Inflammatory vascular diseases

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Inflammatory vascular diseases

Leukocytoclastic vasculitis (LCV)

• Perivascular infiltrate with neutrophils

• Karyorrhexis (nuclear dust, leukocytoclasis)

• Expansion of the vessel wall

• Fibrin deposition within the vessel wall

• Erythrocyte extravasation

Clinical lesions of leukocytoclastic vasculitis are purpuric, and often palpable. Vasculitis involving arterioles commonly produces livedo reticularis or stellate infarcts.

Fig 11-1 Leukocytoclastic vasculitis

Classification of vasculitis

Vasculitis is classified by the type of inflammatory infiltrate, type of vessel involved, the presence or absence of endothelial necrosis, associated systemic findings, immunofluorescent patterns, and serologic findings. American College of Rheumatology (ACR) classification criteria are mostly clinical, with little emphasis on histologic findings. The Chapel Hill criteria include histologic features, especially vessel size. As many entities demonstrate involvement of vessels of various sizes, any classification will have limitations.

Large vessel vasculitis

When a large vessel is involved by vasculitis, it is critical to determine whether the involved vessel is an artery or a vein. Arteries are characteristically round, with a wreath-like muscularis and an internal elastic membrane. Veins are characteristically oval, with a bundled muscularis. They may have visible valves, and lack an internal elastic membrane. So-called “arterialization” of veins occurs when they are subjected to elevated hydrostatic pressure. This phenomenon is occasionally noted in cutaneous vessels, but is best demonstrated in coronary artery bypass grafts. The grafted vein develops a prominent internal elastic membrane, but retains the bundled muscularis characteristic of a vein.

Fig 11-2 Characteristic features of an artery

Fig 11-3 Characteristic features of a vein

Giant cell arteritis (temporal arteritis)

• Muscular artery with wreath-like muscularis and prominent internal elastic membrane

• Subendothelial granulomatous inflammation

• With progression, becomes transmural inflammation

• Incidental atherosclerotic changes (calcification, subintimal plaques) often present in the vessel

Temporal arteritis often involves the vessel in a focal, beaded fashion, so an adequate length of temporal artery (ideally 2 cm) should be submitted for examination.

Chapel Hill criteria

Granulomatous arteritis involving the major branches of the aorta, with a predilection for the extracranial branches of the carotid artery. The temporal artery is frequently involved. Patients are usually >50 years of age. Frequently associated with polymyalgia rheumatica.

American College of Rheumatology criteria

Age >50; new headache; abnormal temporal artery clinically; elevated sedimentation rate; positive temporal artery biopsy (three criteria give >93% sensitivity, >91% specificity).

Fig 11-4 Temporal arteritis

Takayasu arteritis

• Granulomatous vasculitis involving large muscular arteries

Chapel Hill criteria

Granulomatous arteritis involving the aorta and its major branches. Usually <50 years of age.

American College of Rheumatology criteria

Age <40; claudication; decreased pulses; >10 mmHg difference in pressure between arms; bruits; abnormal arteriogram (three criteria give >90% sensitivity, >97% specificity).

Fig 11-5 Takayasu arteritis

Polyarteritis nodosa

• Large artery involved, typically in the deep dermis or subcutaneous tissue

• Often involves branch points of vessels

• Acute phase is neutrophilic with karyorrhexis

• Chronic phase may demonstrate a granulomatous component

• Fat necrosis is common

Polyarteritis nodosa commonly presents with livedo reticularis and subcutaneous erythematous or hyperpigmented nodules. The biopsy typically demonstrates neutrophilic vasculitis involving an artery within the subcutaneous fat. Surrounding lobular necrosis is present.

Chapel Hill criteria

Necrotizing inflammation involving medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules.

American College of Rheumatology criteria

Weight loss >4 kg; livedo reticularis; testicular pain or tenderness; myalgia/myopathy, or muscle tenderness; neuropathy; hypertension (diastolic >90); renal impairment; hepatitis B infection; abnormal arteriogram; biopsy of an artery with neutrophilic inflammation (three criteria give >82% sensitivity, >86% specificity).

Fig 11-6 Polyarteritis nodosa

Thrombophlebitis

• Vasculitis involving an oval vessel with bundled muscularis

• Vessel lacks an internal elastic membrane and may contain valves

• Thrombus present within vessel

Thromboangiitis obliterans (Buerger’s disease)

• Endarteritis

• Prominent neutrophilic inflammation involving the thrombus

Buerger’s disease is a rare disease typically seen in male smokers. It is characterized by a combination of acute inflammation and thrombosis of large distal extremity vessels.

American College of Rheumatology criteria

Age >50; history of smoking; distal peripheral vascular obstructive disease (below knee or elbow); and three additional criteria, such as thrombophlebitis saltans/migrans; involvement of upper extremity; characteristic angiography.

Fig 11-7 Buerger’s disease

Medium vessel vasculitis

These diseases are characterized by leukocytoclastic vasculitis involving vessels larger than the post-capillary venule. The endothelium is frequently necrotic. The biopsy demonstrates a superficial and deep perivascular infiltrate with neutrophils, karyorrhexis, expansion of the vessel wall, fibrin deposition within the vessel wall, and erythrocyte extravasation.

Fig 11-8 “Big 5” pattern of vasculitis

Wegener’s granulomatosis

• Leukocytoclastic vasculitis involving a mix of vessel sizes (post-capillary venule plus larger deeper vessels)

• Endothelial necrosis is common

• May involve skin, upper respiratory tract, kidneys

• LCV evolves into stellate abscess (palisaded granuloma with central neutrophils)

• Giant cells present in the granuloma

Wegener’s granulomatosis commonly involves the upper airway. The skin of the nose may become necrotic. Skin lesions may occur in other locations, especially the extremities. The histologic pattern is that of a “big 5” vasculitic disorder. Individual vasculitic foci may evolve into stellate abscesses (palisaded granulomas with a central stellate collection of neutrophils). Multinucleate giant cells are present in the granulomas. Granulomatous vasculitis may be present in medium-sized vessels.

Chapel Hill criteria

Granulomatous inflammation of the respiratory tract; necrotizing vasculitis of small to medium vessels; necrotizing glomerulonephritis common.

American College of Rheumatology criteria

Nasal or oral inflammation; chest X-ray with nodules; infiltrate or cavities; microscopic hematuria or red cell casts; granulomatous inflammation on biopsy (two criteria give >88% sensitivity, >92% specificity).

Differential Diagnosis

Palisaded granulomatous dermatitis with stellate abscess formation may be seen in Wegener’s granulomatosis (giant cells peripherally, neutrophils centrally), Churg–Strauss syndrome (epithelioid cells peripherally, eosinophils centrally), atypical mycobacterial infection, sporotrichosis, nocardiosis, cat scratch disease, lymphogranuloma venereum, and tularemia.

Fig 11-9 Wegener’s granulomatosis, palisading granuloma with stellate abscess

Fig 11-10 Wegener’s granulomatosis, granulomatous vasculitis

Churg–Strauss syndrome

• Leukocytoclastic vasculitis involving a mix of vessel sizes (post-capillary venule plus larger deeper vessels)

• Endothelial necrosis is common

• Asthma common

• May involve skin and kidneys

• LCV may produce stellate abscesses (palisaded granuloma with central eosinophils)

• Granuloma composed of epithelioid cells without giant cells

The Churg–Strauss syndrome is a vasculitic disorder that commonly presents with a prodrome of asthma. Some cases have been induced by leukotriene inhibitors.

The histologic pattern is that of a “big 5” vasculitic disorder. Palisaded granulomas with central stellate abscesses are commonly seen. Unlike those of Wegener’s granulomatosis, these rarely contain multinucleated giant cells and the central abscess is composed of eosinophils rather than neutrophils. Flame figures (eosinophil granules adherent to collagen fibers) similar to those of Well’s syndrome may be present.

Chapel Hill criteria

Eosinophil-rich and granulomatous inflammation involving respiratory tract; necrotizing vasculitis of small to medium vessels; associated asthma and peripheral eosinophilia.

American College of Rheumatology criteria

Asthma; eosinophilia (>10%); neuropathy; pulmonary infiltrates; paranasal sinus involvement; extravascular eosinophils in tissue (four criteria give >85% sensitivity, >99% specificity).

Fig 11-11 Churg–Strauss syndrome, vasculitis with eosinophils

Fig 11-12 Churg–Strauss syndrome, palisading granuloma with stellate abscess

Microscopic polyangiitis

• Leukocytoclastic vasculitis involving a mix of vessel sizes (post-capillary venules plus larger deeper vessels)

• Endothelial necrosis is common

The histologic pattern is that of a “big 5” vasculitic disorder. Endothelial necrosis is a prominent feature. The histologic pattern, ANCA positivity and systemic involvement define the syndrome.

Chapel Hill criteria

Necrotizing vasculitis, few or no immune deposits, small to medium vessels involved, necrotizing arteriolitis may be present, necrotizing glomerulonephritis and pulmonary capillaritis common.

Rheumatoid vasculitis

• Leukocytoclastic vasculitis involving a mix of vessel sizes (post-capillary venules plus larger deeper vessels)

• Endothelial necrosis is common

The histologic pattern resembles that of the other “big 5” vasculitides. The vasculitis is associated with a rheumatoid factor and rheumatoid arthritis. Unlike most other connective tissue disease-associated vasculitis, rheumatoid vasculitis commonly ulcerates and scars.

Septic vasculitis

• Vasculitis involves a mix of vessel sizes (post-capillary venules plus larger deeper vessels)

• Endothelial necrosis is common

• “Dirty” necrosis with ample neutrophilic debris

Septic vasculitis is typically associated with dirty necrosis of arterioles. Because of the arteriolar involvement, livedo reticularis and stellate infarcts are commonly seen clinically.

Fig 11-13 Septic vasculitis

Small vessel leukocytoclastic vasculitis

The biopsy demonstrates a superficial perivascular infiltrate with neutrophils, karyorrhexis, expansion of the vessel wall, fibrin deposition within the vessel wall, and erythrocyte extravasation. The vasculitis involves primarily the post-capillary venules, although an occasional perforating vessel may be involved. These perforating vessels connect the subpapillary and deep plexus, and are vertically oriented. Endothelial necrosis is exceedingly rare. Direct immunofluorescence may be helpful, especially in the case of Henoch–Schönlein purpura. A urinalysis should routinely be performed to look for signs of active renal involvement.

Fig 11-14 “Little 5” pattern of leukocytoclastic vasculitis

Henoch–Schönlein purpura

• “Little 5” pattern of LCV

• IgA in vessels on direct immunofluorescence (DIF)

• Typically children

• Extensor involvement with large mottled patches of purpura

• Bone, joint gut and renal involvement

Henoch–Schönlein purpura is the most common IgA vasculitis. The clinical features and DIF pattern are distinctive, but the H&E findings are like that of the other “little 5” disorders.

Chapel Hill criteria

Vasculitis with IgA dominant deposits; small to medium vessels; involves skin, gut and glomeruli; associated with arthralgia or arthritis.

American College of Rheumatology criteria

Palpable purpura; age <20; bowel pain; vessel wall neutrophils on biopsy (two criteria give 87% sensitivity, 88% specificity).

Fig 11-15 Henoch–Schönlein purpura, “Little 5” pattern of leukocytoclastic vasculitis

Fig 11-16 Henoch–Schönlein purpura, IgA deposition in vessels (DIF)

Mixed cryoglobulin disease

• “Little 5” pattern of LCV

• Cryoglobulins present

Mixed cryoglobulin disease is often associated with chronic infection, especially with hepatitis C. The H&E findings are like that of the other “little 5” disorders.

Chapel Hill criteria

Vasculitis of small to medium vessels; cryoglobulin deposits; skin and glomeruli often involved.

Drug-induced and idiopathic leukocytoclastic vasculitis (idiopathic leukocytoclastic angiitis)

• “Little 5” pattern of LCV

We use the term idiopathic leukocytoclastic vasculitis here, for cases with no known cause. The ACR criteria lump drug-induced vasculitis into this category. The histologic features of both fall into the “little 5” pattern.

Chapel Hill criteria

Isolated leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis.

American College of Rheumatology criteria

Age >16; implicated drug; palpable purpura; cutaneous eruption; positive biopsy (three criteria give 71% sensitivity, >83% specificity).

Unique forms of vasculitis

Granuloma faciale

• Typically facial skin (sebaceous follicles, Demodex mites)

• LCV with eosinophils

• Onion-skin fibrosis in chronic cases

• “Granuloma” in the name ONLY – not on the slide

Granuloma faciale presents clinically as reddish brown macules or plaques with patulous follicular openings. Histologically, it is a chronic leukocytoclastic vasculitis with eosinophils. Over time, onion-skin fibrosis develops around vessels. A grenz (border) zone commonly separates the infiltrate from the adjacent follicular epithelium. Despite the name, there are no granulomas in the tissue.

Fig 11-17 Granuloma faciale

Question: Where is the granuloma in granuloma faciale? Answer: In the name. (Not in the skin.)

Erythema elevatum diutinum

• Not facial skin

• LCV ± eosinophils

• Onion-skin fibrosis

Erythema elevatum diutinum (EED) presents with red to orange plaques on extensor surfaces. Like granuloma faciale, EED represents a chronic fibrosing form of leukocytoclastic vasculitis. It is distinguished histologically by a non-facial location and greater fibrosis. EED has been associated with chronic streptococcal infection, HIV infection, and IgA gammopathy. The histologic changes are similar to those of granuloma faciale, but the surrounding skin has features of acral skin. Extracellular cholesterol clefts deposit in some chronic cases as a result of years of erythrocyte extravasation.

Fig 11-18 Erythema elevatum diutinum

Fig 11-19 Erythema elevatum diutinum with extensive fibrosis

Kawasaki disease

• Diagnosis is made clinically

• Coronary arteritis presents histologically

Chapel Hill criteria

Involves large, medium and small arteries, with associated mucocutaneous lymph node syndrome; coronary arteries often involved; usually affects children.

Incidental vasculitis

• Not associated with immune complex disease

• Occurs in ulcers and adjacent to suppurative folliculitis

• May mimic “big 5” or “little 5” pattern

Leukocytoclastic vasculitis is frequently seen as an incidental finding in the base of a chronic ulcer or adjacent to a focus of suppurative folliculitis. Focal incidental leukocytoclastic vasculitis also occurs in Sweet’s syndrome, bowel bypass syndrome, pyoderma gangrenosum, and neutrophilic dermatosis of the dorsal hands.

Fig 11-20 Incidental leukocytoclastic vasculitis in the base of a chronic ulcer

Neutrophilic dermatoses

Sweet’s syndrome (acute febrile neutrophilic dermatosis)

• Marked papillary dermal edema

• Nodular and diffuse infiltrate of neutrophils with karyorrhexis

• Focal LCV is common

Sweet’s syndrome is a distinct syndrome characterized by bouts of red, hot, tender erythematous plaques, fever and peripheral leukocytosis. Most cases follow bouts of upper respiratory infection in predisposed individuals. About 10% of patients have an associated myeloproliferative disorder. The most striking histologic features of Sweet’s syndrome are the nodular and diffuse infiltrates of neutrophils, karyorrhexis, and marked papillary dermal edema. In the presence of these findings, and a characteristic clinical presentation, the presence of focal leukocytoclastic vasculitis does not alter the diagnosis of Sweet’s syndrome.

Fig 11-21 Sweet’s syndrome

Other neutrophilic dermatoses

• Look like Sweet’s syndrome

• Marked papillary dermal edema

• Nodular and diffuse infiltrate of neutrophils with karyorrhexis

• Focal LCV is common

Neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, bowel-bypass syndrome, and the autoinflammatory syndromes such as familial Mediterranean Fever and Muckle–Wells syndrome have a similar appearance to the lesions of Sweet’s syndrome. Ulcerative lesions typically demonstrate more prominent foci of leukocytoclastic vasculitis. Erythema marginatum is a superficial gyrate erythema characterized by a superficial perivascular neutrophilic infiltrate. The papillary dermal edema is less prominent.

Urticaria

The edema of an urticarial wheal is not visible histologically. Instead, the only significant finding in acute lesions of urticaria is intravascular margination of neutrophils. With time, the neutrophils travel through the vessel wall into the surrounding dermis and are joined by eosinophils and mononuclear cells. In contrast to leukocytoclastic vasculitis, karyorrhexis is absent, the vessels walls are not expanded, and no fibrin is seen in the vessel walls. Erythrocyte extravasation is uncommon.

Fig 11-22 Acute stage of a wheal

Fig 11-23 Chronic stage of an urticarial wheal

Wells’ syndrome (eosinophilic cellulitis)

• Flame figures (eosinophil degranulation onto collagen)

Wells’ syndrome is characterized by recurrent erythematous plaques that demonstrate flame figures histologically. Some cases may represent a distinct entity, while most represent exaggerated arthropod reactions.

Fig 11-24 Wells’ syndrome

Perivascular lymphoid infiltrates

Pigmenting purpuric eruption

• Inflammation purely lymphoid

• Surrounds capillaries (centered above the level of the post-capillary venule)

• Erythrocyte extravasation

• Hemosiderin deposits over time

All types of pigmenting purpura represent forms of chronic lymphocytic capillaritis. Clinical variants include thumbprint hemosiderosis with cayenne pepper spots (Schamberg’s disease); annular telangiectatic purpura (Majocchi’s purpura); lichenoid purpura (Gougerot–Blum purpura); and eczematous purpura (pigmenting purpura of Doucas and Kapetanakis). In all forms, an iron stain (Perl’s, Prussian blue, ferricyanide, Gomori iron) can be used to demonstrate hemosiderin.

Fig 11-25 Pigmenting purpuric eruption

Gyrate erythemas

• Dense “coat-sleeve” perivascular lymphoid infiltrate

• Vessels are intact

Superficial gyrate erythemas include erythema marginatum (discussed under the neutrophilic disorders) and erythema annulare centrifugum. Erythema annulare centrifugum is characterized clinically by an expanding erythematous ring with a characteristic trailing scale. Histologically, the erythematous ring corresponds to a focus of superficial perivascular coat-sleeve lymphoid infiltrate. Trailing behind this is a small spongiotic focus, and trailing behind that is a small focus of parakeratosis. The infiltrate, spongiotic and parakeratotic foci line up at about a 45° angle. Deep gyrate erythemas lack epidermal changes, and are characterized by a dense superficial and deep coat-sleeve perivascular lymphoid infiltrate.

Fig 11-26 Erythema annulare centrifugum

Fig 11-27 Deep gyrate erythema

Tumid lupus erythematosus

• Perivascular lymphoid inflammation

• Lymphocytes in eccrine coil

• Dermal mucin

Fig 11-28 Tumid lupus erythematosus

Polymorphous light eruption

• Perivascular lymphoid inflammation

• Papillary dermal edema

• ± spongiosis

Fig 11-29 Polymorphous light eruption

Morbilliform drug eruptions

• Evidence of an acute process (basket-weave corneum, papillary dermal edema, dilated superficial vessels, neutrophils in vessels, red cell extravasation)

• Mild vacuolar interface commonly present

Features that suggest a drug eruption include presence of a polymorphous infiltrate, as well as combinations of findings not corresponding to any well-defined disease.

Features that weigh against a diagnosis of a morbilliform drug eruption include signs of chronicity (acanthosis, hyperkeratosis, papillary dermal fibrosis, macrophages in dermis).

Lymphoid vasculitis

• Perivascular lymphoid infiltrate with damage to the vessel wall

True lymphoid vasculitis may be seen in Degos disease, insect bites, rickettsial disease, pityriasis lichenoides, and perniosis.

Degos disease (malignant atrophic papulosis)

• Red papules that develop ivory white atrophic centers

• Bowel perforation and stroke

• Wedge-shaped superficial and deep perivascular lymphoid infiltrate with vascular damage

• Over time, central epidermal depression and atrophy, avascular necrosis of dermal structures, and marked dermal mucinosis

Degos disease is a distinct clinical picture that may be a manifestation of lupus erythematosus.

Fig 11-30 Degos disease

Insect bite

• Dense wedge-shaped perivascular lymphoid infiltrate

• Eosinophils

• Variable vascular damage

• Variable atypical lymphocytes

• Focal leukocytoclastic vasculitis may be present

• Papillary dermal edema may be prominent

Fig 11-31 Insect bite

Perniosis

• Superficial and deep perivascular lymphoid infiltrate

• Fluffy edema and expansion of vessel walls without fibrin

The so-called “fluffy edema” of perniosis is often more prominent in deeper dermal vessels. The vessel wall is expanded, and white space surrounds lymphocyte nuclei within the vessel wall.

Fig 11-32 Perniosis

Occlusive vascular diseases

Type I cryoglobulinemia

• Vessels occluded by pink jelly-like substance

• Erythrocyte extravasation

Type I, monoclonal, cryoglobulinemia is a manifestation of plasma cell dyscrasia. The intravascular deposits have an appearance resembling dark pink to red jelly.

Fig 11-33 Type I cryoglobulinemia

Cholesterol embolization

• Arteriole containing cholesterol clefts

Cholesterol embolization typically occurs after catheterization or anticoagulation. Spontaneous embolization may also occur. The patient presents with livedo reticularis, dark mottled toes and worsening renal function.

Fig 11-34 Cholesterol embolization

Livedoid vasculopathy

• Hyalinized vessel walls

• Cannon-ball tufting of vessels often present in superficial dermis (stasis change)

Fig 11-35 Livedoid vasculopathy

Stasis change

• Cannon-ball tufting of vessels often present in superficial dermis (stasis change)

• Erythrocyte extravasation

• Dermal hemosiderin

• Small thrombi may be present

Fig 11-36 Stasis change

Coagulopathy

• Thrombi in vessels

Purpura fulminans, antiphospholipid syndrome, and inherited deficiencies or mutations affecting protein C, protein S, antithrombin III, factor V Leyden, and prothrombin all result in vascular thrombi with variable purpura and necrosis. Levamisole-induced necrosis may have both thrombi and vasculitis.

Non-inflammatory purpura

Scurvy

• Follicular hyperkeratosis

• Corkscrew hairs

• Perifollicular hemorrhage

Fig 11-37 Scurvy

Solar (“senile”) purpura (Bateman’s or actinic purpura)

• Solar elastosis

• Erythrocyte extravasation

Other non-inflammatory purpura

• Erythrocyte extravasation

Ecchymoses and thrombocytopenic purpura present with erythrocyte extravasation in the absence of inflammation.

Further reading

Bertoli, AM, Alarcón, GS. Classification of the vasculitides: are they clinically useful? Curr Rheumatol Rep. 2005; 7(4):265–269.

Carlson, JA, Ng, BT, Chen, KR. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005; 27(6):504–528.

Knütter, I, Hiemann, R, Brumma, T, et al. Automated interpretation of ANCA patterns – a new approach in the serology of ANCA-associated vasculitis. Arthritis Res Ther. 2012; 14(6):R271.

Lionaki, S, Blyth, ER, Hogan, SL, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum. 2012; 64(10):3452–3462.

Ozen, S. Problems in classifying vasculitis in children. Pediatr Nephrol. 2005; 20(9):1214–1218.

Pagnoux, C, Guillevin, L. Cardiac involvement in small and medium-sized vessel vasculitides. Lupus. 2005; 14(9):718–722.

Saleh, A, Stone, JH. Classification and diagnostic criteria in systemic vasculitis. Best Pract Res Clin Rheumatol. 2005; 19(2):209–221.

Watts, RA, Scott, DG. ANCA vasculitis: to lump or split? Why we should study MPA and GPA separately. Rheumatology (Oxford). 2012; 51(12):2115–2117.

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