Pathology conference vascular disease chapter 8-part 1

1. Pathology conferencevascular diseasechapter 8-part 1 Presented by: F.Fadaei_resident of dermatology Kerman medical university of science

2. Criteria for vasculitis • Although the minimum criteria for vasculitis are contaraversial ,in general,vasculitis must have two components: • An inflammatory cell infilterate • Evidence of vascular injury

3. Vasculitis is an inflammatory process,and thus the absence of inflammation precludes the diagnosis even though vascular alterations may be present. • However in the late healing state the inflammatory cell infilterate may be minimal.

4. Criteria for vascular injeuryhave included: • Evidence of vessel leakiness such as edema and extravasation of RBC • Evidence of vessel destruction of fibrinoid material within the vascular lumina or vessel walls • Evidence of inflammatory compromise of the vascular walls including infiltration by inflammatory cells and leukocytoclasis of the surrounding inflammatory cell infilterate.

5. Primary vascular injury implies that the vascular insult is the predominant disease process. • Secondary or incidental vascular injury indicates that another disease process outside the vessels is the primary pathologic process. • In many instances,distinguishing clearly between a primary and a secondary vascular insult is not possible.

6. The term vasculopathy or pseudovasculitis may be used to describe certain degrees of vascular alteration and injury that fail to satisfy the criteria for vasculitis.

8. Evaluation of vasculitis • In an attempt to standardize nomenclature for vasculitides,an international conference proposed a system primarily based on vessel size. • Large vessels • Medium-sized vessels • Small vessels This classification is helpful because there is some correlation with clinical presentation

9. Purpura,palpable purpura,urticaria,vesicles and bulla and splinter hemorrhage typically reflect small-vessel injury. • Cutaneous nodules ,ulcers,livedo reticularis and digital gangrene suggest the involvement of medium-sized vessels.

10. Histopathology alone is inadequate to classify a vasculitic disease process. • Integration of data from other laboratory tests,clinical findings,and even arteriography may be critical to arrive at a diagnosis.

11. Antineutrophilic cytoplasmic antibodies (ANCA)are serologic markers that have allowed a new classification of certain vasculitides. • These markers may reflect biologic relationships between disease processes. • Best demonstrated by a combination of indirect IF of normal peripheral blood neut. Followed by ELISA to detect specific autoantibodies.

12. Indirect immunoflurescenceassays reveal 2 staining patterns: • Cytoplasmic(c-ANCA) autoab. to proteinase3 • Perinuclear(p-ANCA) specific for myeloperoxidase

13. These antibodies are esp. Helpful ,in combination with clinical features ,in differential diagnosis of 3 small-vessel vasculitides: • Wegners syn. (c-ANCA) • Churg-strauss syn. (p-ANCA) • Microscopic PAN(p or c- ANCA) • They are called Pausi-immune vasculitidesbecause vascular injury is not associated with immunoglobulin deposition in vessel walls, in contrast to the immune complex –mediated small-vessel injury seen in HSP.

14. Vasculitis of large and medium-sized vesselstemporal arteritis • May be unilateral or bilateral • May associate with involvement of other cranial arteries in particular retinal arteries. • Clinical presentation may include:pain and tenderness of the forehead and possible sudden visual impairment. • Erythema and edema of skin are common on involved areas • The invoved artery may be palpable • Elevated ESR

15. Although the clinical presentation is strongly suggestive of the diagnosis ,a biopsy is often performed for confirmation prior to the initiation of systemic steroid therapy. • However results of diagnostic tests are not always positive.

16. Temporal arteritis • Involved areas show an inflammatory process of mainly lymphocytes and macrophages that may extend throughout the entire arterial wall. • Classically fragmentation of the lamina elasticaand elastophagocytosis by multinucleated giant cells are seen. • Step sections may be needed to reveal diagnostic features.

17. Differential diagnosis: • Infection-related vasculitis • Connective tissue disease • PAN

18. Takayasu’s arteritis • Large-vessel chronic and fibrosingvasculitisprimarily involving aorta. • Rarely have cutaneous involvement • Usu.women greater than 40 ys • Clinical features:erythematouse nodules often of the lower extremities,suggesting erythema nodosum or induratum or pyodermagangrenosum like ulcers.

19. Takayasu’s arteritis • Small and medium arteries of the subcutaneous fat usu. Show a necrotizing panarteritis with fibrinoid necrosis and • sparse inflammatory infiltrates containing neut. And lymph. • Additional findings may include granulomatous vasculitis,fibrin thrombi without vasculitis,neutrophilic abscesses and septal and lobular panniculitis.

20. Vasculitis affecting medium-sized and small vesselskawasaki’s disease • Necrotizing arteritis usu.affects young children with peak age incidence at 1 year. • Mucocutaneous findings:polymorphous exanthematous macular rash,conjenctival congestion,dry,reddend lips,strawberry tongue,oropharyngeal reddening and swelling of the hands and feet. • Nonpurulant cervical LAP • The most serious clinical copmlication s are related to arteritis and thrombosis of coronary arteries. • Cutaneaous vasculitis is rare

21. Superficial thrombophelebitis • Usu. Involving the lower extremities and presents as a painful or tender erythematous cordlike structure or nodule • Predisposing factors:varicose veins,hypercoagulable state,ingestion of OCP , underlying malignancy • Variants of STP include mondor’s disease and superficial septic thrombophelebitis.

22. Small and medium sized veins of the lower dermis and subcutaneous fat are involved by an acute vasculitis and thrombosis that occludes the vessel lumina. • Early lesions demonstrate dense inflammatory infiltrates primarily composed of neutrophils within the vessel wall. • In later stages one may observe other inflammatory cells within the walls of veins. • Recanalization of the affected veins ultimately occurs with resolution of the process.

23. Mondor’s disease • It is a thrombophlebitis of the subcutaneous veins of the chest region and the dorsal vein of the penis and is often manifested clinically by a cordlike induration. • Generalized symptoms are usu. Not a feature and resolution within weeks is the norm. • In early lesions a PMN infilterate may be present • Trauma,connective tissue disease,breast carcinoma….

24. Thromboangiitis obliterans(buerger’s disease) • Segmental,thrombosing inflammatory process affecting intermediate and small arteries and sometimes veins and may be closely related to STP. • The vessels of the upper and lower extremities are most commonly involved. • Almost exclusively affects smokers.

25. Active lesions are characterized by luminal thrombotic occlusion and a mixed inflammatory cell infilterate of the vessel wall,characteristically with microabscesses. • Later the thrombus is organized and its lumen may be recanalized. • A granulomatous reaction may be present as well.

26. Polyarteritis nodosa • The term PAN is believed to subsume 3 entities: • Classic systemic PAN • Cutaneous PAN • MPA • Classic PAN is a multisystem disorder characterized by inflammatory vasculitis involving arteriols and small and medium-sized arteries.

27. Some authors maintain that if there is no evidence of systemic involvement by (skin-limited) PAN at the time of initial diagnosis ,then the condition will remain confined to the skin,despite a potentially prolonged clinical course with multiple recurrences.

28. More common in men • Usu, occurs between the ages of 20 and 60 ys. • Fever,malaise,weight loss , weakness,myalgias.arthralgias and anorexia are common symptoms,reflecting the systemic nature of the disease. • Renal involvement present in about 75% of patients is the most common cause of death. • Hematuria,proteinoria,hypertension and azotemia may result from both infarctionowing to disease of renal arteries and sometimes focal ,segmental necrotizing glomerular lesions suggesting involvement of small vessels.

29. Acute abdominal crises,strokes,MI and mononeuritis multiplex result from involvement of the relevant arteries. • Arteriography of visceral arteries often shows multiple aneurysms that are highly suggestive of PAN. • ANCAs are generally absent. • cutaneous manifestations include subcutaneous nodules that may pulsate or ulcerate,ecchymoses and gangrene of the fingers and toes.

30. In classic PAN the lesions typically are in different stages of development. • Early lesions show degeneration of the arterial wall with deposition of fibrinoid material. There is a partial or complete destruction of the external and internal elastic laminae. • an infilterate present within and around the arterial wall is composed largely of neut.showing evidence of leukocytoclasis.

31. At a later stage intimal proliferation and thrombosis lead to complete occlusion of the lumen with subsequent ischemia and possibly ulceration. • In the healing stage there is fibroblastic proliferation extending into the perivascular area.

32. MPA • Systemic small-vessel vasculitis primarily affecting arterioles and capilaries that is typically associated with focal necrotizing glomerulonephritis with crescents and p-ANCA. • Involvement of the small vessels of the kidneys,lungs and skin gives MPA a particular clinical picture and separates MPA from PAN,

33. Majority of patients are men and older than 50 • Prodromal symptoms • The most clinical feature is renal disease. • Although cutaneous involvement is rare in classic PAN, at least 30 to 40 % of patients with MPA have skin changes. • Pulmonary involvement without granulomatous tissue reaction occurs in approximately one third of patients

34. H.badakhsh

35. Wegener's Granulomatosis • M˃F • C-ANCA(diagnosis and monitoring of disease activity) • 35 to 54 years old • majority of patients are Caucasians • involved anatomic sites: • upper respiratory tract, lower respiratory tract, kidneys, joints and skin.

36. Skin involvement : • macular erythematous rash • purpura • papules • papulonecrotic lesions • nodules with and without ulceration

37. Histopathology • nonspecific • perivascular lymphocytic infiltrates. • necrotizing/leukocytoclastic small-vessel vasculitis • granulomatous inflammation • Minute foci of tissue necrosis are surrounded by histiocytes and are similar to lesions described in open lung biopsies from WG patients. • The palisadinggranulomasresembling those of CSS may occur, except that the center of the WG granuloma contains necrobiotic collagen and basophilic fibrillar necrotic debris admixed with neutrophils • True granulomatousvasculitis appears to be rare

38. Differential Diagnosis Other conditions causing LCV and granulomatous reactions • CSS • metastatic Crohn's disease • rheumatoid arthritis • sarcoidosis. Granulomatous vascular reactions : • angiocentric T-cell lymphoma • panniculitic T-cell lymphoma The distinction between CSS and WG relies primarily on clinical findings. The distinction between MPA and WG may be difficult clinically; however, MPA should lack granulomatous inflammation.

39. Palisading necrotizing granuloma

40. Small-Vessel Neutrophilic/ Leukocytoclastic Vasculitis

41. Histopathology of Neutrophilic Small-Vessel Vasculitis • small dermal vessels, almost exclusively postcapillary venules, characterized by a combination of vascular damage and an infiltrate composed largely of neutrophils . • there is often fragmentation of nuclei (karyorrhexis or leukocytoclasis), the term leukocytoclastic vasculitis (LCV) is used. • If edema is prominent, a subepidermal blister may form. • If the neut. infiltrate is dense and there is pustule formation, the term pustular vasculitis may be applied

42. dermal vessels show swelling of the endothelial cells and deposits of strongly eos. strands of fibrin within and around their walls( fibrinoid degeneration) • If the vascular changes are severe, luminal occlusion of vessels may be observed. • The infiltrate consists mainly of neutrophils and of varying numbers of eos. and mononuclear cells. The infiltrate also is scattered throughout the upper dermis in association with fibrin deposits between and within collagen bundles. • Extravasation of erythrocytes is commonly present

43. upper dermal small blood vessel with neutrophil-rich vasculitis

44. Diagnostic Approach to Neutrophilic Small-Vessel Vasculitis • the clinical and histologic manifestations are fairly nonspecific for a particular category of vasculitis. • additional laboratory data: microbiologic cultures, special stains for organisms, or immunofluorescence or serologic studies • the most important diagnostic step in the evaluation of a vasculitis is to rule out an infectious process. • If noninfectious vasculitis is suspected, evidence for systemic vasculitis must be sought. • Clinical findings : hematuria, arthritis, myalgia, enzymatic assays for muscle or liver enzymes, and serologic analysis for ANCAs, antinuclear antibodies, cryoglobulins, hepatitis B and C antibodies, IgA-fibronectin aggregates, and complement levels • Exposure to a potential allergen, such as a drug. • important to address the possibility that the histologic findings of vasculitis may be a secondary phenomenon, as, for example, in ulceration from localized trauma.

45. Infectious Vasculitis • Microorganisms may invade vessels directly or damage them by an immune-mediated mechanism. • Neisseria meningitides is a common cause of infectious cutaneousleukocytoclasticvasculitis. Meningococci may be found within endothelial cells and neutrophils at sites of vascular inflammation. • other Gram-positive or Gram-negative bacteria and fungi • Staphylococcal sepsis can lead to neutrophilicvasculitis with purpura or nodular lesions, which may contain microabscesses. • Rickettsial infections, such as Rocky Mountain spotted fever (RMSF), are characterized by invasion of endothelial cells by organisms causing vascular damage. • Direct immunofluorescence microscopy may demonstrate the organism. Clinically, the spectrum of changes ranges from small macules to papules and purpura.

46. Acid-fast organisms can also cause vasculitis. syndromes that may arise during the course of lepromatous leprosy: • Lucio's phenomenon (erythemanecroticans) • erythemanodosumleprosum (ENL) In both cases, biopsies show LCV. Histologically, Lucio's phenomenon shows necrotizing small-vessel vasculitis, and Fite-Faraco staining reveals large aggregates of acid-fast bacilli within the vascular walls and endothelium and throughout the dermis. Viral organism: hepatitisB HSV Parvovirus B19

47. Septic vasculitis

48. Henoch-SchonleinPurpura cannot be distinguished histologically from other forms of LCV • degree of vascular damage is often not as great as that usually observed in typical LCV. • Immunofluorescence : deposition of IgA in capillaries • Such a limited extent of vascular damage is also commonly observed in urticarialvasculitis and clinical findings may be necessary for distinction of H-SP from urticarialvasculitis. , • serologic detection of IgA-fibronectin aggregates may be associated with greater likelihood of renal or systemic disease in patients with cutaneous LCV

49. UrticarialVasculitis • Scant perivascular and interestitial neut. infiltrates • Ranged from mild to fully developed LCV.

50. Cryoglobulinemias and Other Small-Vessel Vasculitides Associated with Paraproteins • paraproteins include cryoglobulins, cryofibrinogens, macroglobulins, and gamma-heavy chains. three major types of cryoglobulinemia: • type I cryoglobulinemia,monoclonal IgG or IgMcryoglobulins are found, often associated with lymphoma, leukemia, Waldenstrom'smacroglobulinemia, or multiple myeloma, or without known underlying disease. • type II cryoglobulinemia, the cryoprecipitate consists of both monoclonal and polyclonalcryoglobulins, with one cryoglobulin acting as an antibody against the other. These cryoglobulins are circulating immune complexes. The most common combination is IgG-IgM. • type III cryoglobulinemia, the immunoglobulins are polyclonal.