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CVS Pathology Day 2 - Complete Summary Notes

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1. VASCULITIS: OVERVIEW

• Definition: Inflammation of vessel walls ("vessel wall inflammation")
• Manifestations: Highly diverse ("protean") - depend on which vascular bed is affected
• Constitutional symptoms: Fever, myalgias, arthralgias, malaise (driven by systemic inflammation)
• Any vessel can be affected, but majority preferentially affect arterioles → capillaries → venules
• ~20 primary forms recognized; classified by: vessel caliber, immune complex role, autoantibodies, granuloma formation, organ tropism, demographics

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2. TWO PRIMARY PATHOGENIC MECHANISMS

• Critical distinction: Giving immunosuppression for infectious vasculitis can be fatal
• Other causes: Irradiation, mechanical trauma, chemical toxins

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3. NON-INFECTIOUS VASCULITIS: 4 PATHOGENIC MECHANISMS

1. Immune complex deposition
2. ANCA (Antineutrophil cytoplasmic antibodies)
3. Anti-endothelial cell (Anti-EC) antibodies
4. Autoreactive T-cells

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A. Immune Complex-Associated Vasculitis

• Seen in SLE, mirrors Arthus phenomenon / serum sickness
• Challenges: Antigen rarely identified; unclear if complexes deposit from circulation or form in situ; assay sensitivity is low; deposits may be absent ("pauci-immune artifact" - enzymatic degradation)

• Drugs act as haptens (e.g., penicillin) OR foreign proteins (e.g., streptokinase)
• Antibodies → circulating immune complexes → vasculitis
• Skin lesions most common; key management = discontinue the offending drug

• Microbial antigen + host antibody → immune complexes deposit in vessel walls
• Classic example: Polyarteritis nodosa - up to 30% caused by HBsAg-anti-HBsAg immune complexes (Hepatitis B)

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B. ANCA-Associated Vasculitis

• ANCAs = autoantibodies against enzymes in neutrophil primary granules, monocyte lysosomes, endothelial cells
• ANCA titers mirror disease severity; rising titers during remission = predicts relapse
• Results in pauci-immune vasculitis (no antibody/complement deposits on immunofluorescence)

• Drug-induced MPO-ANCA: Propylthiouracil (PTU)

1. Drug/microbial antigen → ANCA formation in genetically susceptible host
2. TNF cytokine primes neutrophils → PR3/MPO translocated to cell surface
3. ANCA binds to surface PR3/MPO → direct EC injury + neutrophil hyper-activation
4. ANCA-activated neutrophils release ROS and granule contents → necrotizing vascular damage

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C. Anti-Endothelial Cell Antibodies

• Antibodies against ECs due to immune dysregulation
• Predisposes to Kawasaki disease

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4. SPECIFIC VASCULITIS SYNDROMES

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GIANT CELL (TEMPORAL) ARTERITIS

• Most common systemic vasculitis in elderly adults (US/Europe)
• Large-to-small arteries of the head; temporal artery most accessible for biopsy
• Also involves: vertebral, ophthalmic arteries, aorta (giant cell aortitis)
• Emergency: Ophthalmic artery involvement → sudden permanent blindness

• T cell-mediated immune response against unidentified vessel wall antigen
• Supported by: granulomatous inflammation, MHC Class II association, excellent corticosteroid response
• TNF and anti-EC antibodies drive secondary damage
• Head tropism possibly due to region-specific antigens from different embryonic anlagen

• Concentric intimal thickening → lumen stenosis (+ thrombus)
• Granulomatous inflammation centered on internal elastic membrane
• Infiltrate: macrophages + T lymphocytes (CD4+ > CD8+)
• Multinucleated giant cells/granulomas in ~75% of biopsies (not mandatory)
• Skip lesions - focal, segmental disease separated by normal vessel
• Healed lesions: medial atrophy, collagenous scarring, >30% internal elastic lamina fragmentation, adventitial fibrosis

• Age >50 (exceedingly rare before age 50)
• Fever, fatigue, weight loss, malaise (constitutional prodrome)
• Severe facial pain/headache along temporal artery course; artery is nodular and tender to palpation
• Ocular symptoms in ~50% (diplopia → complete, irreversible vision loss)
• Biopsy: need ≥1 cm specimen (skip lesions mean negative biopsy doesn't exclude diagnosis)
• Treatment: corticosteroids or anti-TNF therapy

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TAKAYASU ARTERITIS ("PULSELESS DISEASE")

• Chronic granulomatous vasculitis of medium-large arteries
• Transmural fibrous thickening of aorta (especially aortic arch and great vessels) → severe luminal narrowing/obliteration
• Age divide (vs. Giant Cell Aortitis):

  • 50 years → Giant Cell Aortitis

  • <50 years → Takayasu Aortitis
• Demographics: traditionally Japanese but global; autoimmune etiology likely; HLA association

• Aortic arch in 2/3; remaining aorta in 1/3
• Pulmonary arteries involved in half of cases; coronary and renal arteries also targeted
• Irregular intimal hyperplasia → great vessel lumen obliteration
• Histologic stages: adventitial mononuclear infiltrates (perivascular cuffing around vasa vasorum) → medial mononuclear inflammation → granulomatous inflammation with giant cells + medial necrosis
• Chronic: dense collagenous scarring of all three wall layers
• May cause aortic valve insufficiency (retrograde root inflammation)

• Constitutional prodrome: fatigue, weight loss, low-grade fever
• Progressive ischemic symptoms:
  • Upper extremity: reduced BP, weak/absent pulses (asymmetric)
  • Ocular: visual defects, retinal hemorrhages, blindness
  • Neurological deficits (carotid/vertebral involvement)
  • Leg claudication (distal aortic involvement)
  • Pulmonary hypertension (pulmonary artery involvement)
  • Myocardial infarction (coronary ostia narrowing)
  • Systemic hypertension in ~half (renal artery involvement → renin-angiotensin activation)
• Clinical course: highly variable - some rapid lethal progression; some reach quiescence after 1-2 years

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POLYARTERITIS NODOSA (PAN)

• Systemic necrotizing vasculitis of small-to-medium muscular arteries
• Target organs: renal and visceral vasculatures
• Uniquely spares pulmonary circulation (key diagnostic feature)
• ANCA-negative (no ANCA association)
• ~1/3 of patients have chronic Hepatitis B (HBsAg-HBsAb immune complexes); remaining cases: unknown etiology

• Patchy, segmental, transmural necrotizing inflammation ± micro-aneurysms ± luminal thrombosis
• Organ frequency: Kidney > Heart > Liver > GI tract
• Predilection for vascular branch points
• Downstream: tissue ulceration, infarcts, ischemic atrophy, hemorrhage
• Acute phase: Mixed infiltrate (PMNs, eosinophils, mononuclears) + fibrinoid necrosis + luminal thrombosis
• Healed stage: Fibrous wall thickening extending to adventitia
• Pathognomonic: ALL stages coexist simultaneously (temporal mosaic) → indicates repetitive/episodic immune insult

• Primarily young adults
• Remitting/episodic course with symptom-free intervals
• Rapidly accelerating hypertension (renal artery → RAAS activation)
• Abdominal pain + bloody stools (GI ischemic lesions)
• Diffuse myalgias (muscle ischemia)
• Peripheral neuritis/mononeuritis multiplex
• Renal involvement = primary cause of mortality
• Untreated: fatal; with immunosuppression (corticosteroids + cyclophosphamide): 90% remission/cure

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KAWASAKI DISEASE (MUCOCUTANEOUS LYMPH NODE SYNDROME)

• Acute, febrile, usually self-limited systemic vasculitis of infancy/childhood
• 80% of patients < 4 years of age
• Most dangerous: intense tropism for coronary arteries
• Coronary aneurysms → rupture or thrombosis → myocardial infarction
• Global distribution; originally described in Japan
• Etiology: viral triggers in genetically susceptible → delayed-type hypersensitivity (T-cell) against vascular antigens → cytokine production + polyclonal B-cell activation → autoantibodies against ECs and SMCs

• Resembles PAN morphologically
• Transmural inflammatory infiltrate
• Fibrinoid necrosis less prominent than PAN
• Secondary coronary aneurysm formation (after acute vasculitis subsides)
• Healed: intimal thickening → lumen narrowing
• Extra-cardiovascular pathology: rarely significant

• Conjunctival erythema (bilateral, non-exudative red eyes)
• Oral erythema + strawberry tongue (cracked lips, tongue papillae prominent)
• Palmar/plantar erythema + hand/foot edema (non-pitting)
• Desquamative rash - peeling from periungual regions of fingers/toes
• Cervical lymphadenopathy (>1.5 cm, unilateral)
• High fever

• ~20% of untreated patients develop cardiovascular complications: coronary ectasia → giant coronary aneurysms (7-8 mm)
• Giant aneurysms: risk of rupture, thrombosis, MI, sudden cardiac death
• Treatment: IVIG + Aspirin → reduces coronary artery disease to <4%

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MICROSCOPIC POLYANGIITIS (Hypersensitivity / Leukocytoclastic Vasculitis)

• Systemic necrotizing vasculitis of capillaries, small arterioles, venules
• Also called: hypersensitivity vasculitis or leukocytoclastic vasculitis
• Unlike PAN: all lesions are same age (single synchronized immune episode)
• Key organs: 90% necrotizing glomerulonephritis + pulmonary capillaritis (contrast: PAN spares lungs)
• Can occur secondary to: Henoch-Schönlein purpura, essential mixed cryoglobulinemia, connective tissue disorders

• Triggers: drugs (penicillin), microorganisms (streptococci), heterologous/tumor proteins
• Majority: MPO-ANCA (p-ANCA) association
• Neutrophil recruitment + activation in small vessels → destructive manifestations

• Segmental fibrinoid necrosis of media + focal transmural necrotizing lesions
• NO granulomas (absolute distinguishing feature)
• Macroscopic infarcts rare (only microscopic vessels occluded)
• Leukocytoclasis: neutrophils infiltrate + undergo karyorrhexis → "nuclear dust"
• Pauci-immune: early skin lesions may show immunoglobulins/complement; established lesions → little/no immune deposition

• Pulmonary: hemoptysis (pulmonary capillaritis)
• Renal: hematuria + proteinuria (necrotizing glomerulonephritis)
• GI: bowel pain or bleeding
• Neuromuscular: muscle pain/weakness
• Cutaneous: palpable purpura (lower extremities)
• Treatment: immunosuppression → remission + improved survival

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GRANULOMATOSIS WITH POLYANGIITIS (GPA) [formerly Wegener's]

• Systemic necrotizing vasculitis of small-to-medium vessels + granulomatous inflammation of respiratory tract

1. Acute necrotizing granulomas of upper/lower respiratory tract
2. Necrotizing/granulomatous vasculitis (predominantly airways, but any site)
3. Focal necrotizing, often crescentic glomerulonephritis

• "Limited" GPA: respiratory tract only
• Widespread GPA: resembles PAN but requires respiratory involvement

• T-cell mediated hypersensitivity to inhaled microbial/environmental antigens
• PR3-ANCA (c-ANCA) present in up to 95% of cases
• PR3-ANCA titers = mirror of disease activity; rising titers = predicts relapse

• Upper airway: sinusitis → mucosal granulomas → ulcerative lesions (nose, palate, pharynx)
• Geographic necrosis: irregular "geographic" central necrosis + microvascular angiitis
• Granulomas bordered by fibroblasts, giant cells, leukocyte infiltrate (mimics TB/fungi)
• Pulmonary nodules → cavitation; advanced: alveolar hemorrhage + fibrous organization
• Renal:
  • Early: focal and segmental necrotizing GN
  • Advanced: crescentic (rapidly progressive) GN → rapid renal failure

• Males > females; average age ~40 years
• Bilateral pneumonitis (95%): cough, hemoptysis, nodules/cavities
• Chronic sinusitis (90%)
• Nasopharyngeal ulceration (75%): saddle-nose deformity (septal collapse)
• Renal disease (80%): proteinuria, hematuria, rapidly progressive renal failure
• Secondary: purpuric rashes, myalgias, arthritis, peripheral neuritis, fevers
• Untreated: 80% mortality within 1 year (uremia/respiratory failure)
• Treatment: steroids + cyclophosphamide + TNF antagonists + Rituximab → chronic relapsing-remitting disease

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CHURG-STRAUSS SYNDROME (Allergic Granulomatosis and Angiitis)

• Systemic small-vessel necrotizing vasculitis + severe allergic manifestations + tissue eosinophilia
• Classic profile: Refractory asthma + allergic rhinitis + shifting lung infiltrates + peripheral eosinophilia + extravascular necrotizing granulomas + eosinophilic vessel infiltration

• Cutaneous: palpable purpura or nodules
• GI bleeding (eosinophilic ischemic mucosal injury)
• Renal: focal and segmental glomerulosclerosis

• Eosinophils infiltrate myocardium → toxic granule proteins → severe restrictive/dilated cardiomyopathy
• Significant cardiac involvement: 60% of patients = single major cause of morbidity and death

• Immunologic hyperresponsiveness to environmental allergic stimulus
• MPO-ANCA (p-ANCA) present in only a MINORITY of cases (pathogenically heterogeneous - ANCA+ and ANCA- subtypes)

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THROMBOANGIITIS OBLITERANS (BUERGER DISEASE)

• Segmental, thrombosing, acute and chronic inflammatory vasculitis of medium and small arteries
• Targets: tibial and radial arteries → vascular insufficiency of hands/feet
• Occurs almost exclusively in heavy cigarette smokers, typically before age 35

• Direct EC toxicity by tobacco chemical components
• Immune response against tobacco-modified vascular wall proteins
• Patients show hypersensitivity to intradermal tobacco extracts

• Acute + chronic transmural inflammation + complete luminal thrombosis
• Pathognomonic: microabscesses within thrombus (central neutrophil collection + surrounding granulomatous inflammation)
• Neurovascular triad: inflammation extends to contiguous veins AND adjacent nerves (unique to Buerger disease)
• Chronic: all three structures encased in dense fibrous tissue

• Raynaud phenomenon (paroxysmal pallor/cyanosis)
• Instep claudication (severe foot pain with minimal exercise)
• Superficial nodular phlebitis (migratory)
• Rest pain (from nerve encasement by fibrous tissue)
• Chronic ulcers → frank gangrene requiring amputation
• Treatment: complete smoking cessation (early stage can halt progression; established fibrotic lesions do NOT respond)

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VASCULITIS ASSOCIATED WITH OTHER DISORDERS

• Secondary vasculitis mimics MPA or PAN morphologically
• Associated conditions: SLE, Rheumatoid arthritis, visceral malignancies, mixed cryoglobulinemia, Henoch-Schönlein purpura, antiphospholipid antibody syndrome

• Long-standing active RA
• Targets small-to-medium muscular arteries
• Vessel occlusion → visceral infarction
• Can cause rheumatoid aortitis

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INFECTIOUS VASCULITIS

• Direct invasion of vessel walls by bacteria or angioinvasive fungi
• Most angioinvasive fungi: Aspergillus and Mucor (mucormycosis)

1. Localized tissue invasion (bacterial pneumonia, deep abscesses eroding into vessel walls)
2. Hematogenous seeding (systemic septicemia, septic emboli from endocarditis)

• Mycotic aneurysm: endotoxins/proteolytic enzymes digest elastin/collagen → weakened wall → rupture-prone aneurysm
• Luminal thrombosis + downstream infarction: endothelial injury → coagulation cascade activation

• Bacterial meningitis → meningeal vasculitis → thrombosis of meningeal vessels → brain infarction/stroke

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5. DISORDERS OF VESSEL HYPERREACTIVITY

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RAYNAUD PHENOMENON

• Exaggerated vasoconstriction of digital arteries/arterioles triggered by cold or emotional stress
• Affects fingers, toes (also nose, earlobes, lips)
• Tricolor cascade: Red (proximal compensatory vasodilation) → White (central vasoconstriction) → Blue (distal cyanosis/deoxygenation)

• Surveillance mandate: ~10% of seemingly isolated Raynaud patients develop a full systemic autoimmune disorder over time

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MYOCARDIAL VESSEL VASOSPASM ("CARDIAC RAYNAUD")

• Sudden, excessive coronary artery/arteriolar constriction → ischemia
• Brief spasm = reversible angina; >20-30 minutes = irreversible myocardial infarction or sudden cardiac death
• Grouped under INOCA (Ischemia with Non-Obstructive Coronary Arteries)

• Intrinsic SMC hyperreactivity (like primary Raynaud)
• Surge of vasoactive agents:

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6. VENOUS AND LYMPHATIC DISEASES

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LOWER EXTREMITY VARICOSE VEINS

• Abnormally dilated, tortuous veins from chronic increased intraluminal pressure → valve incompetence
• Superficial leg veins most vulnerable (rely on calf-muscle pump against gravity)
• Venous pressure can increase 10x normal with prolonged standing
• Affects up to 20% of men and 1/3 of women
• Risk factors: Obesity, pregnancy (gravid uterus compresses IVC), defective venous wall development (familial)

• Valvular incompetence → venous stasis → hydrostatic edema → pain
• Stasis dermatitis ("brawny induration"): chronic ischemia → hemosiderin deposits (brawny skin color)
• Complications: skin ulcerations, poor wound healing, recurrent infections
• Embolism paradox: superficial varicose vein thrombosis rarely causes PE (contrasts with DVT which carries high PE risk)

• Esophageal varices (at gastroesophageal junction) → catastrophic fatal upper GI hemorrhage (cirrhosis → portal hypertension → portosystemic shunting)
• Hemorrhoids (anorectal junction) → painful, rectal bleeding, prone to thrombosis
• Caput medusae (periumbilical veins) → clinical sign only

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THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS

• Largely interchangeable terms for venous thrombosis + inflammation
• Deep leg veins = primary site (>90% of cases)
• Other sites: periprostatic (M), pelvic venous plexus (F), cerebral veins/dural sinuses, portal vein (peritonitis, appendicitis, salpingitis, polycythemia vera)

• Circulatory stasis: prolonged immobilization, postoperative states, CHF
• Hypercoagulability: pregnancy, obesity, oral contraceptives, genetic syndromes, malignancy

• Paraneoplastic hypercoagulability from adenocarcinomas (tumor secretes procoagulant factors)
• Thromboses appear, resolve, re-appear at different vascular sites

• Deep leg DVT is notoriously silent (minimal/no symptoms)
• Physical signs (vein dilation, leg edema, cyanosis, erythema, pain) may be entirely absent
• Elicitation: pressure over deep veins, calf squeeze, Homan's sign (forced dorsiflexion of foot)
• Negative physical findings do NOT exclude DVT

• DVT → thrombus detaches → travels through right heart → lodges in pulmonary artery
• PE is often the first manifestation of DVT
• Spectrum: small/few clots (minimal/asymptomatic) → massive/saddle clot (sudden death)

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SUPERIOR AND INFERIOR VENA CAVA SYNDROMES

• Caused by neoplasms (most common: bronchogenic carcinoma and mediastinal lymphoma)
• Clinical: dilated head/neck/arm veins, facial edema, upper-body cyanosis, acute respiratory distress (compression of pulmonary vessels)

• Caused by: neoplastic compression/invasion, or cephalad propagation of thrombus from lower extremity/renal/hepatic veins
• Angiotropic tumors invading IVC: renal cell carcinoma (via renal vein), hepatocellular carcinoma (via hepatic veins)
• Clinical: massive lower extremity edema, distended superficial abdominal veins (caput medusae variant), massive proteinuria (renal venous backup)

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LYMPHANGITIS

• Acute inflammation of lymphatic channels; usually from localized bacterial infection
• Most common pathogen: Group A β-hemolytic Streptococcus
• Histopathology: dilated lymphatics filled with neutrophils/monocytes; may spread → cellulitis or abscess
• Clinical: bright red painful subcutaneous streaks along lymphatic channels + lymphadenitis
• If lymph nodes fail to contain infection → bacteremia and sepsis

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LYMPHEDEMA

• Abnormal interstitial fluid accumulation from impaired lymphatic drainage

• Brawny induration - thick, firm fibrotic skin
• Peau d'orange - "orange peel" skin texture (follicular tethering + interstitial edema)
• Chronic ulceration (reduced tissue perfusion)

• Chylous ascites (peritoneal cavity)
• Chylothorax (pleural cavity)
• Chylopericardium (pericardial sac)

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7. VASCULAR TUMORS

• Most: from inner lining endothelium (hemangioma, lymphangioma, angiosarcoma)
• Subset: from perivascular SMCs (glomus tumor)
• Large vessel malignancies: almost always sarcomas (extremely rare)

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BENIGN VASCULAR ECTASIAS & TELANGIECTASIAS

• Not true neoplasms; congenital or acquired vessel dilations
• Ectasia: localized dilation of any hollow structure
• Telangiectasia: permanent dilation of capillaries, venules, arterioles → red-purple skin/mucosal lesions

• Nevus flammeus: flat pink-to-purple birthmark (head/neck); most undergo spontaneous regression
• Port-wine stain: severe variant; does NOT regress; grows and darkens in childhood
• Molecular: somatic GNAQ gene missense mutation (encodes Gα subunit of transmembrane G-protein)

• Port-wine stain along trigeminal nerve distribution (V1/V2)
• Ipsilateral venous angiomas in cortical leptomeninges
• Sequelae: intellectual disability, contralateral hemiplegia, intractable seizures, tram-track skull calcifications

• Central arteriole "spider body" + radial dilated vessels "spider legs"
• Pulsatile (fed by arteriole); direct pressure → blanches immediately
• Predominantly upper body (face, neck, upper chest)
• Associated with hyperestrogenic states: pregnancy + liver cirrhosis (impaired estrogen metabolism)

• Autosomal dominant
• Loss-of-function mutations in TGF-β signaling pathway genes → defective angiogenesis → fragile dilated capillaries/venules lacking structural support
• Distributed: skin, oral mucosa, respiratory tract, GI lining, urinary tract
• Spontaneous rupture: epistaxis (nasal), occult GI bleeding, gross hematuria

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HEMANGIOMAS

• Very common benign tumors; 7% of all benign tumors of infancy/childhood
• Clonal endothelial proliferations (not developmental malformations)
• Most congenital; may undergo spontaneous regression
• Internal involvement: ~1/3 localize to liver; malignant transformation exceedingly rare

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LYMPHANGIOMAS

• Turner Syndrome (45,X) link: Posterior neck cystic hygroma (failure of jugular lymphatic sacs to connect with venous circulation)

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GLOMUS TUMOR (GLOMANGIOMA)

• Completely benign but exquisitely painful
• Arises from modified SMCs of glomus bodies (arteriovenous shunts in skin for thermoregulation)
• Distinct from hemangiomas (hemangioma = EC proliferation; glomus tumor = peri-vascular SMC proliferation)
• Classic location: subungual (under fingernails) - small blue-to-purple nodule
• Treatment: surgical excision (immediately curative)

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BACILLARY ANGIOMATOSIS

• Non-neoplastic reactive vascular proliferation in immunocompromised hosts (primarily AIDS patients)
• Caused by Bartonella species (gram-negative bacilli)
• Sites: skin, bone, brain, visceral organs

• B. henselae (cat vector): immunocompetent → cat-scratch disease (necrotizing granulomatous lymphadenitis); immunocompromised → bacillary angiomatosis
• B. quintana (body lice): historical "trench fever" (WWI); immunocompromised → bacillary angiomatosis

• Bacteria stimulate HIF-1α production → activates VEGF → massive vascular proliferation

1. Capillary proliferation lined by plump epithelioid ECs (with atypia + mitoses, mimics angiosarcoma)
2. Dense neutrophil infiltration throughout stroma
3. Visible Bartonella bacteria clusters (silver stain)

• Treatment: antibiotics (erythromycin or doxycycline) - completely curative

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KAPOSI SARCOMA (KS)

• Intermediate-grade (borderline), locally aggressive vascular neoplasm
• Absolute causal relationship with HHV8 (also known as KSHV; γ-herpesvirus related to EBV)
• AIDS-defining illness in HIV-positive patients

• cART dropped epidemic KS incidence by >80%; risk still 300x greater than transplant recipients and 1000x greater than general population

• Lytic phase: viral G-protein → massive host VEGF production; inflammatory cells pour proliferative cytokines
• Latent phase: viral proteins disrupt cell cycle (viral Cyclin D); downregulate p53 → block apoptosis → cellular selection advantage

• Classic: surgery/radiation; chemo reserved for disseminated nodal disease
• Transplant-associated: reduce/withdraw immunosuppression ± chemo/radiation
• AIDS-associated: combination antiretroviral therapy (cART) as foundation ± chemotherapy

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HEMANGIOENDOTHELIOMA

• Intermediate/borderline-grade neoplasms (between benign hemangioma and malignant angiosarcoma)

• Adults; arises near medium-to-large veins
• Plump, cuboidal (epithelioid) endothelial cells in solid cords; vascular channels inconspicuous
• Clinical behavior: highly variable - local excision often curative; up to 40% local recurrence; 20-30% metastasize; 15% mortality

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ANGIOSARCOMA

• Rare, highly aggressive malignant endothelial neoplasms
• Predominantly older adults; equal sex distribution
• Sites: skin, soft tissue, breast, liver
• Highly invasive; early hematogenous metastases
• 5-year survival: ~30%

• Chronic lymphedema: Stewart-Treves syndrome (upper extremity after radical mastectomy)
• Radiation exposure: post-breast cancer treatment
• Liver-specific carcinogens: Arsenic (pesticides), Thorotrast (historic contrast agent), PVC (polyvinyl chloride) → hepatic angiosarcoma

• Macroscopic: early = small red papules/nodules; advanced = large fleshy unencapsulated masses with central necrosis/hemorrhage
• Microscopic: well-differentiated regions (atypical ECs in anastomosing channels) + anaplastic regions (solid sheets of undifferentiated pleomorphic cells)
• IHC: CD31 and von Willebrand factor positive (confirm endothelial origin)

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8. PATHOLOGY OF VASCULAR INTERVENTION

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ENDOVASCULAR STENTING AND BALLOON ANGIOPLASTY

• Angioplasty: high-pressure balloon fractures atherosclerotic plaque to expand lumen
• Angioplasty alone carries high failure rate due to acute reclosure

1. Vascular dissection: floating intimal flaps collapse inward → block lumen
2. Vessel wall spasm: mechanical irritation → vasoconstrictive SMC spasm
3. Acute thrombosis: fracturing plaque exposes thrombogenic subendothelial collagen/necrotic core → coagulation cascade

• >95% of modern endovascular coronary procedures use concurrent coronary stent placement (tacks down intimal flaps, maintains lumen, prevents spasm)

• Coated with antiproliferative agents:
  • Paclitaxel: binds/hyper-stabilizes microtubules → arrests SMC mitotic spindle → blocks division
  • Sirolimus (Rapamycin): blocks mTOR pathway → halts G1→S cell cycle transition → suppresses SMC migration/growth
• Benefit: 50-80% reduction in 1-year restenosis
• Paradox: Antiproliferative drug simultaneously blocks re-endothelialization → prolonged bare metal exposure → late stent thrombosis risk → requires extended dual antiplatelet therapy (DAPT)

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VASCULAR REPLACEMENT (SURGICAL GRAFTS)

1. Phase 1 (days-weeks): Early occlusion - acute luminal thrombosis
2. Phase 2 (mid-term): Intimal thickening + fibromuscular hyperplasia (vein adapts to arterial pressure)
3. Phase 3 (years): Accelerated vein graft atherosclerosis → plaque rupture, secondary thrombosis, aneurysmal degeneration

• Intervention → endothelial damage + platelet activation → SMC migration from media to intima → ECM synthesis → fibromuscular intimal thickening
• Anastomotic hyperplasia: fibromuscular hyperplasia clusters aggressively at the anastomosis junction

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