Pathology of Vasculitides and Venous Disorders PDF

Pathology of Vasculitides and Venous Disorders Michael Yakubovskyy, MD, PhD Professor of Pathology Ross University School of Medicine 1  Content Introduction Small-vessel vasculitides Medium-vessel vasculitide...

Pathology of Vasculitides and Venous Disorders Michael Yakubovskyy, MD, PhD Professor of Pathology Ross University School of Medicine 1  Content Introduction Small-vessel vasculitides Medium-vessel vasculitides Large-vessel vasculitides Raynaud phenomena Venous disorders (SEFT STUDY) 2  Learning Objectives Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO1. Microscopic polyangiitis LO2. Churg-Strauss syndrome (allergic granulomatosis and angiitis) LO3. Granulomatosis with polyangiitis (former Wegener granulomatosis) LO4. Henoch-Shönlein purpura LO5. Polyarteritis nodosa LO6. Kawasaki disease (mucocutaneus lymph node syndrome) LO7. Buerger disease (thromboangiitis obliterans) LO8. Giant cell (temporal) arteritis LO9. Takayasu arteritis/diseases LO10. Raynaud phenomenon, primary and secondary LO11. Varicose veins LO12. Deep venous thrombosis 3 Introduction 4  Classification of Vasculitides Disease Microscopic polyangiitis (MPA, also leukocytoclastic vasculitis) Churg-Strauss syndrome (CSS) (syn.: allergic granulomatosis and angiits, AGA) Small-vessel Granulomatosis with polyangiitis (GPA, former Wegener vasculitides granulomatosis) Henoch-Shönlein purpura (HSP) Behçet syndrome/disease Polyarteritis nodosa (PAN) Medium-vessel Kawasaki disease (syn.: mucocutaneous lymph node syndrome) vasculitides Buerger disease (syn.: thromboangiitis obliterates) Large-vessel Giant cell arteritis (GCA, syn.: temporal arteritis) vasculitides Takayasu arteritis +Vasculitis in systemic diseases: SLE, SS, RF, etc. +Infectious vasculitides: Lyme disease, Rocky Mountain spotted fever, syphilis, infectious endocarditis, etc.  Common Clinicopathologic Features Morphology: necrotizing or granulomatous inflammation in the vascular wall; complications – Hemorrhages and bleeding – Thrombosis and infarctions – Healing —> scarring —> chronic ischemia (survivors) Immune mechanisms – Deposition of immune complexes – Cell-mediated immune response – Circulating antibodies: ANCAs and IgA in small-vessel vasculitides Systemic manifestations – Clinical: fever, fatigue, weight loss, arthralgia, myalgia, etc. – Labs: leukocytosis, anemia, increased ESR and CRP 6  ANCAs Anti-Neutrophil Cytoplasmic Antibodies Two types – Anti-myeloperoxidase ANCA (MPO-ANCA) Myeloperoxidase (MPO) located within the lysosomes near the perinuclear area (former p-ANCA) – Anti-proteinase-3 ANCA (PR3-ANCA) Proteinase-3 located within the azurophilic granules throughout the cytoplasm (former c-ANCA) 7 ANCAs: Perinuclear vs Cytoplasmic Location Normal neutrophil, diagram MPO-ANCA (perinuclear, p-ANCA) PR3-ANCA (cytoplasmic, c-ANCA)  Protocol for Vasculitides Disease Demographics Etiology and pathogenesis Vessels involved Vascular pathology Characteristic clinical features Immunology Treatment Prognosis  Small-vessel Vasculitides Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO1. Microscopic polyangiitis LO2. Churg-Strauss syndrome (allergic granulomatosis and angiitis) LO3. Granulomatosis with polyangiitis (former Wegener granulomatosis) LO4. Henoch-Shönlein purpura 11  Small Vessels and Vasculitides Small vessels: arterioles, capillaries, and venules – Arterioles, morphologic criteria < 0.1 mm (100 mkm) in d 1 - 3 layers of smooth muscle cells in the media Disease Microscopic polyangiitis (MPA) Churg-Strauss syndrome (CSS) Small-vessel Granulomatosis with polyangiitis (GPA) vasculitides Henoch-Shönlein purpura (HSP) Behçet syndrome/disease 12  Organs Involved and Major Clinicopathologic Manifestations Skin: purpura Kidneys: hematuria due to glomerulonephritis Lungs: hemoptysis due to pneumonitis GI tract: hematochezia, melena Other organ/system involvement: arthralgia, myalgia, coronaritis, myocarditis, etc. 13  Microscopic Polyangiitis (MPA) Demographics Adults Etiology and Immune ANCA-mediated injury pathogenesis Possible triggers: drugs, toxins, etc. 2 Necrotizing vasculitis with neutrophils and segmental Vascular pathology fibrinoid necrosis and thrombosis Glomerulonephritis with hematuria Characteristic clinical Palpable purpura features Pneumonitis with hemoptysis GI bleeding Immunology MPO-ANCAs (NB: MPO —> MPA) Trigger elimination, if it does not help Treatment Then steroids and immunosuppressants Prognosis Good with Tx MPA: Purpura (Gross), Necrotizing Vasculitis with Thrombosis (Histo)  Churg-Strauss Syndrome (CSS) Demographics Adults Immune ANCA-mediated injury Etiology and Associated with allergic rhinitis, asthma, and pathogenesis hypereosinophilia Vascular pathology Necrotizing vasculitis with eosinophils Extravascular necrotizing granulomas Characteristic Pulmonary infiltrates (+ bronchial asthma) clinical features Other: GI bleeding, palpable purpura, myocarditis Immunology MPO-ANCAs (rare) Treatment Corticosteroids Prognosis Good with Tx Churg-Strauss Syndrome: Necrotizing Vasculitis with Fibrinoid Necrosis and Eosinophils  Granulomatosis with Polyangiitis (GPA) Demographics Adult males Etiology and Immune ANCA-mediated injury pathogenesis Possible triggers: drugs, toxins, etc. Vascular pathology Necrotizing and/or granulomatous vasculitis Extravascular granulomas with geographic pattern of central necrosis Characteristic clinical Upper respiratory tract: nose, sinuses, palate, pharynx features Lungs (infiltrates, nodules, cavities) Crescentic glomerulonephritis with hematuria Immunology PR3-ANCAs (NB: PR3 —> WegeneR GRanulomatosis) Treatment Steroids and immunosuppression Fatal if left untreated Prognosis Remitting-relapsing course with Tx GPA: Necrotizing Vasculitis (1), Extravascular Granuloma with Giant Cells (2) 1 2 GPA: Palate Ulcer (1) and Coalescing Pulmonary Granulomas with Central Necrosis/Cavitation (2) 1 2  Henoch-Shönlein Purpura (HSP) Demographics Children; young adults Immune (IgA)- mediated injury Etiology and Associated with a preceding infection (2-3 pathogenesis days ago): upper respiratory, GI, or urinary Vascular pathology Necrotizing vasculitis Palpable purpura Characteristic clinical IgA nephropathy (glomerular mesangial IgA features deposits) with hematuria GI bleeding Immunology (+)IgA; (-)ANCA Treatment Not required: self-limited disorder Prognosis Good HSP: Skin Rash (Purpura), IgA Deposits in Glomerular Mesangium (PAS)  Middle-vessel Vasculitides Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO5. Polyarteritis nodosa LO6. Kawasaki disease (mucocutaneus lymph node syndrome) LO7. Buerger disease (thromboangiitis obliterans) 23  Medium-Sized Vessels and Vasculitides Medium-size vessels (muscular or distributing arteries): coronary, cerebral, brachial, renal, femoral, etc. and their branches – 0.1 – 10 mm in diameter Disease Polyarteritis nodosa (PAN) Medium-vessel Kawasaki disease vasculitides Buerger disease 24  Polyarteritis Nodosa (PAN) Demographics Adults Etiology & Immune-mediated injury pathogenesis Possible triggers: HBV, HCV, etc. Vessels involved Medium-sized and small arteries Vascular pathology Segmental transmural necrotizing arteritis —> aneurysms ( rupture —> hematuria Characteristic clinical Thrombosis —> infarctions features Renal glomeruli are not affected GI bleeding Skin purpura and nodules (+) HBsAg in 30% Immunology (-) ANCA Treatment Steroids and immunosuppression Prognosis Fatal if left untreated; good with treatment  see PAN: Renal Artery Aneurysms, Angiography PAN: False Aneurysms (Black Arrows), Infarcts (White Arrows), Renal Capsule Rupture (Red Arrow) PAN: Fibrinoid Necrosis, Histo Fibrinoid necrosis Unaffected vessel  Kawasaki Disease Children < 5 yrs Demographics Asians > Caucasians Etiology and ?Immune-mediated injury pathogenesis ?Infection Medium- and large-sized arteries, especially coronary Vessels involved arteries Vascular pathology Necrotizing vasculitis —> scarring Coronary arteritis —> ectasia —> aneurysm —> Characteristic clinical If possible rupture and acute MI features Skin rash, conjunctivitis, lymphadenitis Immunology N/A Treatment IV gamma-globulin, aspirin Prognosis Good with Tx Kawasaki Disease: Coronary Artery Aneurysm Kawaski Disease: Skin Rash, Conjunctivitis, Strawberry Tongue  Buerger Disease Demographics Young adults (20 – 40 yrs) Etiology & pathogenesis e Hypersensitivity to tobacco Medium- and large-sized arteries, especially tibial and Vessels involved radial arteries Vasculitis with occlusive thrombosis and Vascular pathology I microabscesses Raynaud phenomenon Characteristic clinical Severe pain in hands and feet features Claudication Necrosis and ulceration of the toes, feet, and fingers Immunology N/A Treatment Cessation of smoking; surgery Prognosis Good, if smoking ceased in time Buerger Disease: Vasculitis with Thrombus and Microabscesses (Arrows, 1), Finger Necrosis (2) 1 2  Large-vessel Vasculitides Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO8. Giant cell (temporal) arteritis LO9. Takayasu arteritis 34  Large Vessels and Vasculitides Large vessels (= elastic or conducting arteries): aorta, brachiocephalic trunk, subclavian and common carotid a., celiac trunk, common iliac a., pulmonary a. – > 10 mm in diameter Disease Large-vessel Giant cell (temporal) arteritis vasculitides Takayasu arteritis 35  Giant Cell Arteritis (GCA, Temporal Arteriits) Demographics Older adults (≥ 50 yrs) Cell-mediated immune injury (granuloma) Etiology and pathogenesis Antigen: ?elastin Large- and medium-sized arteries: the aorta, vertebral arteries, Vessels affected extracranial arteries of the head: temporal, posterior ciliary, ophthalmic, etc. Granulomatous vasculitis with multinucleated giant cells Intimal thickening Vascular pathology Destruction of internal elastic membrane Lumen narrowing Headache E Blurred vision —> blindness Characteristic clinical features Polymyalgia rheumatica in 50% (pain in shoulders, hip girdle, and neck) Systemic signs of inflammation including blood tests: ESR Treatment Corticosteroids, anti-TNF Prognosis Benign and self-limited disease (except vision impairment) Giant Cell Arteritis, Extracranial Arteries and Gross Appearance Giant Cell Arteritis, Granuloma with Giant Cells (Circled) and Loss of Internal Elastic Membrane (Arrow)  Takayasu Arteritis Demographics Young adults; Asians; F >> M Etiology & pathogenesis Cell-mediated immune injury (granuloma) Large- and medium-sized arteries: the aorta, its branches, Vessels affected pulmonary arteries, renal and ophthalmic arteries Granulomatous vasculitis Intimal fibrosis Vascular pathology Transmural thickening Lumen narrowing Low BP and weak pulse on the upper extremities Characteristic clinical (“pulseless disease”) features Coldness or numbness of the fingers Ocular and neurologic disturbances Treatment Corticosteroids Prognosis Good Takayasu Arteritis, Wall Thickening and Lumen Narrowing: Gross and Angiography  Takayasu Arteritis: Granulomatous Inflammation with Multinucleated Giant Cells  Raynaud Phenomena Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO10. Raynaud phenomenon, primary and secondary 42  Primary Raynaud Phenomenon (Raynaud Disease) Paroxysmal pallor or cyanosis of the fingers and toes due to cold-induced vasospasm of small arteries and arterioles – Color changes: —> white —> blue —> red No structural changes in the vessel wall Young adults, mainly females Prognosis: good 43 Primary Raynaud Phenomenon, Pallor —> Cyanosis: Gross  Secondary Raynaud Phenomenon Manifestations: similar to primary Raynaud phenomenon, but more severe and may progress to necrosis and ulceration Primary diseases: systemic sclerosis, CREST syndrome, SLE, Buerger disease, Takayasu arteritis, etc. Age, gender, and prognosis: depend on the primary disease 45 Severe Secondary Raynaud Phenomenon (Necrosis)  Venous Disorders Compare and contrast in terms of Age, gender, and racial predisposition Etiology and pathogenesis (if known) Vessels and organs affected Morphologic changes in the vessel wall Major clinical manifestations the following diseases LO11. Varicose veins (SELF STUDY) LO12. Deep venous thrombosis (SELF STUDY) 47  Varicose Veins Abnormally dilated and tortuous veins due to increased intraluminal pressure and/or incompetence of the venous valves Location – Superficial leg veins (most common, see below) – Submucosal esophageal veins: esophageal varices Portal hypertension – Venous plexus at the recto-anal junction: hemorrhoids (see below) 48  Varicosity of Superficial Leg Veins: Causes Increased intraluminal pressure – Long periods of standing, long automobile or airplane rides F > M (pregnancy) Advanced age (> 50 yrs) Obesity Heredity: defective venous wall development 49  Varicose Superficial Leg Veins: Clinical Aspects Manifestations: venous congestion/dilation, persistent edema, and pain Complications – Thrombosis Thromboembolism is rare – Subcutaneous fibrosis, petechiae, and hemosiderosis (“browny induration”) – Ulcerations and poor wound healing —> varicose ulcers 50 Varicose Veins, Hyperpigmentation, and Ulceration: Gross  Hemorrhoids Dilation and protrusion of the veins at the recto- anal junction Provoking factors – Constipation/straining to defecate – Pregnancy Complications – Thrombosis and inflammation —> pain – Bleeding: mimic colon cancer 52  Deep Venous Thrombosis, Location Deep leg veins – Proper deep venous thrombosis (DVT) Periprostatic venous plexus (males) Pelvic veins (females) Dural sinuses 53  DVT: Predisposing Factors Prolonged bed rest/immobilization Postoperative state Pregnancy Cardiac failure Adenocarcinomas (activation of coagulation —> migratory thrombophlebitis) FV Leiden mutation (associated with recurrent DVT) 54  DVT: Clinical Manifestations Usually manifestations are subtle – Edema distal to the occluded vein – Dusky cyanosis – Dilation of superficial veins Homan sign: pain elicited by pressure over affected veins, squeezing the calf muscles, or forced dorsiflexion of the foot Complication: pulmonary thromboembolism 55 DVT, Gross and Micro Pulmonary Thromboembolism, Gross and Micro The End 58