous Disease (CGD): NADPH oxidase defect → no respiratory burst; recurrent catalase-positive organisms (Staph aureus, Aspergillus)
MPO deficiency: usually mild, lab finding only

Outcomes of acute inflammation:

Resolution (ideal) - complete restoration
Abscess formation - suppurative inflammation, walled-off with fibrous tissue
Fibrosis/scarring - when tissue destruction is extensive
Chronic inflammation - if agent persists

Chronic Inflammation

Duration: Weeks to months/years Triggers: Persistent infections (TB, fungal), autoimmune diseases, prolonged exposure to toxic agents (silica, sutures), certain infections that evade killing

Key cell: Macrophage (central cell of chronic inflammation)

Activated by IFN-γ (from T cells and NK cells)
Functions: phagocytosis, antigen presentation (MHC II), secretes IL-1, TNF, IL-6, reactive oxygen species, growth factors (PDGF, TGF-β, VEGF)

Other cells: Lymphocytes (T and B), plasma cells, eosinophils (parasites/allergy), mast cells

Granulomatous inflammation:

Specialized form of chronic inflammation
Consists of clusters of activated macrophages (epithelioid cells) + giant cells + lymphocytes
Granuloma formation: antigen-driven macrophage activation; IL-12 from macrophages → IFN-γ from T cells → activates more macrophages
Types:
- Non-caseating: sarcoidosis, Crohn's disease, foreign body reactions, berylliosis
- Caseating: tuberculosis (most important)

Giant cell types:

Langhans giant cell: nuclei arranged peripherally in horseshoe pattern (TB)
Foreign body giant cell: nuclei scattered randomly
Touton giant cell: foamy cytoplasm, seen in fat necrosis, xanthomas

1.3 Cytokines, Complement & Coagulation Cascade

Key Cytokines

Cytokine	Source	Key Functions
IL-1	Macrophages	Fever, acute phase proteins, leukocyte activation; endogenous pyrogen
IL-2	T cells (Th1)	T cell proliferation and survival
IL-4	Th2 cells	IgE class switching, mast cell growth, inhibits Th1
IL-5	Th2 cells	Eosinophil production and activation
IL-6	Macrophages, T cells	Fever, acute phase proteins (CRP, fibrinogen), B cell differentiation
IL-8 (CXCL8)	Macrophages	Neutrophil chemotaxis
IL-10	Macrophages, Tregs	Anti-inflammatory, inhibits macrophage activation
IL-12	Macrophages, DCs	NK cell activation, Th1 differentiation, IFN-γ production
IL-17	Th17 cells	Neutrophil recruitment; anti-fungal, anti-extracellular bacterial
TNF-α	Macrophages	Fever, cachexia, acute phase response, activates endothelium (ICAM-1 upregulation), apoptosis
IFN-γ	Th1 cells, NK cells	Macrophage activation, MHC I & II upregulation
TGF-β	Macrophages, T cells	Anti-inflammatory, fibrosis, Treg differentiation

Acute Phase Response:

Triggered by IL-1, IL-6, TNF
Liver produces: CRP, serum amyloid A (SAA), fibrinogen, complement components
CRP: opsonin, activates complement; most sensitive marker of acute inflammation
SAA: precursor to secondary amyloid (AA type)

Complement System

Three pathways of activation:

Classical pathway:

Activated by: antigen-antibody complexes (IgG or IgM) → C1q binds
Sequence: C1 → C4 → C2 → C3 → C5-C9

Alternative pathway:

Activated by: microbial surfaces (LPS, fungal cell walls) directly; no antibody required
Sequence: C3 → Factor B, D, properdin → C3 convertase (C3bBb) → C5

Lectin (MBL) pathway:

Activated by: mannose-binding lectin (MBL) binds mannose on microbes
Similar to classical after MBL-MASP-C4-C2

Key products and functions:

Product	Function
C3a, C5a	Anaphylatoxins → mast cell degranulation, histamine release, vascular permeability
C5a	Most potent chemotactic factor; also anaphylatoxin
C3b	Opsonization (coats bacteria for phagocytosis)
C5b-9 (MAC)	Membrane attack complex → lysis of cells/bacteria
C1q	Initiates classical pathway; binds to apoptotic cell debris (clearance)

Complement deficiencies:

C1, C4, C2 (classical): SLE-like disease (impaired immune complex clearance)
C3: recurrent pyogenic infections (most severe)
C5-C9 (terminal): recurrent Neisseria infections (meningococcal/gonococcal)
DAF/CD59 deficiency: Paroxysmal Nocturnal Hemoglobinuria (PNH)

Coagulation Cascade

Two pathways converging at Factor X:

Extrinsic pathway (tissue factor pathway):

Triggered by: tissue factor (TF/Factor III) exposure from damaged subendothelium
TF + Factor VII → activates Factor X
Monitored by: PT (Prothrombin Time); INR standardizes this

Intrinsic pathway (contact activation):

Triggered by: exposed collagen, negatively charged surfaces
Factor XII (Hageman) → XI → IX → VIII → X
Monitored by: aPTT (activated Partial Thromboplastin Time)

Common pathway:

Factor X + Factor V (prothrombinase complex) → converts Prothrombin → Thrombin
Thrombin → Fibrinogen → Fibrin; also activates XIII (cross-links fibrin), V, VIII, platelets

Key inhibitors:

Antithrombin III: inhibits thrombin and Xa, IXa; heparin potentiates this 1000x
Protein C + S: inactivate Va and VIIIa; Vitamin K-dependent; activated by thrombin-thrombomodulin
TFPI: inhibits TF-VIIa complex
Plasmin: degrades fibrin → D-dimers (elevated in DIC, PE, DVT)

PART 2: IMMUNOLOGY

2.1 Innate vs. Acquired Immunity

Innate Immunity

Characteristics: Rapid (minutes to hours), non-specific, no memory, present from birth

Components:

Physical barriers: skin, mucociliary escalator, stomach acid, normal flora
Cells: neutrophils (first responders), macrophages, NK cells, dendritic cells, mast cells, eosinophils
Soluble mediators: complement (alternative/lectin pathways), acute phase proteins, defensins, interferons (IFN-α, IFN-β = type I)

Pattern recognition receptors (PRRs):

Toll-like receptors (TLRs): recognize PAMPs (pathogen-associated molecular patterns)
- TLR4: LPS (gram-negative bacteria)
- TLR9: CpG DNA (bacteria, viruses)
- TLR3: double-stranded RNA (viruses)
NOD receptors (NLRs): intracellular bacteria recognition → inflammasome activation → IL-1β, IL-18
RIG-I: intracellular RNA viruses

NK cell function:

Kill cells with low/absent MHC I (missing-self recognition) - virally infected or tumor cells
Activated by NKG2D ligands on stressed cells
Kill via perforin/granzyme and Fas-FasL
Inhibited by KIR (killer immunoglobulin-like receptors) binding MHC I
Produce IFN-γ (important bridge to adaptive immunity)

Acquired (Adaptive) Immunity

Characteristics: Slow (days), antigen-specific, memory, acquired during life

Two arms:

Humoral (B cell/antibody-mediated) - effective against extracellular pathogens
Cell-mediated (T cell) - effective against intracellular pathogens, tumors, transplants

Antigen presentation:

MHC I (HLA-A, B, C): presents endogenous (intracellular) peptides → to CD8+ CTLs
- On all nucleated cells
MHC II (HLA-DR, DP, DQ): presents exogenous (extracellular/phagocytosed) peptides → to CD4+ Th cells
- On professional APCs: dendritic cells (most potent), macrophages, B cells

T helper cell subsets:

Subset	Inducing cytokines	Secretes	Function
Th1	IL-12, IFN-γ	IFN-γ, TNF	Activate macrophages; cell-mediated immunity; fight intracellular pathogens
Th2	IL-4	IL-4, IL-5, IL-13	B cell help; IgE, IgG class switching; eosinophil activation; parasites/allergy
Th17	IL-6 + TGF-β	IL-17, IL-22	Neutrophil recruitment; extracellular bacteria/fungi
Treg	TGF-β	IL-10, TGF-β	Suppress immune responses; self-tolerance; FOXP3 transcription factor

B cell activation:

T-dependent: requires Th cell help (CD40L-CD40), class switching (to IgG, IgA, IgE)
T-independent: polysaccharide antigens; produce IgM only; no memory

2.2 Hypersensitivity Reactions (Gell & Coombs Classification)

Type I - Immediate (IgE-mediated)

Mechanism:

Sensitization: Allergen → Th2 → IL-4 → IgE production by B cells
IgE binds Fc receptors on mast cells/basophils
Re-exposure: allergen cross-links IgE → mast cell degranulation
Preformed mediators (immediate, within minutes): histamine, tryptase, heparin, chemotactic factors
Newly synthesized mediators (late phase, 6-12 hrs): prostaglandins, leukotrienes (LTC4, LTD4, LTE4 = most potent bronchoconstrictors), PAF, cytokines

Clinical examples:

Anaphylaxis (systemic) - peanuts, bee stings, penicillin
Allergic rhinitis, asthma (atopic)
Urticaria, atopic dermatitis
Food allergies

Treatment: Epinephrine (anaphylaxis), antihistamines (H1), corticosteroids

Type II - Antibody-Mediated Cytotoxicity

Mechanism: IgG or IgM antibodies bind cell surface antigens → cell destruction by:

Complement activation (MAC)
ADCC (antibody-dependent cellular cytotoxicity) by NK cells
Phagocytosis (opsonization)
Receptor blockade or stimulation (stimulatory type II)

Clinical examples:

Hemolytic transfusion reactions - ABO mismatch; anti-A/anti-B IgM
Hemolytic disease of newborn - anti-Rh IgG crosses placenta; erythroblastosis fetalis
Autoimmune hemolytic anemia - anti-RBC antibodies
Immune thrombocytopenic purpura (ITP) - anti-GP IIb/IIIa antibodies
Goodpasture syndrome - anti-GBM antibodies (also Type IV component); hematuria + hemoptysis
Graves disease - TSI (TSH receptor stimulating Ig) → stimulatory hyperthyroidism
Myasthenia gravis - anti-AChR antibodies → block receptor → muscle weakness
Pernicious anemia - anti-intrinsic factor antibodies → B12 deficiency

Type III - Immune Complex-Mediated

Mechanism:

Antigen-antibody (IgG, IgM) complexes form in blood
Deposited in vessel walls, glomeruli, synovium
Activate complement (C3a, C5a) → neutrophil recruitment → tissue damage

Key examples:

SLE - anti-dsDNA complexes in glomeruli (class III/IV lupus nephritis), skin, joints
PSGN - streptococcal antigen-antibody complexes in glomeruli
Serum sickness - 7-10 days after foreign serum/drug; fever, arthralgia, glomerulonephritis, urticaria
Arthus reaction - localized skin necrosis after repeated intradermal injection of antigen
Cryoglobulinemia - in hepatitis C
Hypersensitivity pneumonitis (farmer's lung, bird fancier's lung)

Laboratory: Low complement (C3, C4), positive ANA, anti-dsDNA; immune complex deposits on immunofluorescence (granular pattern)

Type IV - Delayed-Type Hypersensitivity (DTH) / Cell-Mediated

Mechanism: T cell-mediated (no antibody); 48-72 hour delay

Two subtypes:

Classical DTH (Th1 mediated):
- CD4+ Th1 cells sensitized → re-exposure → IFN-γ → macrophage activation → tissue damage
- Examples: tuberculin skin test (PPD), granuloma formation (TB, sarcoidosis), contact dermatitis (poison ivy, nickel), Hashimoto's, Type 1 DM
CTL-mediated (CD8+ T cell):
- Direct killing of target cells (MHC I presentation)
- Examples: viral exanthems, graft rejection

Contact dermatitis specifics: hapten (small molecule) + carrier protein → APC presents → sensitized; re-exposure → CD4+ Th1 + CD8+ response → 48-72 hr delayed reaction (spongiosis, vesicles)

2.3 CD Markers

CD Marker	Cell type	Key function
CD1a	Langerhans cells, DCs	Lipid antigen presentation
CD2	T cells, NK cells	Adhesion, activation
CD3	All T cells	TCR signal transduction complex
CD4	T helper cells	MHC II co-receptor; HIV receptor
CD5	T cells, B cell subset	Present on CLL cells
CD7	T cells	Pan-T cell marker
CD8	CTL, suppressor T cells	MHC I co-receptor
CD10 (CALLA)	Pre-B cells, germinal center B cells	Neutral endopeptidase; marker in ALL (pre-B)
CD11b (Mac-1)	Monocytes, macrophages, NK	Complement receptor (CR3)
CD14	Monocytes, macrophages	LPS receptor co-receptor
CD15	Neutrophils, Reed-Sternberg cells	Marker in Hodgkin lymphoma
CD16 (FcγRIII)	NK cells, macrophages	ADCC
CD19	All B cells	B cell marker (pan-B)
CD20	Mature B cells	B cell marker; target of rituximab
CD21 (CR2)	Mature B cells	EBV receptor; complement receptor
CD23	B cells, mast cells	IgE low-affinity Fc receptor; positive in CLL
CD25 (IL-2Rα)	Activated T cells, Tregs	IL-2 receptor; target of basiliximab; marker in HCL
CD28	T cells	Co-stimulatory receptor; binds B7 (CD80/86) on APCs
CD30	Activated T & B cells, Reed-Sternberg cells	Marker in Hodgkin lymphoma and ALCL
CD34	Stem cells, endothelium	HSC marker; target of G-CSF mobilization
CD38	Plasma cells	Marker in multiple myeloma; target of daratumumab
CD45 (LCA)	All leukocytes	Leukocyte common antigen
CD56	NK cells, plasma cells	NK cell marker; also in multiple myeloma
CD57	NK cells, T cell subset	NK marker
CD117 (c-Kit)	Mast cells, hematopoietic progenitors	SCF receptor; positive in AML (some), GIST
CD138 (Syndecan-1)	Plasma cells	Myeloma marker

2.4 Transplant Rejection & GVHD

Transplant Rejection

Hyperacute rejection (minutes to hours):

Mechanism: Pre-formed antibodies (Type II/III HS) against HLA or ABO antigens
Cause: ABO mismatch, prior sensitization (blood transfusion, pregnancy)
Pathology: Thrombosis of graft vessels, ischemic necrosis
Prevention: Crossmatch testing pre-transplant

Acute rejection (days to months):

Cellular (T cell mediated): CD8+ CTLs destroy donor cells; CD4+ T cells activate macrophages
- Pathology: Interstitial mononuclear infiltrate, tubulitis (kidney)
Humoral: Anti-donor antibodies form post-transplant
- Pathology: Vasculitis, fibrinoid necrosis, neutrophilic infiltrate

Chronic rejection (months to years):

Mechanism: Slow immune-mediated vascular injury + TGF-β-driven fibrosis
Pathology: Vascular intimal thickening (transplant arteriosclerosis), interstitial fibrosis/tubular atrophy (IFTA) in kidney, bronchiolitis obliterans (lung)
No effective treatment; main cause of late graft failure

Immunosuppression used:

Calcineurin inhibitors (cyclosporine, tacrolimus) - block IL-2 production
mTOR inhibitors (sirolimus, everolimus) - block T cell proliferation
Mycophenolate - block purine synthesis in lymphocytes
Corticosteroids
Azathioprine

Graft-versus-Host Disease (GVHD)

Definition: Donor T cells in graft recognize host as foreign and attack host tissues

Occurs in:

Allogeneic bone marrow/hematopoietic stem cell transplantation
Blood transfusion in immunocompromised patients

Acute GVHD (< 100 days):

Affects: Skin (maculopapular rash), liver (jaundice, elevated LFTs), GI tract (watery/bloody diarrhea)
Mechanism: Donor CD4+ and CD8+ T cells attack host epithelium; conditioning regimen-related damage amplifies response (alarmins, cytokine storm)

Chronic GVHD (> 100 days):

Resembles autoimmune diseases
Affects: skin (scleroderma-like), eyes (sicca), oral mucosa (lichenoid), liver (biliary cirrhosis), lungs (bronchiolitis obliterans)

Graft-versus-Leukemia (GVL) effect: The same donor T cells that cause GVHD also attack residual leukemic cells - beneficial anti-tumor effect

Prevention: HLA matching, T cell depletion, immunosuppression

2.5 Amyloidosis

Definition: Extracellular deposition of misfolded proteins in a characteristic beta-pleated sheet configuration

Key features:

Staining: Congo red → apple-green birefringence under polarized light (diagnostic)
Electron microscopy: 7.5-10 nm non-branching fibrils
All amyloid contains serum amyloid P (SAP) component

Classification by protein type:

Type	Protein Precursor	Disease Context	Distribution
AL	Immunoglobulin light chains (λ > κ)	Multiple myeloma, plasma cell dyscrasias, primary amyloidosis	Systemic
AA	Serum amyloid A (acute phase reactant)	Secondary to chronic inflammation (RA, IBD, TB, FMF, osteomyelitis)	Systemic; spares heart
ATTR	Transthyretin (TTR)	Senile systemic (wild-type TTR); hereditary familial (mutant TTR)	Heart, peripheral nerves
Aβ2M	β2-microglobulin	Long-term dialysis	Joints (carpal tunnel)
Aβ	APP (amyloid precursor protein)	Alzheimer's disease	Brain (senile plaques)
Prion (PrPSc)	Prion protein	CJD, kuru, Gerstmann-Straussler	Brain
AIAPP	Islet amyloid polypeptide	Type 2 diabetes	Pancreatic islets
AEt (calcitonin)	Calcitonin	Medullary thyroid carcinoma	Thyroid

Clinical manifestations of systemic amyloidosis:

Kidney (most common in AA, AL): Nephrotic syndrome (most common presentation), renal failure
Heart (AL, ATTR): Restrictive cardiomyopathy; "sparkling" on echo; low voltage on ECG
Liver: Hepatomegaly, cholestasis, rarely liver failure
Spleen: Sago spleen (white follicles - early) or lardaceous spleen (waxy, confluent deposits)
Nervous system: Peripheral/autonomic neuropathy
Tongue: Macroglossia (classic AL)
Adrenal: Adrenal insufficiency

Diagnosis: Tissue biopsy - abdominal fat pad (safest, most common), rectal mucosa, or affected organ Treatment: Treat underlying cause (AA); chemotherapy for AL; tafamidis for ATTR cardiomyopathy

2.6 Autoimmune Disorders

Mechanisms of self-tolerance failure:

Molecular mimicry - microbial antigen resembles self (GAS → rheumatic fever)
Bystander activation - inflammation activates autoreactive T cells non-specifically
Epitope spreading - new autoantigens exposed after initial damage
Polyclonal B cell activation - EBV, LPS
Defective Treg function
Abnormal apoptosis of self-reactive lymphocytes

Key autoimmune diseases and antibodies:

Disease	Key Antibodies	Key Features
SLE	ANA, anti-dsDNA (most specific), anti-Sm (most specific), anti-histone (drug-induced), anti-Ro, anti-La, antiphospholipid	Butterfly rash, discoid rash, photosensitivity, serositis, nephritis, hematologic
Sjögren syndrome	Anti-Ro/SSA, anti-La/SSB	Dry eyes (xerophthalmia), dry mouth (xerostomia), parotid enlargement; risk of lymphoma
Rheumatoid arthritis	Rheumatoid factor (IgM anti-IgG), anti-CCP (most specific)	Symmetric polyarthritis, pannus formation, subcutaneous nodules
Systemic sclerosis (Scleroderma)	Anti-Scl-70 (topoisomerase I) = diffuse; anti-centromere = limited (CREST)	Skin fibrosis, Raynaud's, pulmonary hypertension, ILD
Polymyositis/Dermatomyositis	Anti-Jo-1, anti-Mi-2	Proximal muscle weakness; heliotrope rash (DM)
Myasthenia gravis	Anti-AChR, anti-MuSK	Fatigable weakness; thymic hyperplasia/thymoma
Goodpasture syndrome	Anti-GBM (type IV collagen α3 chain)	Pulmonary hemorrhage + glomerulonephritis
Hashimoto's thyroiditis	Anti-TPO, anti-thyroglobulin	Hypothyroidism; most common cause of hypothyroidism in iodine-sufficient areas
Graves disease	TSI (thyroid-stimulating Ig)	Hyperthyroidism; exophthalmos; pretibial myxedema
Antiphospholipid syndrome	Anti-cardiolipin, anti-β2-GP1, lupus anticoagulant	Arterial/venous thrombosis, recurrent pregnancy loss, thrombocytopenia

2.7 Immunodeficiency Disorders

Primary (Congenital) Immunodeficiencies

B cell deficiencies:

Disease	Defect	Key Features
X-linked agammaglobulinemia (Bruton's)	BTK (Bruton's tyrosine kinase) mutation → no B cell maturation	Recurrent pyogenic infections after 6 months; absent tonsils, no lymph nodes; XL inheritance
Common Variable Immunodeficiency (CVID)	Unknown; failure of B cell to plasma cell	Late onset; low all Ig; recurrent infections; increased lymphoma, autoimmunity
IgA deficiency (most common primary ID)	Selective failure of IgA production	Usually asymptomatic; anaphylaxis to blood products (anti-IgA antibodies); GI/respiratory infections
Hyper-IgM syndrome	CD40L defect (XL most common); AID defect (AR)	Normal/elevated IgM; no other Ig; Pneumocystis jirovecii; Cryptosporidium

T cell deficiencies:

Disease	Defect	Key Features
DiGeorge syndrome	22q11 deletion → thymic aplasia	Absent T cells; intact B cells; tetany (hypocalcemia - absent parathyroids); cardiac defects; "CATCH-22"
Nude mice model	FOXN1 mutation	No thymus, no T cells

Combined (T + B) deficiencies:

Disease	Defect	Key Features
SCID (X-linked)	γc chain (IL-2Rγ) mutation → no T/NK cells; B cells dysfunctional	Most common SCID; all infections; give irradiated blood products; treat with HSCT
SCID (ADA deficiency)	Adenosine deaminase → toxic metabolites kill lymphocytes	Autosomal recessive; gene therapy available
Wiskott-Aldrich syndrome	WASp protein defect → abnormal actin cytoskeleton	Triad: eczema + thrombocytopenia + recurrent infections; XL; risk of lymphoma
Ataxia-telangiectasia	ATM kinase defect → impaired DNA repair	Cerebellar ataxia, telangiectasias, low IgA/IgG; sensitivity to radiation; lymphoma risk

Complement deficiencies (see section 1.3)

Phagocyte deficiencies:

CGD: NADPH oxidase defect → no respiratory burst → recurrent catalase-positive organisms (Staph, Aspergillus, Klebsiella, Serratia, Nocardia)
Chediak-Higashi: giant granules, albinism, peripheral neuropathy
LAD: CD18 mutation; no neutrophil adhesion

Secondary (Acquired) Immunodeficiencies

HIV/AIDS (covered separately in infectious disease)
Malnutrition, diabetes, renal failure, lymphoma/leukemia, immunosuppressive drugs

PART 3: NEOPLASIA

3.1 Carcinogens

Definition: Agents that cause cancer by inducing mutations, epigenetic changes, or promoting tumor growth

Categories:

Chemical Carcinogens

Carcinogen	Associated Cancer
Aflatoxin B1 (Aspergillus)	Hepatocellular carcinoma (p53 mutation at codon 249)
Benzene	AML, aplastic anemia
Vinyl chloride	Angiosarcoma of liver
Asbestos	Mesothelioma (pleural); lung carcinoma (synergy with smoking)
Aromatic amines (β-naphthylamine)	Bladder carcinoma
Benzidine	Bladder carcinoma
Nitrosamines	Gastric carcinoma
Polycyclic aromatic hydrocarbons (cigarette smoke)	Lung, bladder, oral cancers
Alkylating agents (cyclophosphamide)	Secondary AML, bladder
Arsenic	Squamous cell carcinoma of skin, angiosarcoma
Chromium/Nickel	Lung cancer

Two-step model of chemical carcinogenesis:

Initiation: Mutagen causes irreversible DNA mutation (permanent)
Promotion: Promoter causes clonal expansion of initiated cell (reversible; requires continued exposure)
Progression: Accumulation of additional mutations → invasive cancer

Radiation Carcinogens

Radiation type	Cancer
UV-B light	Squamous/basal cell carcinoma; melanoma; xeroderma pigmentosum (NER defect)
Ionizing radiation (X-ray, γ)	Leukemia (especially AML, CML), thyroid, breast, sarcomas
Radon (naturally occurring)	Lung cancer
Radioactive iodine (I-131)	Thyroid carcinoma

Oncogenic Viruses and Microbes

Agent	Cancer	Mechanism
HPV (16, 18)	Cervical, oropharyngeal, anal, penile	E6 → p53 degradation; E7 → Rb degradation
HPV (6, 11)	Genital warts (benign)	Low risk
EBV	Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin's (EBV+), PTLD	LMP-1 mimics CD40; EBERs
HBV, HCV	Hepatocellular carcinoma	Cirrhosis → HCC; HBV direct mutagenesis
HTLV-1	Adult T-cell leukemia/lymphoma	Tax protein activates NF-κB
HHV-8 (KSHV)	Kaposi sarcoma; primary effusion lymphoma	LANA protein
H. pylori	Gastric adenocarcinoma, MALT lymphoma	CagA protein; chronic inflammation
Schistosoma haematobium	Squamous cell carcinoma of bladder
Clonorchis sinensis	Cholangiocarcinoma

3.2 Tumor Markers

Definition: Substances (proteins, hormones, antigens) produced by or in response to tumors; used for screening, diagnosis, monitoring, not usually for primary diagnosis

Marker	Tumor	Clinical Notes
AFP (alpha-fetoprotein)	Hepatocellular carcinoma, hepatoblastoma, yolk sac tumor (testis)	Also elevated in normal pregnancy, liver disease
HCG	Gestational trophoblastic disease, choriocarcinoma, testicular germ cell tumors	Used to monitor treatment
CEA (carcinoembryonic antigen)	Colorectal, gastric, pancreatic, lung, breast	Not specific; used for monitoring recurrence of CRC
CA-125	Ovarian carcinoma (epithelial)	Also elevated in endometriosis, other GYN conditions
CA 19-9	Pancreatic carcinoma, cholangiocarcinoma	Used for monitoring
CA 15-3	Breast carcinoma	Monitoring treatment response
PSA (prostate-specific antigen)	Prostate carcinoma	Elevated in BPH, prostatitis too; free PSA ratio helps
Thyroglobulin	Thyroid carcinoma (differentiated)	Monitor post-thyroidectomy
Calcitonin	Medullary thyroid carcinoma (MEN2)	Amyloid in stroma
Chromogranin A	Carcinoid tumor, pheochromocytoma, neuroendocrine tumors	Universal NET marker
ACTH	Small cell lung carcinoma (ectopic), pituitary tumors	Cushing syndrome
PTH-rP	Squamous cell lung cancer, breast, renal	Hypercalcemia of malignancy
S-100	Melanoma, schwannoma, Langerhans cell histiocytosis	Neural crest origin marker
PLAP	Seminoma
CD30 + ALK	Anaplastic large cell lymphoma (ALCL)
Beta-2 microglobulin	Multiple myeloma

PART 4: HEMATOLOGY

4.1 Anemia Patterns & Iron Profiles

Classification of anemia:

By MCV (mean corpuscular volume):

Category	MCV	Causes
Microcytic	<80 fL	Iron deficiency, Thalassemia, Sideroblastic anemia, Anemia of chronic disease (usually normocytic)
Normocytic	80-100 fL	Anemia of chronic disease, aplastic anemia, hemolytic anemia, acute blood loss, renal failure
Macrocytic	>100 fL	Megaloblastic (B12/folate deficiency), non-megaloblastic (liver disease, hypothyroidism, alcohol, drugs)

Iron profile comparison:

Parameter	Iron Deficiency	Anemia of Chronic Disease	Thalassemia	Sideroblastic
Serum Iron	↓	↓	Normal/↑	↑
TIBC	↑	↓	Normal	Normal/↑
Ferritin	↓	↑ (acute phase)	Normal/↑	↑
Transferrin sat	↓	↓	Normal	↑
Mentzer index (MCV/RBC count)	>13	-	<13	-

Iron deficiency anemia:

Most common nutritional anemia worldwide
Causes: inadequate intake, malabsorption (celiac, postgastrectomy), chronic blood loss (GI, menstruation)
Blood smear: hypochromic microcytes, pencil cells, target cells
Clinical: fatigue, pallor, koilonychia (spoon nails), pica, Plummer-Vinson syndrome (dysphagia + iron def + esophageal web in women)
Treatment: ferrous sulfate (oral); IV iron if malabsorption

Megaloblastic anemia:

Impaired DNA synthesis → large cells with nuclear-cytoplasmic asynchrony
Blood smear: macro-ovalocytes, hypersegmented neutrophils (>5 lobes)
B12 (cobalamin) deficiency:
- Causes: pernicious anemia (anti-IF), strict veganism, ileal resection (absorption site), tapeworm (D. latum)
- Neurologic: subacute combined degeneration of spinal cord (posterior + lateral columns) - paresthesias, ataxia, dementia
Folate deficiency:
- Causes: poor diet, alcohol, methotrexate (DHF reductase inhibitor), pregnancy
- No neurologic symptoms
Distinction: Both have same CBC/smear; B12 deficiency has elevated methylmalonic acid + homocysteine; folate deficiency has only elevated homocysteine

4.2 Hereditary Spherocytosis

Defect: Mutations in spectrin, ankyrin, band 3, or band 4.2 → defective anchoring of lipid bilayer to cytoskeleton → membrane loss → spherocyte formation

Inheritance: Autosomal dominant (most common); AR forms

Pathophysiology: Spherocytes lack central pallor, less deformable → trapped and destroyed in spleen (extravascular hemolysis)

Clinical features:

Hemolytic anemia (variable severity)
Jaundice (unconjugated hyperbilirubinemia)
Splenomegaly
Pigment gallstones (bilirubin stones)
Aplastic crisis (parvovirus B19 infection suppresses erythropoiesis)
Folate deficiency (high turnover)

Labs: ↑ MCHC (hyperchromic), ↑ reticulocytes, ↑ unconjugated bilirubin, negative Coombs test (distinguish from AIHA), osmotic fragility test positive

Diagnosis: Flow cytometry with EMA binding (most sensitive); osmotic fragility test (older)

Treatment: Folic acid supplementation; splenectomy in severe cases (curative for anemia; increases Howell-Jolly bodies + thrombocytosis post-splenectomy)

4.3 G6PD Deficiency

Defect: G6PD enzyme deficiency → reduced NADPH production → reduced glutathione regeneration → RBCs cannot neutralize oxidative stress → hemolysis

Inheritance: X-linked recessive (common in African, Mediterranean, Middle East populations)

Pathophysiology: Oxidative stress → Heinz body (denatured Hb aggregates) formation → "bite cells" (macrophages bite out Heinz bodies in spleen) on smear

Triggers:

Infections (most common overall trigger)
Oxidant drugs: primaquine, dapsone, rasburicase, nitrofurantoin
Fava beans (type A: African variant milder; Mediterranean variant severe)
Neonatal jaundice

Clinical: Self-limited hemolytic episodes; back/abdominal pain, hemoglobinuria (dark urine), jaundice

Labs: Low G6PD enzyme activity; Heinz bodies on crystal violet stain; bite cells on smear; negative Coombs test

Note: G6PD level may be falsely normal during acute crisis (reticulocytes have high G6PD) - check 2-3 months later

Females: Carrier state; Lyon hypothesis (X-inactivation) may cause some enzyme deficiency

4.4 Sickle Cell Anemia

Mutation: HbS - single amino acid substitution: glutamic acid → valine at position 6 of β-globin chain (GAG → GTG)

Pathophysiology:

Deoxygenated HbS polymerizes → sickle-shaped cells
Factors favoring sickling: hypoxia, acidosis, dehydration, cold, infection
HbF (fetal Hb, γ-chains) inhibits sickling - used therapeutically (hydroxyurea ↑ HbF)

Genotypes:

HbSS (homozygous): Sickle cell disease - full manifestations
HbSC: milder disease; retinal complications, avascular necrosis
HbS/β-thalassemia: severity depends on β-thal type

Clinical manifestations:

Manifestation	Mechanism
Vaso-occlusive pain crisis	Sickled cells block microvasculature
Dactylitis (hand-foot syndrome)	Earliest manifestation in infants; avascular necrosis of small bones
Acute chest syndrome	Vaso-occlusion/fat embolism in pulmonary vasculature; fever + chest pain + pulmonary infiltrate
Stroke	Cerebrovascular occlusion; transcranial doppler screening
Avascular necrosis of femoral head	Bone ischemia
Splenic sequestration crisis	Massive acute splenomegaly; hypovolemia; functional asplenia
Aplastic crisis	Parvovirus B19; abrupt anemia
Autosplenectomy	Repeated infarcts → functional asplenia by age 5; Howell-Jolly bodies
Increased infection	Functional asplenia → encapsulated organisms (Strep pneumoniae, H. flu, N. meningitidis); Salmonella osteomyelitis (most common osteomyelitis in SCD)
Priapism	Vaso-occlusion in penile vessels
Retinopathy	HbSC > HbSS
Renal papillary necrosis	Medullary ischemia; hematuria
Pigment gallstones	Chronic hemolysis

Labs: HbS on HPLC; sickle cells + target cells on smear; Howell-Jolly bodies; elevated bilirubin; reticulocytosis

Treatment:

Hydroxyurea (increases HbF; reduces crises - first-line)
Prophylactic penicillin (until age 5)
Vaccinations: pneumococcal, meningococcal, Hib
Folic acid supplementation
Exchange transfusion: acute chest syndrome, stroke, severe pain
Voxelotor (Hb-S polymerization inhibitor), crizanlizumab (P-selectin inhibitor)
Curative: allogeneic HSCT; gene therapy (betibeglogene alterparvovec - approved 2023)

4.5 Thalassemias

Definition: Reduced or absent synthesis of one or more globin chains → imbalanced chain synthesis → ineffective erythropoiesis + hemolysis

Alpha-Thalassemia

Genetics: 4 α-globin genes (2 per chromosome 16); gene deletion most common

Genotype	Deleted genes	Clinical
Silent carrier	1/4 deleted	Asymptomatic; normal CBC
α-thal trait	2/4 deleted	Mild microcytic hypochromic anemia
HbH disease	3/4 deleted	HbH (β4 tetramers); moderate hemolytic anemia; splenomegaly
Hydrops fetalis	4/4 deleted	HbBarts (γ4); incompatible with life; stillbirth/immediate death

Beta-Thalassemia

Genetics: Point mutations in β-globin gene (chromosome 11); affects synthesis of β chains

Type	Genotype	Clinical
β-thal minor (trait)	β/β+ or β/β0	Mild microcytic anemia; target cells; elevated HbA2 (>3.5%) - diagnostic
β-thal intermedia	β+/β+	Moderate anemia; splenomegaly; may need occasional transfusion
β-thal major (Cooley's anemia)	β0/β0	Severe hemolytic anemia from 6 months; transfusion-dependent

Pathophysiology of β-thal major:

Absent β chains → excess α chains precipitate → intravascular hemolysis + ineffective erythropoiesis
Erythropoietin surge → massive extramedullary hematopoiesis → hepatosplenomegaly, frontal bossing, "hair on end" skull X-ray
Iron overload from transfusions + increased GI absorption → hemosiderosis → cardiomyopathy, diabetes, hypogonadism, cirrhosis

Treatment: Regular blood transfusions + iron chelation (deferoxamine, deferasirox); curative HSCT; luspatercept (activin receptor trap - reduces transfusion burden); gene therapy (betibeglogene - approved for HbE/β-thal)

4.6 Leukemias (ALL, AML, CLL, CML)

Acute Lymphoblastic Leukemia (ALL)

Most common childhood cancer; peak age 2-5 years

Cell of origin: Lymphoid precursors (B or T cell)

B-ALL (most common, 85%):

TdT+ (terminal deoxynucleotidyl transferase), CD10+, CD19+, CD20+/-
Most common chromosomal abnormalities:
- t(12;21) - TEL-AML1/ETV6-RUNX1: most common in children; best prognosis
- Hyperdiploidy (>50 chromosomes): good prognosis
- t(9;22) - BCR-ABL (Philadelphia chromosome): adults; worst prognosis → add imatinib
- t(4;11) - MLL rearrangement: infants; very poor prognosis

T-ALL (15%):

Adolescent males; mediastinal (thymic) mass
TdT+, CD1-8, CD7+

Clinical: Bone pain (marrow infiltration), lymphadenopathy, hepatosplenomegaly, CNS involvement, pallor, fever, bleeding

Treatment: Multi-agent chemotherapy (induction, consolidation, maintenance); CNS prophylaxis; HSCT for high-risk

Acute Myeloid Leukemia (AML)

Most common acute leukemia in adults; can arise de novo or from MDS/therapy

WHO classification based on genetic alterations

Key chromosome translocations:

Translocation	Gene fusion	Clinical
t(15;17)	PML-RARα	AML-M3 (APML) - best prognosis; treat with ATRA + arsenic trioxide; DIC risk
t(8;21)	RUNX1-RUNX1T1 (ETO)	AML-M2; good prognosis; Auer rods
inv(16)	CBFB-MYH11	AML-M4 eos; good prognosis
t(9;11)	MLL (KMT2A)	AML-M5 (monocytic); intermediate prognosis
FLT3-ITD	Internal tandem duplication of FLT3	Poor prognosis; midostaurin added
NPM1 mutation	Normal localization	Good prognosis (without FLT3)

Morphologic subtypes (FAB):

M0: undifferentiated; M1: minimal differentiation; M2: maturation (t(8;21), Auer rods); M3: APML (t(15;17)); M4: myelomonocytic; M5: monocytic; M6: erythroleukemia; M7: megakaryoblastic (Down syndrome)

Clinical: Pancytopenia → infections, bleeding, anemia; gum infiltration (M4/M5); DIC (M3); skin lesions (leukemia cutis)

Diagnosis: Bone marrow biopsy: ≥20% blasts; Auer rods (myeloperoxidase-positive, elongated crystalline granules in blast cytoplasm) - pathognomonic for AML

Treatment: Induction: cytarabine (7 days) + anthracycline ("7+3"); ATRA + ATO for M3; allogeneic HSCT for adverse risk

Chronic Lymphocytic Leukemia (CLL)

Most common leukemia in adults (Western countries); median age ~70 years

Cell of origin: Mature naive B cells

Immunophenotype: CD5+ (aberrant), CD19+, CD20+ (dim), CD23+, FMC7-, surface Ig (dim) - CD5 co-expression on B cells is hallmark

Cytogenetics (prognostic):

Abnormality	Prognosis
del(13q)	Best (most common)
del(11q)	Intermediate
Trisomy 12	Intermediate
del(17p)/TP53 mutation	Worst; ibrutinib preferred

Clinical:

Often asymptomatic at diagnosis (elevated lymphocyte count incidentally)
Lymphadenopathy, splenomegaly
"Smudge (smear) cells" on blood smear (pathognomonic)
Autoimmune complications: AIHA (warm), ITP
Hypogammaglobulinemia → recurrent infections
Transformation: Richter's transformation → diffuse large B cell lymphoma (aggressive)

Staging: Rai (0-IV) and Binet (A-C) based on lymphadenopathy, organomegaly, cytopenias

Treatment: Watch and wait for early stage; ibrutinib (BTK inhibitor), venetoclax (BCL-2 inhibitor) + obinutuzumab; FCR (fludarabine + cyclophosphamide + rituximab) for fit patients with no del17p

Chronic Myeloid Leukemia (CML)

Pathognomonic: Philadelphia chromosome - t(9;22)(q34;q11) → BCR-ABL fusion gene → constitutively active tyrosine kinase → uncontrolled myeloid proliferation

Phases:

Chronic phase (~5-6 years): elevated WBC (100k-500k), left shift, basophilia (hallmark), thrombocytosis, eosinophilia; minimal blasts (<10%)
Accelerated phase: 10-19% blasts, progressive disease
Blast crisis: ≥20% blasts → either myeloid (60%) or lymphoid (40%) - acute leukemia

Clinical: Massive splenomegaly, constitutional symptoms, sternal tenderness

Labs: Low LAP (leukocyte alkaline phosphatase) score - distinguishes from leukemoid reaction (LAP high in leukemoid); basophilia

Treatment:

Imatinib (Gleevec) - first BCR-ABL tyrosine kinase inhibitor; revolutionary treatment; deep molecular response in most
Second-gen TKIs: dasatinib, nilotinib (first-line alternatives); bosutinib
Third-gen: ponatinib (for T315I "gatekeeper" mutation)
Allogenic HSCT: reserved for blast crisis or TKI failure

4.7 Hodgkin vs. Non-Hodgkin Lymphoma

Hodgkin Lymphoma (HL)

Pathognomonic cell: Reed-Sternberg (RS) cell - large binucleated/multinucleated cell with prominent "owl-eye" nucleoli; CD15+, CD30+, CD45- (LCA negative), PAX5+

Bimodal age distribution: Young adults (15-35) and older adults (>55)

EBV association: ~40% of classical HL (especially mixed cellularity subtype)

WHO subtypes of classical HL:

Subtype	Frequency	Key Features	EBV
Nodular sclerosis (NS)	65-70%	Most common; collagen bands + lacunar cells; young women; mediastinal mass	20-25%
Mixed cellularity (MC)	20-25%	Many RS cells + eosinophils; intermediate prognosis	50-75%
Lymphocyte-rich (LR)	5%	Few RS cells; best prognosis	30-40%
Lymphocyte-depleted (LD)	<1%	Many RS cells, few lymphocytes; worst prognosis; elderly, HIV+	50%

Nodular lymphocyte predominant HL (NLPHL): Different disease; "popcorn (LP) cells" CD20+, CD45+, CD15-, CD30-; excellent prognosis

Clinical: Painless cervical lymphadenopathy (most common); contiguous spread; mediastinal mass; B symptoms (fever >38°C, drenching night sweats, >10% weight loss); pruritus; alcohol-induced pain in lymph nodes (unusual symptom)

Staging (Ann Arbor/Lugano):

Stage I: Single node region
Stage II: 2+ node regions, same side of diaphragm
Stage III: Both sides of diaphragm
Stage IV: Extranodal involvement

Treatment: ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) ± radiation; escalated BEACOPP for advanced disease; brentuximab vedotin (anti-CD30) for relapsed/refractory

Non-Hodgkin Lymphoma (NHL)

85% B cell, 15% T cell/NK cell

Key B-cell NHLs:

Lymphoma	Genetics	Immunophenotype	Key Features
Diffuse Large B Cell Lymphoma (DLBCL)	BCL-6, MYC, BCL-2 rearrangements	CD19+, CD20+, CD45+	Most common NHL; aggressive; curable with R-CHOP; germinal center vs activated B cell subtypes
Follicular Lymphoma	t(14;18) → BCL-2 overexpression	CD10+, BCL-2+, CD20+	Indolent; waxing and waning; transformation to DLBCL (Richter's-like); BCL-2 blocks apoptosis
Mantle Cell Lymphoma	t(11;14) → cyclin D1 overexpression	CD5+, CD23-, cyclin D1+, CD20+	Aggressive; "mantle zone" pattern; GI involvement (lymphomatous polyposis)
Burkitt Lymphoma	t(8;14) → MYC overexpression	CD10+, BCL-6+, TdT-, Ki-67 ~100%	Highly aggressive; starry-sky pattern; jaw mass (endemic-EBV), sporadic (abdominal), immunodeficiency-related; treat with dose-intensive chemo
Marginal Zone Lymphoma (MALT)	t(11;18), t(14;18)	CD5-, CD23-, CD10-	Associated with H. pylori (gastric), Sjögren's, Hashimoto's; treat H. pylori first
Small Lymphocytic Lymphoma (SLL)	del(13q), trisomy 12	CD5+, CD23+, CD20 dim	= CLL but tissue-based; treat similarly
Primary CNS Lymphoma		CD20+	EBV+ in immunocompromised; MRI ring-enhancing lesion (periventricular); high-dose methotrexate

Key T-cell NHLs:

Mycosis fungoides/Sézary syndrome: Cutaneous T cell lymphoma; CD4+ T cells; Pautrier microabscesses; Sézary cells (cerebriform nuclei) in blood
ALCL: Anaplastic large cell lymphoma; CD30+, ALK+ (better prognosis); EMA+; horseshoe nuclei ("hallmark cells"); treat with brentuximab

4.8 DIC, Hemophilia & von Willebrand Disease

Disseminated Intravascular Coagulation (DIC)

Definition: Simultaneous widespread activation of coagulation AND fibrinolysis → thrombosis + bleeding

Causes (triggers excessive thrombin generation):

Sepsis (most common): gram-negative LPS, gram-positive toxins → monocyte TF expression
Obstetric complications: amniotic fluid embolism, abruptio placentae, retained dead fetus
APML (M3): granules contain TF-like substances; classic cancer association
Massive transfusion, burns, trauma
Mucin-secreting adenocarcinomas (Trousseau's syndrome - chronic DIC/thromboembolism)
Snake venom

Pathophysiology:

Trigger → massive thrombin generation
Thrombin → fibrin clots throughout microvasculature → microthrombi → organ ischemia
Fibrinogen, platelets, Factors V, VIII consumed → bleeding (consumption coagulopathy)
Fibrinolysis activated (plasmin) → D-dimers elevated

Labs:

Test	Finding in DIC
PT/PTT	Prolonged
Platelet count	↓ (thrombocytopenia)
Fibrinogen	↓ (consumed)
D-dimers	↑↑↑ (most sensitive)
Fibrin degradation products	↑
Blood smear	Schistocytes (microangiopathic hemolysis)

Treatment: Treat underlying cause (primary); FFP (replace factors), cryoprecipitate (fibrinogen, vWF, Factor VIII), platelet transfusion; heparin for thrombosis-dominant DIC (controversial); ATRA for M3-associated DIC

Hemophilia

Hemophilia A:

Factor VIII deficiency
X-linked recessive (males affected); 1:5,000 males
aPTT prolonged; PT normal
Intrinsic pathway defect

Hemophilia B (Christmas disease):

Factor IX deficiency
X-linked recessive; 1:30,000 males
Same lab pattern as Hemophilia A; clinically identical

Hemophilia C:

Factor XI deficiency
Autosomal recessive; milder; Ashkenazi Jewish population

Severity:

Severity	Factor level	Clinical
Mild	5-40%	Bleeding with major surgery/trauma
Moderate	1-5%	Bleeding with minor trauma
Severe	<1%	Spontaneous bleeding

Clinical manifestations:

Hemarthroses (joints - knees, elbows, ankles) → chronic hemophilic arthropathy
Muscle hematomas
Prolonged bleeding after surgery/trauma
Not: petechiae/purpura (those are platelet disorders)
No mucosal bleeding (unlike vWD/platelet disorders)

Treatment:

Hemophilia A: Factor VIII concentrates (recombinant preferred); DDAVP (desmopressin) for mild cases → releases stored vWF/VIII from endothelium
Hemophilia B: Factor IX concentrates
Emicizumab (bispecific antibody mimicking VIIIa): for Hemophilia A, especially with inhibitors

Inhibitor development (~30% of severe Hem A): alloantibodies against Factor VIII; treat with bypassing agents (aPCC, recombinant FVIIa)

Von Willebrand Disease (vWD)

Most common inherited bleeding disorder (1% of population)

von Willebrand factor (vWF) functions:

Platelet adhesion to subendothelium (bridges GpIb on platelets to collagen)
Carrier protein for Factor VIII (protects from degradation)

Types:

Type	Defect	Inheritance	Frequency
Type 1	Quantitative ↓ vWF (partial deficiency)	Autosomal dominant	75-80%; most common; mild
Type 2 (A, B, M, N)	Qualitative defect in vWF function	Dominant/Recessive	~20%; type 2B: gain-of-function → binds GpIb constitutively → thrombocytopenia
Type 3	Complete absence of vWF	Autosomal recessive	<5%; most severe; Factor VIII also very low

Labs:

Prolonged bleeding time (platelet plug defect)
Prolonged aPTT (low Factor VIII)
Normal PT
Low vWF antigen, low Factor VIII activity, low ristocetin cofactor activity
Ristocetin agglutination test: ristocetin normally induces vWF-platelet binding → abnormal in vWD (except type 2B where it's enhanced)

Treatment:

DDAVP (1-desamino-8-D-arginine vasopressin): releases stored vWF from Weibel-Palade bodies; works for Type 1 (not Type 3); avoid in Type 2B (worsens thrombocytopenia)
vWF concentrates / cryoprecipitate
Tranexamic acid (antifibrinolytic) for mucosal bleeding

PART 5: RENAL PATHOLOGY

5.1 Nephrotic vs. Nephritic Syndrome

Nephrotic Syndrome:

Proteinuria > 3.5 g/day (massive)
Hypoalbuminemia → pitting edema, anasarca
Hyperlipidemia + lipiduria (fatty casts, oval fat bodies, "Maltese cross")
Thromboembolism (loss of antithrombin III, protein C/S)
Increased infections (loss of IgG, complement)
Frothy urine

Causes:

Primary: Minimal Change Disease (children), FSGS (adults/African Americans), Membranous nephropathy (adults), MPGN
Secondary: Diabetic nephropathy (most common worldwide cause), Amyloidosis, SLE, hepatitis B/C, drugs, malignancy

Nephritic Syndrome:

Hematuria (RBC casts - pathognomonic for glomerulonephritis)
Proteinuria (sub-nephrotic, usually <3.5 g/day)
Hypertension (Na/water retention)
Oliguria, azotemia
Edema (less pronounced than nephrotic)

Causes: PSGN, IgA nephropathy (Berger's), RPGN, Henoch-Schönlein Purpura, lupus nephritis, Goodpasture's, ANCA vasculitis

5.2 Specific Glomerulonephritides

Post-Streptococcal Glomerulonephritis (PSGN)

Trigger: Group A β-hemolytic Streptococcus infection (pharyngitis or skin infection); 1-3 weeks latency

Mechanism: Type III hypersensitivity - streptococcal antigen-antibody immune complexes deposit in glomeruli

IF: Granular ("starry sky") pattern → IgG + C3 deposits; subepithelial humps on EM

Clinical: Children; abrupt hematuria, proteinuria, hypertension, oliguria; ASO titer elevated (throat infection); anti-DNase B (skin infection)

Labs: ↓ C3 (markedly), ↓ C4 (mildly); elevated creatinine; hematuria + RBC casts

Prognosis: Excellent in children (>95% recovery); adults may develop chronic GN

Rapidly Progressive Glomerulonephritis (RPGN)

Hallmark: Crescents on biopsy (proliferating parietal epithelial cells + fibrin in Bowman's space)

Three types based on IF:

Type	IF Pattern	Antibody	Cause
Type I (Anti-GBM)	Linear IgG along GBM	Anti-GBM (type IV collagen α3)	Goodpasture syndrome (lung + kidney); RPGN alone
Type II (Immune complex)	Granular deposits	Various	Lupus nephritis, PSGN, IgA nephropathy
Type III (Pauci-immune)	Negative/minimal deposits	ANCA	Microscopic polyangiitis (p-ANCA), Granulomatosis with polyangiitis (c-ANCA), EGPA

Treatment: Pulse steroids ± cyclophosphamide; plasmapheresis for Type I (remove anti-GBM antibodies)

IgA Nephropathy (Berger Disease)

Most common primary GN worldwide

Mechanism: Defectively glycosylated IgA1 → autoantibodies → IgA immune complexes → mesangial deposition

Clinical: Young men; episodic gross hematuria 1-3 days after upper respiratory infection ("synpharyngitic hematuria" - no latency period unlike PSGN); persistent microscopic hematuria between episodes; hypertension

IF: Mesangial IgA deposits (+ IgG, C3); granular pattern

Complement: C3 low; C4 normal (alternative pathway activation)

Prognosis: 20-40% develop ESRD over 20 years; poor prognosis: hypertension, proteinuria >1g/day, creatinine elevation, crescents

HSP (Henoch-Schönlein Purpura): Systemic form of IgA nephropathy; IgA vasculitis; palpable purpura (lower extremities) + arthralgia + abdominal pain + GN; children; self-limited in most

Minimal Change Disease (MCD)

Most common cause of nephrotic syndrome in children; also called "nil disease" or "lipoid nephrosis"

Pathology:

LM: Normal (hence "minimal change")
IF: Negative
EM: Effacement (fusion) of podocyte foot processes (most important finding)

Associations: Hodgkin lymphoma (T cell-derived lymphokine damaging glomerular polyanion charge); NSAIDs; atopy

Clinical: Sudden onset nephrotic syndrome in children 2-8 years; no hematuria/hypertension; highly selective proteinuria (albumin only)

Treatment: Highly steroid-responsive (80-90%); prednisone; cyclophosphamide for frequent relapsers; excellent prognosis

Focal Segmental Glomerulosclerosis (FSGS)

Most common cause of nephrotic syndrome in adults (especially African Americans)

Pathology:

LM: Sclerosis involving SOME (focal) glomeruli and PART OF (segmental) those glomeruli
IF: IgM + C3 in sclerosed segments (non-specific)
EM: Diffuse podocyte foot process effacement

Genetic causes: NPHS2 (podocin), ACTN4 (α-actinin 4), WT1, INF2, TRPC6 mutations

Secondary causes: HIV nephropathy (collapsing variant, classic in HIV), heroin abuse, morbid obesity, reflux nephropathy, sickle cell disease, prior IgA nephropathy

Clinical: Nephrotic range proteinuria; hypertension; hematuria possible; non-selective proteinuria (large proteins)

Prognosis: 50% reach ESRD in 10 years; poor steroid response; treat with ACE inhibitors + corticosteroids + calcineurin inhibitors for resistant cases

Membranoproliferative Glomerulonephritis (MPGN)

Pathology:

LM: "Tram-track" or "double contour" appearance of GBM due to mesangial interposition
IF/EM based classification:

Type	Mechanism	IF	EM
Type I	Immune complex (classic pathway)	C3, C1q, C4, IgG (granular)	Subendothelial + mesangial deposits
Type II (Dense deposit disease)	Alternative pathway; C3 nephritic factor (C3NeF) stabilizes C3 convertase	C3 only; no Ig	Dense osmiophilic deposits in GBM (intramembranous)
Type III	Combined	C3, Ig	Subepithelial + subendothelial

Causes: HCV (type I most common), HBV, SLE, cryoglobulinemia, C3 glomerulopathy (mutations in complement regulators - type II/III)

Clinical: Mixed nephrotic-nephritic; low C3 (alternative pathway activation in Type II); "sea blue histiocytes" in Type II; may recur in transplant

5.3 Renal Cell Carcinoma (RCC)

Most common primary renal malignancy in adults (peak 50-70 years, M>F)

Types:

Type	Frequency	Genetics	Key Features
Clear cell RCC	70-80%	VHL deletion (3p) - Von Hippel-Lindau → VEGF/HIF overproduction	Rich in glycogen/lipid (clear cytoplasm); yellow tumor; bilateral/hereditary in VHL disease
Papillary RCC	10-15%	MET mutation (Type 1); PRCC-TFE3 (Type 2)	Two types; multifocal; hereditary papillary RCC syndrome (MET mutation)
Chromophobe RCC	5%	Multiple chromosome losses	Pale eosinophilic cytoplasm; best prognosis; associated with Birt-Hogg-Dubé syndrome

Clinical "classic triad" (present in <10%): flank pain + hematuria + palpable mass

Paraneoplastic manifestations:

Polycythemia (ectopic EPO)
Hypercalcemia (ectopic PTH-rP)
Hypertension (ectopic renin)
Stauffer syndrome (non-metastatic hepatic dysfunction)
Cushing syndrome (ectopic ACTH)

Spread: Hematogenous (renal vein → IVC → right heart → lungs); "cannonball" pulmonary metastases; tumor thrombus in renal vein/IVC is characteristic

Treatment: Surgery (radical/partial nephrectomy) for localized disease; sunitinib (VEGFR TKI), pembrolizumab + axitinib, or ipilimumab + nivolumab for metastatic; everolimus (mTOR inhibitor)

5.4 Bladder Carcinoma

Most common cause of hematuria in adults >40 years; M>F (4:1)

Risk factors: Smoking (most important), aromatic amines (β-naphthylamine, benzidine - industrial), cyclophosphamide, chronic cystitis, Schistosoma haematobium (SCC in endemic areas)

Types:

Type	Frequency	Features
Urothelial (transitional cell) carcinoma	~90%	Papillary (low grade, non-invasive, "papillary fronds") or flat/invasive (higher grade); FGFR3 mutation in low grade; p53/Rb in high grade
Squamous cell carcinoma	~5% in West, majority in Middle East/Africa	Associated with chronic cystitis, Schistosoma haematobium, stones; poor prognosis
Adenocarcinoma	1-2%	Associated with urachal remnant or bladder exstrophy

Staging:

Ta: Papillary, non-invasive
T1: Invades lamina propria (submucosa)
T2: Invades muscularis propria (must-resect with radical cystectomy)
T3: Perivesical fat
T4: Adjacent organs

Treatment:

Low-grade superficial: TURBT (transurethral resection) + intravesical BCG (immune response against tumor); mitomycin C
Muscle-invasive (T2+): radical cystectomy + neoadjuvant cisplatin-based chemo
Metastatic: gemcitabine + cisplatin; pembrolizumab/atezolizumab (PD-1/L1 inhibitors)

PART 6: GIT & RESPIRATORY PATHOLOGY

6.1 Barrett Esophagus & Gastric Carcinoma

Barrett Esophagus

Definition: Metaplasia of normal stratified squamous esophageal epithelium → intestinal columnar epithelium (intestinal metaplasia with goblet cells) due to chronic GERD

Pathophysiology: Chronic acid/bile reflux → mucosal injury → metaplasia → dysplasia → adenocarcinoma sequence

Diagnosis: Upper endoscopy + biopsy showing specialized intestinal metaplasia (goblet cells with alcian blue)

Progression: Metaplasia → Low-grade dysplasia → High-grade dysplasia → Esophageal adenocarcinoma (lower esophagus/GEJ)

Risk factors for progression: Older white males, obesity, smoking, length of Barrett's, low-grade to high-grade dysplasia

Surveillance: Endoscopy every 3-5 years (no dysplasia); more frequent with dysplasia; radiofrequency ablation for dysplastic Barrett's

Esophageal cancers:

Adenocarcinoma: lower 1/3; associated with Barrett's, GERD, obesity; rising incidence
Squamous cell carcinoma: upper/middle 1/3; associated with smoking, alcohol, nitrosamines, achalasia, hot beverages, Plummer-Vinson syndrome; more common in developing countries

Gastric Carcinoma

Epidemiology: Declining in West; high in Japan, Korea, China, Eastern Europe, South America; H. pylori is the most important risk factor

Risk factors: H. pylori (major), atrophic gastritis, intestinal metaplasia, smoking, high salt/processed meat diet, blood group A (intestinal type)

Correa cascade (intestinal type): Normal → Chronic gastritis → Atrophic gastritis → Intestinal metaplasia → Dysplasia → Carcinoma

Types:

Type	Location	Gross	Histology	Molecular	Prognosis
Intestinal	Distal (antrum, pylorus)	Ulcerating/polypoid	Glands, tubular	CDX2, H. pylori related	Better
Diffuse	Diffuse/proximal	Linitis plastica ("leather bottle")	Signet ring cells dispersed in stroma	CDH1 (E-cadherin loss), hereditary diffuse gastric cancer	Worse

Signet ring cells: Intracytoplasmic mucin displaces nucleus to periphery - pathognomonic of diffuse type

Special presentations:

Virchow node: Left supraclavicular lymph node metastasis
Sister Mary Joseph nodule: Periumbilical metastasis
Krukenberg tumor: Ovarian metastasis (bilateral) - signet ring cells
Blumer shelf: Rectal shelf (peritoneal implants in pouch of Douglas)

Treatment: Surgery (gastrectomy); perioperative FLOT (fluorouracil + leucovorin + oxaliplatin + docetaxel); anti-HER2 (trastuzumab for HER2+ tumors); anti-PD-1 (pembrolizumab for MSI-H or PD-L1+)

6.2 Colon Carcinoma & Polyps

Colonic Polyps

Hyperplastic polyps:

Non-neoplastic; most common colonic polyp
Serrated architecture; small, pale
No malignant potential (except sessile serrated lesions in right colon)

Neoplastic polyps (adenomas):

Type	Malignant potential	Features
Tubular adenoma	5%	Tubular glands; most common adenoma; usually pedunculated
Tubulovillous	20%	Mixed pattern
Villous adenoma	40%	Finger-like projections; sessile; most malignant potential

Features predicting malignant potential: Size (>2 cm), villous histology, severe dysplasia, sessile configuration

Polyposis syndromes:

Syndrome	Gene	# Polyps	Cancer Risk	Other Features
FAP (Familial Adenomatous Polyposis)	APC (5q21)	100s-1000s	100% by age 40	Desmoid tumors, CHRPE, Gardner syndrome (osteomas, fibromas, epidermoid cysts)
HNPCC (Lynch syndrome)	MLH1, MSH2, MSH6, PMS2 (MMR genes)	Few adenomas	80% lifetime CRC	Right-sided; endometrial (2nd most common), ovarian, gastric cancers; Amsterdam criteria
PJS (Peutz-Jeghers)	STK11/LKB1	Hamartomatous throughout GI	Moderate (GI + extra-GI)	Mucocutaneous melanin pigmentation (lips, buccal mucosa)
Juvenile polyposis	SMAD4, BMPR1A	Hamartomatous	Moderate	Young age; protein-losing enteropathy
Cowden syndrome	PTEN	Hamartomatous	Moderate	Breast + thyroid cancer; macrocephaly; trichilemmomas

Colorectal Carcinoma (CRC)

Epidemiology: 2nd most common cause of cancer death in US; M = F

Molecular pathways:

Chromosomal Instability (CIN) pathway (~85%):
- APC (tumor suppressor) → β-catenin pathway; loss of APC is initiating event
- APC → KRAS → SMAD4/DCC (18q loss) → TP53 → invasive carcinoma
- "Vogelstein sequence" (Fearon-Vogelstein model)
- MSI-stable (MSS)
Microsatellite Instability (MSI) pathway (~15%):
- Mismatch repair gene defects (hereditary = Lynch; sporadic = MLH1 methylation)
- MSI-H tumors: right colon, mucinous/signet ring histology, tumor-infiltrating lymphocytes, pushing borders
- Better prognosis; respond to immunotherapy (pembrolizumab); do NOT benefit from 5-FU alone
Serrated pathway:
- BRAF V600E mutation + MLH1 methylation
- Sessile serrated adenomas in right colon

Clinical:

Left colon: "apple-core" lesion on barium enema; obstruction, change in bowel habits, "pencil stools"
Right colon: occult bleeding, iron deficiency anemia, large masses
Rectal: hematochezia, tenesmus

Screening: Colonoscopy every 10 years starting age 45 (average risk); flexible sigmoidoscopy, stool FIT, CT colonography alternatives

Treatment: Surgical resection; FOLFOX/FOLFIRI adjuvant for Stage III; bevacizumab (anti-VEGF) + cetuximab/panitumumab (anti-EGFR, only for KRAS wild-type) for metastatic; pembrolizumab for MSI-H metastatic

6.3 Asthma, COPD, ARDS & Emphysema

Asthma

Definition: Chronic inflammatory airway disease with hyperresponsiveness to various stimuli → reversible airflow obstruction

Pathophysiology:

Allergen → Th2 → IL-4 (IgE) + IL-5 (eosinophil activation) + IL-13 (mucus)
IgE on mast cells → re-exposure → degranulation (histamine, LTC4/D4/E4, PGD2) → bronchoconstriction
Late phase: eosinophils, MBP, cationic proteins → epithelial damage + airway remodeling
Airway remodeling: subepithelial fibrosis, smooth muscle hypertrophy, goblet cell metaplasia, mucus plugs

Types:

Atopic (extrinsic): type I hypersensitivity; childhood onset; IgE elevated; positive skin test; associated with atopic dermatitis/allergic rhinitis
Non-atopic (intrinsic): adult onset; no allergen trigger; aspirin-induced (inhibition of COX-1 → arachidonic acid → excessive leukotrienes)
Occupational: workplace irritants
Exercise-induced
Cardiac asthma (from heart failure - not true asthma)

Morphology: Mucus plugs with Curschmann spirals and Charcot-Leyden crystals (eosinophil granule proteins); airway thickening

Treatment: ICS (inhaled corticosteroids), SABA (β2 agonist), LABA, LAMA; montelukast (LT antagonist); omalizumab (anti-IgE); dupilumab (anti-IL-4Rα); biologics targeting IL-5 (mepolizumab, reslizumab) for severe eosinophilic asthma

COPD

Definition: Persistent airflow limitation, not fully reversible; includes chronic bronchitis + emphysema

Chronic Bronchitis (clinical definition):

Productive cough for ≥3 months/year for ≥2 consecutive years
Pathology: mucus gland hypertrophy (Reid index >0.5 = ratio of mucus gland to total wall thickness), goblet cell metaplasia, squamous metaplasia, airway inflammation
"Blue bloater": cyanosis, cor pulmonale, ↑PaCO2, ↑PaO2 preserved polycythemia

Emphysema

Definition: Permanent abnormal enlargement of airspaces distal to terminal bronchiole with destruction of alveolar walls (no fibrosis)

Types:

Type	Location	Cause	Key Association
Centriacinar (Centrilobular)	Upper lobes; respiratory bronchioles	Cigarette smoking	Most common; macrophage-mediated elastase damage
Panacinar (Panlobular)	Lower lobes; entire acinus	α1-antitrypsin deficiency	Protease-antiprotease imbalance; also liver cirrhosis
Paraseptal	Adjacent to pleura/septa	Distal acinus	Bullae → spontaneous pneumothorax in young adults
Irregular	Around scars	Post-inflammatory

α1-antitrypsin deficiency:

SERPINA1 gene mutations (PiZZ worst genotype)
Lungs: panacinar emphysema (uninhibited elastase destroys alveoli)
Liver: PiZ protein misfolded, accumulates in hepatocytes → cirrhosis; PAS-positive, diastase-resistant globules in liver cells
Treatment: IV α1-AT augmentation therapy

COPD pathophysiology:

Smoking → macrophage/neutrophil activation → elastase, protease release → alveolar destruction
Also: oxidative stress, impaired protease inhibitors

PFTs in COPD/Asthma: ↓FEV1, ↓FVC but FEV1/FVC ratio <0.70 (obstructive pattern); in asthma reverses with bronchodilator; hyperinflation (↑TLC, ↑RV)

Treatment COPD: Smoking cessation (most important); SABA + LAMA; ICS + LABA for severe/exacerbations; oxygen if PaO2 <55 mmHg; pulmonary rehabilitation; lung volume reduction surgery (severe emphysema); LVRS; transplant

ARDS (Acute Respiratory Distress Syndrome)

Definition: Acute hypoxic respiratory failure (PaO2/FiO2 <300) with bilateral pulmonary infiltrates, NOT due to cardiac cause

Triggers (direct or indirect lung injury):

Direct: pneumonia, aspiration, inhalation injury, drowning
Indirect (systemic): sepsis (most common overall trigger), severe trauma, pancreatitis, massive transfusion, burns

Pathophysiology (3 phases):

Exudative phase (days 1-6):
- Diffuse alveolar damage (DAD): hyaline membrane formation (fibrin + necrotic debris)
- Neutrophil infiltration, epithelial/endothelial damage
- Non-cardiogenic pulmonary edema
Proliferative phase (days 7-21):
- Type II pneumocyte proliferation (trying to repair)
- Fibrin organization
Fibrotic phase (>21 days):
- Progressive fibrosis → restrictive pattern
- Collagen deposition

Morphology: Hyaline membranes (fibrin exudate lining alveoli), inflammation, hemorrhage, edema

Management: Lung-protective ventilation (tidal volume 6 mL/kg), PEEP, prone positioning (improves V/Q matching), conservative fluid strategy; treat underlying cause; NO steroids routinely (except COVID-19 with dexamethasone); IL-6 inhibitors for COVID-associated

6.4 Lung Cancer & Pneumoconiosis

Lung Cancer

Leading cause of cancer death in men and women

Major histologic types:

Type	Frequency	Location	Molecular/Special	Key Features
Adenocarcinoma	40%	Peripheral (most common in non-smokers, women)	EGFR (exon 19/21), KRAS, ALK, ROS1, BRAF, MET	Most common lung cancer overall; Clara cells/type II pneumocytes; associated with lung scars; BAC (now lepidic adenocarcinoma) subtype
Squamous cell carcinoma	30%	Central (near hilar); endobronchial	p53 + Rb loss; FGFR1	Keratin pearls, intercellular bridges; cavitation; PTH-rP (hypercalcemia); more strongly linked to smoking
Small cell carcinoma (SCLC)	15%	Central; perihilar	RB1, TP53, MYC; neuroendocrine markers (chromogranin, synaptophysin, CD56, NSE, TTF-1)	Very aggressive; early metastasis; paraneoplastic syndromes (SIADH, Cushing, Lambert-Eaton, anti-Hu encephalitis); Eaton-Lambert: anti-P/Q-type VGCC antibodies; treatment: EP (etoposide + cisplatin/carboplatin) ± atezolizumab
Large cell carcinoma	10%	Peripheral	Diagnosis of exclusion; may have neuroendocrine features	Poorly differentiated; poor prognosis

Paraneoplastic syndromes:

Syndrome	Cancer
SIADH (hyponatremia)	SCLC (most common)
Cushing (ectopic ACTH)	SCLC
Lambert-Eaton myasthenic syndrome	SCLC (anti-VGCC)
Hypercalcemia (PTH-rP)	Squamous cell carcinoma
Hypertrophic osteoarthropathy	Adenocarcinoma, large cell
Subacute sensory neuropathy (anti-Hu)	SCLC

Superior vena cava syndrome: Obstruction of SVC → facial/arm swelling, plethora, dilated neck veins; most often from central lung cancer (SCLC) or mediastinal lymphoma

Pancoast tumor (superior sulcus tumor):

Apex lung tumor → invades brachial plexus (C8-T1), stellate ganglion, subclavian vessels
Horner syndrome (ptosis, miosis, anhidrosis, enophthalmos)
C8-T1 distribution pain/weakness (wasting of hand muscles)

Treatment:

NSCLC: Surgery (stages I-III); EGFR inhibitors (erlotinib/osimertinib); ALK inhibitors (crizotinib/alectinib); pembrolizumab (PD-L1 high); platinum-based chemo
SCLC: Extensive - EP ± atezolizumab; Limited - concurrent EP + radiation (potentially curative)

Pneumoconioses (Dust Diseases)

Disease	Dust	Pathology	Key Features
Coal worker's pneumoconiosis	Coal dust	Coal macules + nodules; progressive massive fibrosis (PMF) in severe	Caplan syndrome (RA + large cavitary nodules)
Silicosis	Crystalline silica (SiO2)	Silicotic nodules (concentric layers of hyalinized collagen); hilar eggshell calcification	Most common occupational lung disease; increased risk of TB ("silicotuberculosis"); increased lung cancer
Asbestosis	Asbestos fibers (serpentine/amphibole)	Diffuse interstitial fibrosis; asbestos bodies (ferruginous bodies = fibers coated with iron/protein)	Pleural plaques (calcified); mesothelioma (amphibole > chrysotile); lung cancer (synergy with smoking); 15-40 year latency
Berylliosis	Beryllium	Non-caseating granulomas (identical to sarcoidosis)	Electronic/aerospace industry; beryllium lymphocyte proliferation test diagnostic; treat with steroids
Byssinosis	Cotton, flax, hemp dust	Airway obstruction	"Monday fever" (symptoms worse at start of work week)

PART 7: CVS, ENDOCRINE & CNS PATHOLOGY

7.1 Vasculitis & ANCA Patterns

Vasculitis: Inflammation of blood vessel walls → ischemia/infarction downstream

Classification by vessel size:

Large vessel vasculitis:

Disease	Vessels	Demographics	Features
Giant Cell (Temporal) Arteritis	Temporal + aortic branches	>50 years; women	Headache, scalp tenderness, jaw claudication, visual loss (anterior ischemic optic neuropathy); biopsy: granulomas, multinucleated giant cells; very high ESR; treat with high-dose steroids promptly; associated polymyalgia rheumatica
Takayasu arteritis	Aorta + major branches	Young Asian women (<40)	"Pulseless disease"; arm claudication, bruits, renovascular hypertension; granulomatous inflammation

Medium vessel vasculitis:

Disease	Vessels	ANCA	Features
Polyarteritis Nodosa (PAN)	Medium-sized muscular arteries	pANCA negative (no ANCA)	Hepatitis B associated; renal, GI, peripheral nerve involvement; spares lungs and glomeruli; fibrinoid necrosis; "string of beads" angiogram
Kawasaki disease	Coronary arteries	Negative	Children <5; fever >5 days, rash, oral/conjunctival changes, lymphadenopathy, coronary aneurysms; treat with IVIG + aspirin

Small vessel vasculitis (ANCA-associated):

Disease	ANCA	Organ	Key Features
Granulomatosis with Polyangiitis (GPA) (formerly Wegener's)	c-ANCA / anti-PR3	Upper + lower respiratory + kidney	"Saddle-nose deformity"; destructive upper airways + pulmonary granulomas + necrotizing GN; "horse-shoe-shaped" granulomas
Microscopic Polyangiitis (MPA)	p-ANCA / anti-MPO	Kidney + lung	No granulomas; RPGN + pulmonary hemorrhage (pulmonary-renal syndrome)
Eosinophilic Granulomatosis with Polyangiitis (EGPA) (formerly Churg-Strauss)	p-ANCA / anti-MPO	Lung + heart + nerve + skin	Asthma + eosinophilia + granulomatous vasculitis; cardiac involvement (restrictive CM); peripheral neuropathy
Henoch-Schönlein Purpura (IgA vasculitis)	Negative (IgA mediated)	Skin + GI + kidney + joints	Children; palpable purpura on buttocks/legs; Type III HS; IgA deposits
Behçet's disease	Negative	Multiple	Oral + genital ulcers + uveitis; HLA-B51; pathergy test; venous + arterial involvement

ANCA summary:

c-ANCA (anti-PR3) → Granulomatosis with Polyangiitis (GPA)
p-ANCA (anti-MPO) → MPA, EGPA, drug-induced vasculitis, PAN (some), Goodpasture's

7.2 IHD & Cardiomyopathies

Ischemic Heart Disease (IHD)

Definition: Cardiovascular disease caused by insufficient coronary artery blood flow (CAD)

Spectrum: Stable angina → Unstable angina → NSTEMI → STEMI → Sudden cardiac death

Atherosclerosis:

Fatty streak (earliest lesion) → fibrous plaque → complicated plaque (calcification, hemorrhage, ulceration, thrombosis)
Risk factors: hypertension, smoking, hyperlipidemia, diabetes, family history, obesity, sedentary
Stable plaque: thick fibrous cap, small lipid core, gradual occlusion
Vulnerable (unstable) plaque: thin cap, large lipid core, macrophage infiltration → rupture → thrombosis → ACS

Acute Coronary Syndromes (ACS):

Type	Definition	Troponin	ECG	Pathology
Unstable angina	New onset, rest, or crescendo angina	Negative	ST depression/T-wave changes	Non-occlusive thrombus
NSTEMI	Myocardial necrosis without ST elevation	Elevated	ST depression/T-wave changes	Partial occlusion or transient
STEMI	Full-thickness infarction	Elevated	ST elevation (later Q waves)	Complete occlusion → transmural necrosis

Temporal sequence of MI pathology:

Time	Gross	Microscopic	Enzyme
0-6 hrs	Normal	Wavy fibers, eosinophilic change	Troponin rises (3-6 hrs)
6-24 hrs	Pallor	Coagulative necrosis, PMN infiltrate begins	CK-MB peaks
1-3 days	Yellow pallor	Intense PMN infiltration	LDH elevated
3-10 days	Hyperemic border	Macrophage infiltration, granulation tissue starts
10 days - weeks	Yellow center, red border	Granulation tissue; phagocytosis of necrotic material
Weeks - months	White scar	Dense collagen scar (fibrous)

MI complications:

Day 1-3: Arrhythmias (ventricular fibrillation - most common early cause of death); heart failure
Day 3-7: Free wall rupture → hemopericardium → tamponade; papillary muscle rupture → acute MR; interventricular septal rupture → VSD
Week 2: Pericarditis (Dressler's syndrome = autoimmune pericarditis 2-10 weeks later)
Long-term: LV aneurysm, mural thrombus, chronic heart failure

Territories:

LAD: anterior wall + anterior septum + apex (anterior STEMI - most common)
RCA: inferior + posterior wall (inferior STEMI - ST elevation in II, III, aVF)
LCX: lateral wall

Cardiomyopathies

Type	Morphology	Key Cause	Pathophysiology	Clinical	Key Finding
Dilated (DCM)	All 4 chambers dilated; systolic dysfunction	Idiopathic (~50%), alcohol, peripartum, viral myocarditis (Coxsackie B), hemochromatosis, Chagas, drugs (doxorubicin)	Impaired contraction	Biventricular failure; S3 gallop; MR/TR; emboli	"Dilated" big heart; EF <50%
Hypertrophic (HCM)	Asymmetric septal hypertrophy; LV cavity small; systolic function preserved; diastolic dysfunction	MYBPC3, MYH7 mutations (AD); also in athletes	Systolic anterior motion (SAM) of mitral valve → LVOT obstruction	Most common cause of sudden death in young athletes; dynamic obstruction; harsh systolic ejection murmur; Valsalva increases obstruction	Myocardial disarray on biopsy
Restrictive (RCM)	Normal-sized heart; diastolic dysfunction; stiff ventricles	Amyloidosis (most common), hemochromatosis, sarcoidosis, endomyocardial fibrosis, Löffler endocarditis (hypereosinophilic)	Impaired filling	Biventricular failure; elevated JVP; Kussmaul sign	Mimics constrictive pericarditis
Arrhythmogenic (ARVC)	Fibrofatty replacement of RV	Desmosomal gene mutations (DSP, PKP2)	RV dilation + dysfunction; arrhythmias	Young athletes; RV failure; sudden cardiac death; "epsilon wave" on ECG; LBBB morphology VT	Fibrofatty replacement of RV

7.3 Thyroid Disorders

Hypothyroidism

Cause	Mechanism	Key Features
Hashimoto's thyroiditis (most common in iodine-sufficient areas)	Autoimmune: anti-TPO, anti-thyroglobulin; lymphocytic infiltration + Hürthle cell change	Goiter initially, then atrophy; most common cause of primary hypothyroidism in adults; risk of B-cell lymphoma
Riedel's thyroiditis	Fibrosis replacing thyroid + surrounding tissue	"Woody" hard thyroid; associated IgG4-related disease
Iodine deficiency	↓ T3/T4 synthesis	Most common worldwide; endemic goiter; cretinism in neonates (irreversible mental retardation if untreated)
Subacute (de Quervain's) thyroiditis	Viral (self-limited); granulomatous	Painful thyroid; transient hyperthyroid → hypothyroid → recovery

Clinical features of hypothyroidism: Cold intolerance, weight gain, fatigue, constipation, dry skin, myxedema, bradycardia, delayed deep tendon reflexes, macroglossia; TSH ↑, Free T4 ↓

Hyperthyroidism

Cause	Mechanism	Key Features
Graves disease (most common)	TSI (TSH receptor stimulating IgG); Type II HS	Diffuse goiter; exophthalmos (proptosis - TSI + orbital fibroblasts); pretibial myxedema (non-pitting); onycholysis; thyroid bruit; thyroid storm (emergency)
Toxic multinodular goiter	Autonomous nodules (TSH-independent)	Older women; no exophthalmos; common cause in iodine-deficient areas
Toxic adenoma	Single autonomous nodule	"Hot nodule" on thyroid scan
Hashitoxicosis	Early Hashimoto's	Transient hyperthyroidism

Clinical features: Heat intolerance, weight loss, tachycardia, anxiety, tremor, diarrhea, exophthalmos (Graves); TSH ↓, Free T4 ↑

Treatment: Antithyroid drugs (propylthiouracil = PTU in pregnancy, methimazole); radioactive iodine (I-131); thyroidectomy; β-blockers for symptoms

Thyroid Carcinomas

Type	Origin	%	Key Features	Prognosis
Papillary	Follicular cells	75-80%	BRET V600E or RET/PTC rearrangements; "Orphan Annie eye" nuclei, nuclear grooves, psammoma bodies; papillary architecture; spreads to lymph nodes; associated with Hashimoto's, radiation	Excellent (99% 5-yr)
Follicular	Follicular cells	10-15%	RAS, PAX8-PPARγ mutations; vascular/capsular invasion (distinguish from benign adenoma); hematogenous spread (bone, lung); Hurthle cell variant	Good
Medullary	Parafollicular C cells	5%	Calcitonin production; amyloid in stroma; RET mutations; MEN2A/2B; sporadic 75%; screen family with RET mutation	Intermediate
Anaplastic	Follicular cells (de-differentiated)	<5%	TP53 + TERT mutations; older patients; rapidly fatal; diffuse tracheal invasion	Very poor (<6 months)

Pheochromocytoma

Definition: Catecholamine-secreting tumor of chromaffin cells of adrenal medulla

"Rule of 10s":

10% bilateral
10% extra-adrenal (paraganglioma)
10% malignant
10% in children
10% hereditary (but with genetic testing, >30% have germline mutations)

Hereditary associations:

VHL syndrome (VHL gene): often bilateral pheochromocytoma
MEN 2A + 2B (RET mutation): bilateral; often presenting tumor
NF1 (neurofibromatosis): rare
SDHB/D mutations: paraganglioma; SDHB = high malignancy risk

Clinical: Episodic "5 Ps" = Pressure (hypertension - most common; paroxysmal), Pain (headache), Palpitations, Perspiration, Pallor (or flushing); hypertensive crisis may be triggered by surgery, palpation, beta-blockers (unopposed alpha)

Diagnosis:

24-hour urine: metanephrines + VMA (most reliable)
Plasma free metanephrines (most sensitive)
CT/MRI for localization; MIBG scan for extra-adrenal/metastatic

Histology: Zellballen (cell balls) pattern; chromaffin cells; positive for chromogranin A, synaptophysin, S-100

Treatment: Surgical adrenalectomy; pre-operatively: alpha-blocker (phenoxybenzamine) FIRST → then beta-blocker (prevent reflex tachycardia after alpha-blockade)

7.4 CNS Tumors

General principles:

Primary brain tumors rarely metastasize outside CNS
Most common brain tumor = metastatic (not primary)
Most common primary brain tumors: glioblastoma (adults), medulloblastoma (children)

Grading: WHO I-IV (I = benign, IV = most malignant)

Primary Brain Tumors:

Tumor	Cell of Origin	WHO Grade	Key Features
Glioblastoma Multiforme (GBM)	Astrocytes	IV	Most common malignant primary brain tumor in adults; butterfly (crosses corpus callosum); pseudopalisading necrosis + vascular proliferation (pathognomonic); IDH wild-type (primary) vs IDH-mutant (secondary); MGMT methylation = better response to temozolomide
Astrocytoma	Astrocytes	II (low-grade); III (anaplastic)	IDH1/2 mutation (good prognosis); 1p/19q co-deletion absent (distinguishes from oligodendroglioma)
Oligodendroglioma	Oligodendrocytes	II-III	IDH mutation + 1p/19q co-deletion; "fried egg" cells; calcifications; relatively better prognosis
Ependymoma	Ependymal cells	II-III	Lines ventricles; children: 4th ventricle (infratentorial); adults: spinal cord; perivascular pseudorosettes; NF2 association (spinal)
Medulloblastoma	Granule cell precursors (cerebellum)	IV	Most common malignant brain tumor in children; posterior fossa; seeding of CSF ("drop metastases"); Homer-Wright rosettes; WNT pathway (best prognosis), SHH pathway, Group 3/4
Meningioma	Meningothelial cells (arachnoid)	I (most); II-III rare	Most common benign brain tumor; parasagittal or sphenoid wing; psammoma bodies; whorled pattern; NF2 mutations; hormone-receptor positive (may grow in pregnancy); may cause seizures
Schwannoma	Schwann cells	I	CN VIII (acoustic neuroma) = vestibular schwannoma; unilateral: sporadic; bilateral: NF2; S-100+; pale (Antoni A) and loose (Antoni B) areas
Craniopharyngioma	Rathke's pouch remnants	I	Children + adults; suprasellar; bitemporal hemianopia; calcifications; "machine oil" fluid; derived from enamel-like tissue; BRAF V600E (papillary type); β-catenin mutation (adamantinomatous type)
Hemangioblastoma	Endothelial cells	I	Posterior fossa; cystic with mural nodule; VHL association; polycythemia (EPO production)
Pilocytic Astrocytoma	Astrocytes	I	Children; posterior fossa (cerebellum); cystic + mural nodule; Rosenthal fibers; BRAF-KIAA fusion; excellent prognosis with resection

7.5 Breast Carcinoma Classification

Epidemiology: Most common non-skin cancer in women; second cause of cancer death in women

Risk factors: BRCA1/2 mutations, early menarche, late menopause, nulliparity/late first pregnancy, HRT, prior breast cancer, radiation, obesity (postmenopausal), alcohol

BRCA genes:

BRCA1 (17q): breast + ovarian + cervical; TNBC risk; also increased colon cancer
BRCA2 (13q): breast (female + male) + ovarian + pancreatic + prostate

Precursor lesions:

ALH/LCIS (lobular carcinoma in situ): risk indicator, not obligate precursor; bilateral risk; no treatment needed (surveillance)
DCIS (ductal carcinoma in situ): true precursor; calcifications on mammography; comedonecrosis in high-grade; treat with excision ± radiation ± tamoxifen

Invasive carcinomas:

Type	%	Key Features
Invasive ductal (NST = no special type)	75%	Most common; stellate mass; desmoplasia; variable grade
Invasive lobular carcinoma	10-15%	E-cadherin loss (CDH1 mutation); single-file "Indian file" pattern; bilateral; difficult to detect on imaging; often ER+
Medullary carcinoma	5%	BRCA1-related; lymphocytic infiltrate; pushing borders; ER-/PR-/HER2-; paradoxically better prognosis
Mucinous (colloid)	2-3%	Mucin pools; older women; better prognosis
Tubular carcinoma	2-3%	Well-differentiated tubular structures; excellent prognosis
Inflammatory carcinoma	1-3%	Dermal lymphatic invasion; peau d'orange skin; no discrete mass; ER-/HER2+ common; worst prognosis
Paget disease of nipple	<2%	Malignant cells in nipple epidermis; associated with underlying DCIS or IDC; eczema-like nipple changes

Molecular (intrinsic) subtypes:

Subtype	ER/PR	HER2	Ki-67	Prognosis	Treatment
Luminal A	+	-	Low	Best	Endocrine therapy; low-dose chemo
Luminal B	+	+/-	High	Intermediate	Endocrine + chemo ± anti-HER2
HER2-enriched	-	+	High	Intermediate	Anti-HER2 + chemo (trastuzumab)
Triple-negative (TNBC)	-	-	High	Worst	Chemo only; immunotherapy (pembrolizumab); PARP inhibitors (BRCA+)

HER2 positivity: Gene amplification by FISH or 3+ IHC; treated with trastuzumab (Herceptin), pertuzumab, T-DM1 (ado-trastuzumab emtansine), T-DXd

Prognostic factors:

Lymph node status (most important prognostic factor)
Tumor size
Grade (Scarff-Bloom-Richardson: tubule formation + nuclear pleomorphism + mitotic rate)
Hormone receptor status (ER/PR+: better prognosis)
HER2 status (treatment target)
OncotypeDX/Mammaprint scores guide chemo decision in ER+/HER2- early breast cancer

Treatment:

Surgical: lumpectomy + sentinel node biopsy (preferred) vs mastectomy + axillary dissection
Radiation: after lumpectomy, after mastectomy with high-risk features
Endocrine: tamoxifen (premenopausal); aromatase inhibitors (postmenopausal); CDK4/6 inhibitors (palbociclib + AI for metastatic ER+)
Anti-HER2: trastuzumab, pertuzumab, T-DM1
Chemotherapy: anthracyclines + taxanes (AC-T most common)
PARP inhibitors: olaparib/talazoparib for BRCA-mutated metastatic

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