VASCULAR PATHOLOGY By DR. OLA OMRAN ASSOCIATE PROFESSOR PATHOLOGY CONSULTANT PATHOLOGY DEPARTMENT

VASCULITIS DEFINITION: It means “inflammation of the walls of the vessels” and can be associated to many different clinical conditions 20 primary forms of vasculitis are recognized Classifications according to vessel size, role of immune complexes, presence of specific autoantibodies, granuloma formation, organ tropism, and even population demographics. Several vasculitides tend to affect only vessels of particular caliber or tissue beds

VASCULITIS The two most common pathogenic mechanisms of vasculitis are: immune-mediated inflammation direct invasion of vascular walls by infectious pathogens. Predictably, infections can also indirectly induce a noninfectious vasculitis, for example, by generating immune complexes or triggering cross-reactivity. Physical and chemical injury, such as from irradiation, mechanical trauma, and toxins, can also cause vasculitis.

VASCULAR PATHOLOGY VASCULITIS . CLASSIFICATION OF VASCULITIS BASED ON THE PATHOGENESIS: *Direct Infection. -Bacterial(Neisseria) -Rickettsial(spotted fever) -Spirochetal(Syphilis) -Fungal(aspergillosis) -Viral(herpes zoster)

*Immunologic. A. Immune complex- mediated. -Infection-induced(Hepatitis B,C) -Henoch-Schonlein purpura -SLE, etc. -Drug-induced -Cryoglobulinemia(Ig, IgM) -Serum sickness B. ANCA-mediated. -Wegener granulomatosis -Microscopic polyangeitis -Churg-Strauss syndrome C. Direct Ab-induced -Goodpasture syndrome(anti-GBM Abs) -Kawasaki disease(anti-endoth.Ab)

VASCULAR PATHOLOGY D. Cell-mediated. -Organ-allograft rejection -Inflammatory bowel disease -Paraneoplastic vasculitis *Unknown. -Giant.cell arteritis -Takayasu arteritis -Polyarteritis nodosa

Noninfectious Vasculitis (immune-mediated inflammation) Immune complex deposition 1.  Vasculitis associated with drug hypersensitivity (e.g., penicillin), antibodies directed against the drug-modified self proteins lead to the formation of immune complexes. Manifestations frequently involving the skin and can be mild and self-limiting or severe and even fatal. Discontinuation of the offending agent is often curative. 2. vasculitis associated with viral infections, antibody to viral proteins may form immune complexes detectable in the serum and in the vascular lesions; for example, as many as 30% of patients with polyarteritis nodosa have an underlying hepatitis B infection with vasculitis attributable to complexes of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg.  

2. Antineutrophil Cytoplasmic Antibodies (ANCA): Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic antigens, so-called ANCAs. ANCAs are a heterogeneous group of autoantibodies directed against constituents (mainly enzymes) of neutrophil primary granules, monocyte lysosomes, and endothelial cells. Two general types of ANCAs based on immunofluorescence staining patterns: Cytoplasmic localization (c-ANCA), wherein the most common target antigen is p roteinase-3 (PR3), a neutrophil granule constituent Perinuclear localization (p-ANCA), wherein most of the autoantibodies are specific for myeloperoxidase (MPO). c-ANCA in Wegener granulomatosis & p-ANCA in microscopic polyangiitis and Churg-Strauss syndrome.  ANCAs is useful quantitative diagnostic markers for the ANCA-associated vasculitides, and their levels reflect the degree of inflammatory activity.  Although the mechanisms are unknown, ANCAs can directly activate neutrophils and stimulates neutrophils to release reactive oxygen species and proteolytic enzymes.

3. Anti-Endothelial Cell Antibodies Antibodies to ECs may predispose to certain vasculitides, for example Kawasaki disease. Another Classifications according to vessel size:………  

Vasculitis type* Examples Description Giant-cell (temporal) arteritis Large-Vessel Vasculitis (Aorta and Large Branches to Extremities, Head, and Neck) Giant-cell (temporal) arteritis Granulomatous inflammation; also frequently involves the temporal artery. Usually occurs in patients older than age 50 and is associated with polymyalgia rheumatica.   Takayasu arteritis Granulomatous inflammation usually occurring in patients younger than age 50 Medium-Vessel Vasculitis (Main Visceral Arteries and Their Branches) Polyarteritis nodosa Necrotizing inflammation typically involving renal arteries but sparing pulmonary vessels Kawasaki disease Arteritis with mucocutaneous lymph node syndrome; usually occurs in children. Coronary arteries can be involved with aneurysm formation and/or thrombosis. Small-Vessel Vasculitis (Arterioles, Venules, Capillaries, and Occasionally Small Arteries) Wegener granulomatosis Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small vessels, including glomerulonephritis. Associated with c-ANCAs. Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small vessels. Associated with asthma and blood eosinophilia. Associated with p-ANCAs. Microscopic polyangiitis Necrotizing small-vessel vasculitis with few or no immune deposits; necrotizing arteritis of small and medium-sized arteries can occur. Necrotizing glomerulonephritis and pulmonary capillaritis are common. Associated with p-ANCAs.

1. GIANT CELL (TEMPORAL) ARTERITIS. MOST common form of systemic vasculitis Adults males over 50ys acute or chronic large sized vessels ( affects temporal arteries, ophtalmic(blindness) and aorta (aneurysm) GP: tender, nodular thickening of the artery reduction of the lumenthrombosis. MP: Granulomatous inflammation in inner half of media with giant cells.

GIANT CELL (TEMPORAL) ARTERITIS. Thickened, nodular, and tender arteries

Temporal (giant cell) arteritis thickened, nodular, and tender segment Giant cells & granuloma at the degenerated internal elastic membrane in active arteritis H&E Elastic tissue stain demonstrating focal destruction of internal elastic membrane (arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis

Giant cell arteritis Elastic tissue stain demonstrating: focal destruction of internal elastic membrane (arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis.

GIANT CELL ARTERITIS...(cont.) CLINICAL FEATURES: Old patients with fever, fatigue, loss of weight, with or w/o facial pain and headache. More severe form ….involvement of ophtalmic artery  diplopia or blindness of abrupt onset.

2. TAKAYASU ARTERITIS. Predominant in females below 50´s Propable autoimmune mechanism, characterized by ocular manifestations/weakness of pulses in upper extremities (reduced brachial pulse), due to vasculitis of Aortic Arch + branches  narrowing  obliteration.

TAKAYASU ARTERITIS...(cont.) MICROSCOPIC: Mononuclear infiltration of adventecia. Giant-cell granulomatous inflammation NOT distinguishable from giant-cell arteritis. CLINICAL: Reduced brachial pulse, difference in BP between R & L arm>10 mm Hg, coldness+ numbness of fingers,, Visual defects  blindness.

Takayasu arteritis A, Aortic arch angiogram showing narrowing of the brachiocephalic, carotid, and subclavian arteries (arrows). B, Gross photograph of two cross-sections of the right carotid artery demonstrating marked intimal thickening with minimal residual lumen. C, Destruction and fibrosis of the arterial media and an infiltrate of mononuclear inflammation, including giant cells.

3. POLYARTERITIS NODOSA (PAN). Medium sized arteritis affecting multiple organs (skin, peripheral nerves, gut, kidney and heart. Childhood late adulthood (average 40 ys) Associated with Hepatitis B, C or both (most common in injection drug abusers). Probably mediated by immune complexes (Igs + viral Ags)  circulating and deposited in inflammed vessels.

3. POLYARTERITIS NODOSA (PAN). ...(cont.) CLINICAL FEATURES: Onset is gradual (wks  mos.) Non specific: malaise,fever, weight loss, abdominal pain, melena, myalgias, muscular weakness, diastolic pressure >90 mm Hg, Specific: Renal involvementhypertension GI tract abdominal angina (hemorrhage, perforation). heart: myocarditis/myocardial infarction. Eye: scleritis. About 1/3 of patients  HBAb+.

POLYARTERITIS NODOSA..(cont.) Diagnosis: *Elevated BUN or creatinine *Proven hepatitis B/C virus infection *Angiographic signs of aneuryms/vascular occlusion (60% sensitive) *MP: Demonstration of necrotizing inflammation (segmental fibrinoid necrosis) & granulocytes in medium sized vessels (biopsy).

Polyarteritis nodosa There is segmental fibrinoid necrosis and thrombotic occlusion of the lumen of this small artery. Note that part of the vessel wall at the upper right (arrow) is uninvolved 24

4. WEGENER´S GRANULOMATOSIS. Granulomatous inflammation & necrotizing vasculitis Average age is about 40 yrs. Affects upper respiratory tract, lower respiratory tract and kidneys. Other organs affected: Eye (proptosis/diplopia), Skin (ulcers, purpura) It may remain localized to one site for yrs./mos.  systemic later (fever, fatigue, loss of weight, anemia, leukocytosis and increased ESR ESR

4. WEGENER´S GRANULOMATOSIS….CONT CLINICAL FEATURES: *Chronic sinusitis(90%) *Chronic pneumonitis in about 95% of patients. *Mucosal ulcerations of nasopharynx (75%) *Renal disease (80%)

WEGENER´S GRANULOMATOSIS

Wegener granulomatosis inflammation of a small artery along with adjacent granulomatous inflammation, in which epithelioid cells and giant cells (arrows)

5. BUERGER´S DISEASE (Thromboangiitis obliterans) Characterized by segmental thrombosis + acute / chronic inflammation of medium and small arteries MOSTLY tibial and radial ar teries, and secondarily involvement of veins and nerves of limbs. Apparently heavy cigarette-smokers are MOST frequently affected (endoth. cells hypersensitivity?) Moreover  increased prevalence of HLA-A9/ HLA-B5 in these patients and in Israel, Japan, India (genetic trait?)

Buerger disease The lumen is occluded by a thrombus containing two abscesses (arrows). The vessel wall is infiltrated with leukocytes.

BUERGER´S DISEASE..(cont.) Microscopically: acute + chronic inflammation in arterial walls + thrombosisorganization/recanalization. Also, thrombosis contains microabscesses + granulomatous inflammation extension to veins/nerves. Late complication: chronic ulceration of toes or fingers  gangrene.

BUERGER´S DISEASE...(cont.) CLINICAL FEATURES: Claudication in feet and/or hands sometimes centrally radiated. Numbness and tingling in limbs + Raynaud´s phenomenon. Skin ulcerations + gangrene of digits

TUMORS OF BLOOD VESSELS Cavernous hemangioma Large blood filled vascular spaces Separated by mild to moderate amount of CT stroma Intravascular thrombosis may be seen.

Kaposi sarcoma Coalescent red-purple macules and plaques of the skin sheets of plump, proliferating spindle cells