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LONG ANSWERS

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1. Acute and Chronic Renal Failure

ACUTE KIDNEY INJURY (AKI) / Acute Renal Failure

• Reduced effective circulating volume: hemorrhage, dehydration, burns, third-spacing
• Cardiac causes: heart failure, cardiogenic shock, cardiac tamponade
• Hepatorenal syndrome (liver cirrhosis with portal hypertension)
• Renal vasoconstriction: NSAIDs (inhibit prostaglandins causing afferent arteriolar constriction), ACE inhibitors/ARBs (efferent vasodilation reducing GFR in setting of RAS or bilateral RAS)
• Mechanism: reduced renal perfusion pressure → decreased GFR. The tubules function normally. Urinary sodium is low (<20 mEq/L), fractional excretion of sodium (FENa) <1%.

• Tubular: Acute tubular necrosis (ATN) - ischemic or nephrotoxic (see Short Note below)
• Glomerular: Rapidly progressive glomerulonephritis, acute proliferative GN
• Interstitial: Acute interstitial nephritis (drugs, infections)
• Vascular: Renal artery thrombosis, TTP-HUS, malignant hypertension, renal cortical necrosis

• Obstruction of urinary flow at any level: bilateral ureteric obstruction (stones, retroperitoneal fibrosis, pelvic tumors), bladder outlet obstruction (BPH, prostate cancer, urethral stricture), bilateral pelviureteric junction obstruction
• Early relief of obstruction is reversible; prolonged obstruction leads to tubular atrophy and permanent damage

• Hemodynamic: Afferent arteriolar vasoconstriction (via angiotensin II, endothelin, thromboxane), tubuloglomerular feedback activation
• Tubular damage: Loss of tubular cell polarity and cytoskeleton integrity, detachment of cells from basement membrane, intraluminal cast obstruction, backleak of glomerular filtrate across damaged tubular epithelium into interstitium
• Inflammatory cascade: Ischemia/reperfusion injury triggers neutrophil and monocyte infiltration, release of reactive oxygen species, cytokine-mediated damage
• Intrarenal hypoxia: The outer medulla (thick ascending limb of Henle) is most vulnerable due to high metabolic demand and low baseline oxygen tension. Diabetes increases this susceptibility markedly.

• Urine output <400 mL/day (oliguric AKI) or normal/increased (non-oliguric ATN - better prognosis)
• Rising BUN, serum creatinine
• Hyperkalemia (dangerous - cardiac arrhythmias), hyperphosphatemia, metabolic acidosis (high anion gap)
• Hyponatremia due to water retention
• Fluid overload: pulmonary edema, hypertension, peripheral edema
• Uremic symptoms: nausea, vomiting, confusion, pericarditis, asterixis

• Recovery of tubular function; large volumes of dilute urine
• Risk of dehydration, hypokalemia, hyponatremia

• Pre-renal: Volume resuscitation, treat underlying cause; cautious fluid challenge
• Intrinsic: Treat underlying cause; avoid nephrotoxins, adjust drug doses
• Post-renal: Urgent relief of obstruction (catheter, nephrostomy, stenting)
• Supportive: Maintain fluid and electrolyte balance; restrict K⁺, phosphate, protein (in uremia)
• Indications for dialysis (AEIOU): Acidosis (refractory), Electrolyte imbalance (hyperkalemia), Intoxication, fluid Overload, Uremia (pericarditis, encephalopathy, bleeding)

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CHRONIC KIDNEY DISEASE (CKD) / Chronic Renal Failure

• Most common worldwide: Diabetic nephropathy (diabetic kidney disease, DKD) - accounts for ~40% of new dialysis patients
• Hypertensive nephrosclerosis (~25%)
• Glomerulonephritis (IgA nephropathy, FSGS, membranous nephropathy)
• Polycystic kidney disease (hereditary)
• Obstructive uropathy (chronic)
• Reflux nephropathy
• Analgesic nephropathy, heavy metal toxicity
• Myeloma kidney, amyloidosis

1. Hyperfiltration theory (Brenner hypothesis): Loss of nephrons → remaining nephrons develop compensatory hypertrophy and hyperfiltration (increased glomerular capillary pressure and flow) → glomerular hypertension → mesangial cell activation, podocyte injury, proteinuria → glomerulosclerosis → further nephron loss (vicious cycle)
2. Proteinuria-mediated tubular injury: Filtered proteins (albumin, transferrin, complement) are toxic to proximal tubular cells → tubular cell death → tubulointerstitial fibrosis (the best histological correlate of GFR loss)
3. Activation of RAAS: Intrarenal angiotensin II promotes glomerular hypertension, pro-fibrotic cytokine release (TGF-β), and tubular apoptosis
4. Systemic hypertension: Transmitted to glomeruli → further injury
5. Inflammation and fibrosis: Infiltrating macrophages/lymphocytes release TGF-β, TNF-α, IL-6 → activation of myofibroblasts → interstitial fibrosis

• Slow progression: BP control (<130/80 mmHg), proteinuria reduction (ACE inhibitor/ARB first-line), glycemic control in diabetes, SGLT-2 inhibitors (finerenone/dapagliflozin shown to slow CKD progression)
• Treat complications: Anemia - EPO, IV iron; Bone disease - phosphate binders, calcitriol, cinacalcet; Acidosis - sodium bicarbonate
• Dietary: Restrict protein (0.6-0.8 g/kg/day), potassium, phosphate, sodium
• Renal replacement therapy: Hemodialysis, peritoneal dialysis, kidney transplantation (best long-term outcomes)

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2. Etiopathogenesis of Conditions Producing Non-Selective Proteinuria

1. Fenestrated glomerular endothelium - has pores ~70-100 nm; coated with glycocalyx/proteoglycans bearing negative charge
2. Glomerular basement membrane (GBM) - type IV collagen, laminin, heparan sulfate proteoglycans (charge barrier)
3. Podocytes - terminally differentiated epithelial cells with foot processes connected by the slit diaphragm (nephrin, podocin, CD2AP) - the primary size-selective barrier

• Selective proteinuria: Only albumin and similarly sized proteins pass (<65 kDa). Charge selectivity maintained but size selectivity lost. Seen in minimal change disease. Selectivity index (IgG/transferrin clearance) <0.1.
• Non-selective proteinuria: Both albumin AND large molecular weight proteins (IgG, IgA, C3, transferrin, fibrinogen) pass. Both charge and size barriers disrupted. Seen in most other glomerular diseases.

A. Membranous Nephropathy (MN)

• Primary (80%): Circulating antibodies (mainly anti-PLA2R - phospholipase A2 receptor in 70-80% of cases) target podocyte antigens → in situ immune complex (IC) formation on the subepithelial surface of GBM
• Secondary (20%): SLE (lupus nephritis class V), solid tumors (lung, colon, breast), drugs (penicillamine, gold, NSAIDs), infections (HBV, HCV, malaria, syphilis)
• Pathogenesis: Subepithelial IC deposits activate complement (C5b-9 membrane attack complex) → podocyte injury and foot process effacement → disruption of slit diaphragm → loss of charge and size selectivity → non-selective proteinuria
• Histology: Silver stain shows "spike and dome" appearance; IF shows granular IgG and C3 along capillary walls; EM shows subepithelial electron dense deposits

B. Focal Segmental Glomerulosclerosis (FSGS)

• Primary FSGS: Circulating permeability factor (possibly soluble urokinase receptor, suPAR) injures podocytes → podocyte detachment and loss (podocytopenia) → denudation of GBM → adhesion to Bowman's capsule → segmental sclerosis
• Secondary FSGS: Obesity (adaptive hyperfiltration), HIV (HIV-associated nephropathy - collapsing variant), heroin, vesicoureteral reflux, reduced nephron mass
• Genetic/familial: Mutations in NPHS1 (nephrin), NPHS2 (podocin), ACTN4 (α-actinin-4), TRPC6
• Pathogenesis: Podocyte injury → cytoskeletal collapse of foot processes → disruption of slit diaphragm → loss of both charge and size barriers → non-selective heavy proteinuria
• Histology: Focal (<50% of glomeruli) and segmental (<50% of tuft) sclerosis; IF: IgM and C3 in sclerotic segments (trapped proteins, not IC); EM: diffuse foot process effacement

C. Diabetic Nephropathy (DKD)

• Stage 1: Glomerular hyperfiltration and hypertrophy (increased GFR)
• Stage 2: Normal excretion but thickening of GBM and mesangial expansion
• Stage 3 (Incipient nephropathy): Microalbuminuria 30-300 mg/day; beginning charge selectivity loss
• Stage 4 (Overt nephropathy): Albuminuria >300 mg/day (macroalbuminuria) → progresses to non-selective proteinuria (>3.5 g/day) as GBM develops disrupted texture, gaps, and holes (per Comprehensive Clinical Nephrology)
• Pathogenesis of non-selective proteinuria: Advanced glycation end products (AGEs) → cross-link GBM collagen → loss of normal pore architecture; mesangial expansion (Kimmelstiel-Wilson nodules) compresses capillaries; podocyte loss → extensive GBM exposure → non-selective leak of all serum proteins
• Histology: Diffuse glomerulosclerosis, Kimmelstiel-Wilson nodules, capsular drop, fibrin cap lesions; "wire loop" lesions in SLE

D. Lupus Nephritis (Class III, IV, V)

• Pathogenesis: Anti-dsDNA and other antinuclear antibodies form immune complexes → deposited in glomeruli (mesangium, subendothelial, subepithelial depending on class) → complement activation → neutrophil/monocyte infiltration → GBM disruption → non-selective proteinuria
• Class IV (diffuse proliferative) is most severe; subendothelial deposits → "full house" IF (IgG, IgA, IgM, C3, C1q), "wire loop" lesions on light microscopy

E. Amyloidosis

• AL amyloidosis (light chain): plasma cell dyscrasia → misfolded immunoglobulin light chains (λ>κ) aggregate as amyloid fibrils → deposit in glomerular mesangium and capillary walls
• AA amyloidosis: chronic inflammation (rheumatoid arthritis, chronic infections) → excess serum amyloid A protein → fibrillogenesis
• Pathogenesis: Amyloid fibrils disrupt glomerular architecture → massive non-selective proteinuria; >90% of AA amyloidosis patients have non-selective proteinuria; nephrotic syndrome occurs in >50% (Firestein & Kelley's Textbook of Rheumatology)
• Histology: Congo red staining → apple-green birefringence under polarized light; EM: 8-10 nm non-branching fibrils

F. Membranoproliferative Glomerulonephritis (MPGN)

• Type I (IC-mediated): HCV-associated cryoglobulinemia, lupus, endocarditis → subendothelial ICs → complement activation → mesangial proliferation → GBM duplication ("tram-track" or "double-contour" appearance on silver stain)
• Type II (Dense Deposit Disease): C3 nephritic factor (autoantibody against C3 convertase) → uncontrolled alternative complement pathway activation → dense osmiophilic deposits within GBM
• Pathogenesis: Complement-mediated and direct podocyte injury → disruption of filtration barrier → non-selective proteinuria + hematuria (nephritic features overlap)

G. IgA Nephropathy (with heavy proteinuria)

• Galactose-deficient IgA1 → circulating immune complexes → mesangial deposition → complement (lectin pathway) and alternative pathway activation
• Usually selective/non-nephrotic proteinuria, but when nephrotic-range non-selective proteinuria occurs: active mesangial proliferative GN with podocyte injury, or coexisting MCD, or advanced scarring (Comprehensive Clinical Nephrology)

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3. Nephrotic Syndrome

• Massive proteinuria >3.5 g/day/1.73m² (or >40 mg/m²/h in children)
• Hypoalbuminemia <3 g/dL (serum)
• Pitting edema
• Hyperlipidemia (mostly hypercholesterolemia)
• Lipiduria (oval fat bodies, "Maltese cross" birefringence, fatty casts)

• Minimal Change Disease (MCD) - most common in children (80%), adults (20%)
• Focal Segmental Glomerulosclerosis (FSGS) - most common cause of nephrotic syndrome in adults in the USA
• Membranous Nephropathy - most common in adults in Europe/Asia
• Membranoproliferative Glomerulonephritis (MPGN)

• Metabolic: Diabetic nephropathy (most common secondary cause worldwide)
• Systemic: SLE (lupus nephritis class V)
• Infectious: HBV (membranous), HCV (MPGN/cryoglobulinemia), HIV (FSGS-collapsing), malaria (membranous/MPGN), syphilis
• Neoplastic: Solid tumors (lung, colon - membranous); lymphoma/leukemia (MCD - Hodgkin's lymphoma classic association)
• Drugs: NSAIDs, gold, penicillamine, heroin, captopril
• Hereditary: Congenital nephrotic syndrome (Finnish type - NPHS1 mutation)
• Amyloidosis: AL or AA

1. Proteinuria

• Injury to podocytes and slit diaphragm (loss of nephrin, podocin) → increased permeability of filtration barrier → massive protein loss
• Initially selective (MCD), becomes non-selective in progressive disease

2. Hypoalbuminemia

• Urinary albumin loss exceeds hepatic synthetic capacity
• Hepatic upregulation of albumin synthesis occurs but is insufficient
• Reduced amino acid availability due to protein catabolism
• Intestinal protein loss (edematous bowel)

3. Edema - Two Theories

• Supported by: low blood pressure, activated RAAS, high plasma renin activity in some patients (especially MCD)

• Supported by: many nephrotic patients have normal or expanded plasma volume, suppressed renin

4. Hyperlipidemia

• Reduced plasma oncotic pressure → stimulates hepatic lipoprotein synthesis (non-specific protein synthesis upregulation)
• Increased VLDL and LDL synthesis (primarily cholesterol)
• Decreased lipoprotein lipase activity → reduced clearance of VLDL and chylomicrons → hypertriglyceridemia
• Reduced plasma albumin → decreased clearance of LDL
• Resulting pattern: hypercholesterolemia (predominant), hypertriglyceridemia

5. Lipiduria

• Lipoproteins pass through damaged filtration barrier → reabsorbed by tubular cells → appear in urine as lipid-laden tubular cells (oval fat bodies) → show "Maltese cross" birefringence under polarized light
• Free fat droplets and fatty casts also seen

6. Hypercoagulability (important complication)

• Pro-thrombotic: Loss of antithrombin III, protein C, protein S, plasminogen in urine; elevated fibrinogen (hepatic synthesis increased); platelet hyperaggregability; hemoconcentration
• Most feared: renal vein thrombosis (especially in membranous nephropathy), deep vein thrombosis, pulmonary embolism
• Membranous nephropathy: highest risk; present in up to 30-40%

7. Infections

• Loss of immunoglobulins (IgG) and complement factors (factor B, factor D - properdin pathway) in urine → susceptibility to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae)
• Peritonitis with S. pneumoniae is classic in children with nephrotic syndrome (ascitic fluid infection)
• Edematous skin is also prone to cellulitis

8. Other Metabolic Complications

• Hypothyroidism risk: Loss of thyroid-binding globulin → low total T4 (TSH usually normal)
• Iron-deficiency anemia: Loss of transferrin
• Vitamin D deficiency: Loss of vitamin D-binding protein → hypocalcemia, osteomalacia
• Zinc deficiency: Loss of zinc-binding proteins

• Urine: 24-hour protein, protein:creatinine ratio, lipiduria on microscopy
• Blood: albumin, lipid profile, complement (C3, C4), ANA, anti-dsDNA, anti-PLA2R (for membranous), ANCA, HBV/HCV/HIV serology, serum protein electrophoresis (for myeloma)
• Renal biopsy: essential in adults; children with steroid-sensitive nephrotic syndrome (presumed MCD) may not need biopsy initially

• Treat underlying cause (steroids for MCD, cyclophosphamide/rituximab for membranous, etc.)
• Edema: sodium restriction, loop diuretics (furosemide), avoid aggressive diuresis (risk of AKI)
• Hyperlipidemia: statins
• Anticoagulation: in membranous nephropathy with serum albumin <2 g/dL or thrombotic events
• ACE inhibitor/ARB: reduce proteinuria by 30-40%
• Prophylactic penicillin in children with ascites

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SHORT NOTES

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1. Acute Tubular Necrosis (ATN)

• Shock: septic (most common), cardiogenic, hypovolemic, distributive
• Major surgery (especially cardiac, vascular, hepatic)
• Burns, trauma, rhabdomyolysis
• Renal artery occlusion, aortic cross-clamping

• Endogenous toxins: myoglobin (rhabdomyolysis), hemoglobin (hemolysis), myeloma light chains (cast nephropathy), bile acids (hepatorenal)
• Exogenous toxins:
  • Aminoglycosides (gentamicin, tobramycin) - proximal tubule toxicity; non-oliguric ATN
  • Radiocontrast agents - especially in diabetes, CKD, volume depletion
  • Cisplatin, amphotericin B
  • Organic solvents (ethylene glycol → calcium oxalate deposits)
  • Heavy metals (lead, mercury, cadmium)

1. Tubular obstruction: Necrotic and apoptotic tubular cell debris, together with Tamm-Horsfall protein and filtered proteins, form intraluminal casts → obstruction of tubular flow → back-pressure opposes filtration → reduced GFR
2. Backleak: Disrupted tubular epithelium allows filtered glomerular filtrate to leak back into the peritubular interstitium → effective loss of filtrate → reduced net GFR
3. Tubular cell polarity disruption: Na⁺/K⁺-ATPase normally concentrated at basolateral membrane; ischemia causes redistribution → impaired Na⁺ transport → loss of tubular function; actin cytoskeleton disruption → cell detachment from basement membrane
4. Afferent arteriolar vasoconstriction: Loss of tubular integrity → increased NaCl delivery to macula densa → tubuloglomerular feedback → afferent arteriolar vasoconstriction → further GFR reduction

• Proximal tubular cells: vacuolation, loss of brush border, nuclear pyknosis/karyolysis
• Tubular epithelial cell detachment, intraluminal casts (muddy brown granular casts)
• Necrosis typically focal (not diffuse) and may be missed on biopsy
• Apoptosis prominent; regenerative changes (flattened basophilic cells) appear early
• Interstitium: edema, mild leukocyte infiltration
• Glomeruli: relatively preserved in isolated ATN

1. Initiation phase (hours to days): initiating insult; GFR falls; oliguria begins
2. Maintenance/oliguric phase (1-2 weeks): GFR stable at low level; oliguria; uremia; hyperkalemia; metabolic acidosis; BUN and creatinine rise ~10-20 mg/dL/day; urinary sediment shows muddy brown granular casts, tubular epithelial cells
3. Recovery/diuretic phase (days to weeks): tubular cells regenerate; large volumes of dilute urine; risk of dehydration and electrolyte loss

• FENa >2% (distinguishes from pre-renal: FENa <1%)
• Urine Na >40 mEq/L
• Urine osmolality <350 mOsm/kg (isosthenuria - tubules cannot concentrate)
• Muddy brown granular casts + tubular epithelial cell casts (pathognomonic)

• Remove precipitating cause; stop nephrotoxins; correct volume status
• Prevent/treat complications: hyperkalemia (ECG monitoring, calcium gluconate, kayexalate, insulin/dextrose, dialysis), fluid overload, acidosis
• No proven pharmacologic intervention to accelerate recovery (no role for mannitol, furosemide, or dopamine)
• Supportive nutrition (enteral preferred)
• Dialysis if indications met (AEIOU criteria)
• Prognosis: most recover if managed correctly, but those requiring dialysis have ~50% mortality (due to underlying sepsis/multiorgan failure)

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2. RPGN (Rapidly Progressive Glomerulonephritis)

• Rapid loss of kidney function over days to weeks (50%+ decline in GFR within 3 months)
• Clinical features of nephritic syndrome (hematuria, proteinuria, hypertension, oliguria)
• Histology: crescents in >50% of glomeruli (hence also called "crescentic GN")

• Rapid decline in kidney function (days to weeks)
• Hematuria (gross or microscopic), red cell casts (dysmorphic RBCs), proteinuria (usually non-nephrotic except if secondary to lupus)
• Oliguria/anuria
• Hypertension, fluid overload
• Constitutional symptoms (fatigue, fever, weight loss in vasculitis)
• Pulmonary hemorrhage in Goodpasture and ANCA-GPA (hemoptysis, pulmonary infiltrates)

• Urinalysis: red cell casts, proteinuria, hematuria
• Serology: ANCA (c-ANCA = PR3-ANCA for GPA, p-ANCA = MPO-ANCA for MPA), anti-GBM antibody, ANA, anti-dsDNA, complement (C3, C4), ASOT, blood cultures, HBV/HCV, cryoglobulins
• Kidney biopsy: essential (crescents >50% = RPGN; confirms type by IF)
• Chest X-ray/CT for pulmonary involvement

• Must be initiated rapidly - delays worsen prognosis
• All types: High-dose methylprednisolone pulse (IV 1g × 3 days), then oral prednisolone
• Type I (anti-GBM): Plasma exchange (removes circulating antibodies) + cyclophosphamide
• Type II: Treat underlying disease (e.g., antibiotics for post-streptococcal, hydroxychloroquine + immunosuppression for lupus)
• Type III (ANCA): Cyclophosphamide or rituximab + plasma exchange if severe (dialysis-dependent or pulmonary hemorrhage)
• Dialysis support as needed

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3. Pigmented Lesions of Skin and Premalignant Lesions of Skin

PIGMENTED LESIONS OF SKIN

• Small, flat, brown macules on sun-exposed areas
• Normal melanocyte number but increased melanin production per cell
• Darken in summer; no malignant potential

• Lentigo simplex: Small tan macule; increased melanocytes and pigmentation; appears in childhood; no sun exposure needed
• Solar (actinic) lentigo: "Liver spots"; sun-exposed areas in middle-aged/elderly; increased melanocytes and basal pigmentation; very low malignant potential (must distinguish from lentigo maligna)

• Junctional nevus: Nevus cells at the dermal-epidermal junction; flat, brown; most common in children
• Compound nevus: Nevus cells at junction AND dermis; slightly elevated, pigmented
• Intradermal nevus: Nevus cells entirely in dermis; raised, flesh-colored or lightly pigmented; most common in adults; least risk of malignant transformation
• Dysplastic (Clark) nevus: >5 mm, irregular borders, variegated color, architectural and cytological atypia → marker of increased melanoma risk; component of familial dysplastic nevus syndrome (CDKN2A mutation)
• Spitz nevus: Spindle and epithelioid cells; predominantly in children; may mimic melanoma histologically but benign behavior; "starburst" pattern on dermatoscopy

• Deeply situated melanocytes with abundant melanin (appear blue due to Tyndall effect)
• Common blue nevus vs. cellular blue nevus (larger, some risk of malignant transformation)

• Present at birth; giant congenital nevi (>20 cm) have ~5-10% lifetime risk of melanoma

• Port wine stain (nevus flammeus): Ectatic dermal capillaries; facial distribution following trigeminal nerve (associated with Sturge-Weber syndrome)
• Café-au-lait macules: Uniform tan patches; 6 or more ≥1.5 cm = diagnostic criterion for neurofibromatosis type 1
• Mongolian spots: Blue-gray macules over sacrum; dermal melanocytes; disappear in early childhood

• Benign epidermal tumor; waxy, "stuck-on" appearance; brown/black; found on trunk, face, extremities of older adults
• Horn cysts (pseudohorn cysts) on histology
• Sign of Leser-Trelat: sudden appearance of multiple seborrheic keratoses → paraneoplastic sign (associated with GI adenocarcinoma, lymphoma)

• Firm, button-like dermal nodule; brown/tan; lower extremities; benign

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PREMALIGNANT LESIONS OF SKIN

• Most common premalignant skin lesion
• Caused by cumulative UV-B radiation exposure → keratinocyte DNA damage (p53 mutations, CDKN2A deletions)
• Occurs on sun-exposed areas (face, scalp, dorsum of hands, forearms) in fair-skinned individuals
• Appearance: rough, scaly, erythematous papule/plaque; sandpaper-like texture; may have cutaneous horn
• Histology: epidermal dysplasia (atypical keratinocytes in lower epidermis), parakeratosis, solar elastosis in dermis
• Risk of SCC transformation: ~0.1-0.3%/lesion/year; in patients with multiple lesions, cumulative risk is significant
• Treatment: cryotherapy, 5-fluorouracil cream, imiquimod, photodynamic therapy, diclofenac

• Intraepidermal squamous cell carcinoma (carcinoma in situ); full-thickness epidermal dysplasia
• Not limited to sun-exposed areas; can occur on trunk, extremities, genitalia (genital Bowen's = erythroplasia of Queyrat on glans penis)
• Caused by: UV radiation, HPV (especially HPV 16/18 on genitalia), arsenic exposure, immunosuppression
• Appearance: well-defined, erythematous, scaly plaque; may be hyperkeratotic or eroded
• Histology: full-thickness epidermal dysplasia, atypical keratinocytes with large irregular nuclei, dyskeratosis, mitotic figures at all levels; basement membrane intact (distinguishes from invasive SCC)
• ~3-5% risk of invasion into dermis (invasive SCC)
• Treatment: excision, cryotherapy, 5-FU, photodynamic therapy

• Bowen's disease on mucous membranes (glans penis, vulva)
• Bright red, velvety plaque
• Higher rate of invasion (~10-33%) than cutaneous Bowen's
• Associated with HPV

• In situ melanoma (melanoma in situ) arising in sun-damaged skin of elderly
• Slowly enlarging, irregularly pigmented macule on face (cheek, temple, nose)
• Atypical melanocytes proliferate along the dermal-epidermal junction without invasion (radial growth phase)
• If dermis is invaded → lentigo maligna melanoma (~5-30% lifetime risk of invasion)
• Histology: atypical melanocytes singly along DEJ, solar elastosis, no invasive component

• Architecturally disordered nevus with cytological atypia; precursor to (and marker of) melanoma
• Familial dysplastic nevus syndrome (FAMMM syndrome): multiple dysplastic nevi + family history of melanoma + CDKN2A mutation; very high melanoma risk

• Controversial; some consider it a well-differentiated SCC, others a benign self-limiting lesion
• Rapid growth (weeks) to dome-shaped nodule with central keratin plug → spontaneous involution over months
• Histologically resembles well-differentiated SCC (crateriform architecture with glassy keratinocytes)
• Treated by excision

• White patch on mucous membranes (oral, vulval) that cannot be scraped off
• Represents squamous hyperplasia/dysplasia; caused by tobacco, alcohol, chronic irritation, HPV
• Erythroplakia (red counterpart) has higher malignant potential
• ~5-25% risk of SCC transformation

• Asymmetry
• Border irregularity
• Color variegation
• Diameter >6 mm
• Evolution (change in size, shape, color, symptoms)

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4. Alzheimer's Disease - Pathophysiology

• Prevalence doubles every 5 years after age 65
• 1% at age 65 → 40% over age 85
• Most cases (>95%) are sporadic (late-onset, >65 years)
• ~1-5% are familial/autosomal dominant (early onset, <65 years)

1. Medial temporal lobes - hippocampal formation (especially CA1), amygdala, entorhinal cortex (explains early memory loss)
2. Basal temporal cortex extending to lateral posterior temporal, parieto-occipital, posterior cingulate (default mode network)
3. Frontal lobes (explains executive dysfunction in later stages)
4. Cholinergic nuclei: Nucleus basalis of Meynert (cholinergic projections to cortex), septal nuclei, nucleus of the diagonal band
5. Brainstem: Locus coeruleus (norepinephrine), raphe nuclei (serotonin)
6. Relatively spared initially: Primary motor, sensory, visual, and auditory cortices (explains preserved motor/sensory function until late stages)

1. Amyloid (Senile) Plaques

• Composition: Core of insoluble β-amyloid protein (Aβ) surrounded by dystrophic neurites (abnormal axons and dendrites), reactive astrocytes, and activated microglia; also contains apolipoprotein E
• Types:
  • Neuritic (classic) plaques: Aβ core + dystrophic neurites; associated with cognitive decline
  • Diffuse plaques: Aβ without neuritic component; may be presymptomatic
• Origin of β-amyloid:
  • APP (amyloid precursor protein) is a normal transmembrane protein of unknown function
  • Normal processing: α-secretase cleaves APP within the Aβ domain → non-amyloidogenic (sAPPα + p3 fragment)
  • Amyloidogenic processing: β-secretase (BACE1) cleaves → then γ-secretase complex (containing presenilin 1 or 2) cleaves → releases Aβ40 (predominant) or Aβ42 (more hydrophobic, more prone to aggregation)
  • Aβ42 forms toxic soluble oligomers → aggregates into protofibrils → insoluble fibrils → plaques
  • The amyloid cascade hypothesis proposes that Aβ42 accumulation is the initiating event that triggers tau pathology, neuroinflammation, synapse loss, and neuronal death

2. Neurofibrillary Tangles (NFTs)

• Intraneuronal accumulations of hyperphosphorylated tau protein
• Tau is normally a microtubule-associated protein that stabilizes axonal microtubules
• In AD: abnormal kinase activity (CDK5, GSK-3β) → hyperphosphorylated tau → loses affinity for microtubules → forms paired helical filaments (PHFs) → aggregates as NFTs
• NFTs cause microtubule destabilization → impaired axonal transport → neuronal dysfunction and death
• Spread follows Braak staging (I-VI): entorhinal cortex → hippocampus → association cortex → primary cortex

3. Synaptic Loss and Neuronal Death

• Loss of synapses (especially cholinergic) is the best correlate of cognitive decline
• Cholinergic deficit: loss of neurons in nucleus basalis of Meynert → depleted acetylcholine in cortex → basis of cholinesterase inhibitor therapy (donepezil, rivastigmine, galantamine)
• Also: glutamate excitotoxicity (basis for memantine therapy - NMDA receptor antagonist)

4. Neuroinflammation

• Aβ oligomers activate microglia and astrocytes → release pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) → complement activation → neuronal damage (chronic neuroinflammation accelerates neurodegeneration)

• Cortical atrophy (widened sulci, narrowed gyri), most pronounced in hippocampus, entorhinal cortex, temporal and parietal lobes
• Ventricular enlargement (hydrocephalus ex vacuo)
• Relative sparing of occipital, motor, and sensory cortex until late stages

• ↓ Acetylcholine (cholinergic deficit - most clinically relevant)
• ↓ Norepinephrine (locus coeruleus)
• ↓ Serotonin (raphe nuclei)
• ↓ Somatostatin
• Glutamate excitotoxicity (overactivation of NMDA receptors by Aβ)

• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine): inhibit AChE → increase synaptic ACh; mild-moderate AD
• Memantine: NMDA antagonist; blocks glutamate excitotoxicity; moderate-severe AD
• Anti-amyloid immunotherapy: lecanemab (Leqembi) and donanemab received FDA approval (2023-2024) for early AD; clear plaques but modest clinical benefit with significant ARIA (amyloid-related imaging abnormalities) risk
• Tau-targeted therapies: under investigation

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