J A Carlson, Department of Pathology, Divisions of Dermatology and Dermatopathology, Albany Medical College, MC-81, 47 New Scotland Ave., Albany, NY 12208, USA. e-mail: email@example.com
Carlson J A (2010) Histopathology56, 3–23 The histological assessment of cutaneous vasculitis
Vasculitis is defined as inflammation directed at vessels, which compromises or destroys the vessel wall leading to haemorrhagic and/or ischaemic events. Skin biopsy is the gold standard for the diagnosis of cutaneous vasculitis, whose manifestations include urticaria, infiltrative erythema, petechiae, purpura, purpuric papules, haemorrhagic vesicles and bullae, nodules, livedo racemosa, deep (punched out) ulcers and digital gangrene. These varied morphologies are a direct reflection of size of the vessels and extent of the vascular bed affected, ranging from a vasculitis affecting few superficial, small vessels in petechial eruptions to extensive pan-dermal small vessel vasculitis in haemorrhagic bullae to muscular vessel vasculitis in lower extremity nodules with livedo racemosa. Skin biopsy, extending to subcutis and taken from the earliest, most symptomatic, reddish or purpuric lesion is crucial for obtaining a high-yielding diagnostic sample. Based on histology, vasculitis can be classified on the size of vessels affected and the dominant immune cell mediating the inflammation (e.g. neutrophilic, granulomatous, lymphocytic, or eosinophilic). Disruption of small vessels by inflammatory cells, deposition of fibrin within the lumen and/or vessel wall coupled with nuclear debris allows for the confident recognition of small vessel, mostly neutrophilic vasculitis (also known as leukocytoclastic vasculitis). In contrast, muscular vessel vasculitis can be identified solely by infiltration of its wall by inflammatory cells. Extravasation of red blood cells (purpura) and necrosis are supportive, but not diagnostic of vasculitis as they are also seen in haemorrhagic and/or vaso-occlusive disorders (pseudovasculitis). Vasculitic foci associated with extravascular granulomas (palisaded neutrophilic and granulomatous dermatitis), tissue eosinophilia, or tissue neutrophilia signal the risk for, or co-existence of systemic disease. This essential histological information coupled with direct immunofluorescence and anti-neutrophil cytoplasmic data and clinical findings enables more precise and accurate diagnosis of localized and systemic vasculitis syndromes.
Vasculitis is a histological diagnosis defined as inflammation targeting blood vessel walls and compromising their function, leading to haemorrhagic and/or ischaemic events.1–5 Aetiologically, vasculitis can be separated into primary vasculitis [idiopathic, e.g. cutaneous leukocytoclastic angiitis (CLA), Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS) and microscopic polyangiitis (MPA)], secondary vasculitis [a manifestation of connective tissue disease (CTD), infection, adverse drug eruption, or a paraneoplastic phenomenon], or incidental vasculitis, a histological finding that is the consequence of another pathological process such as traumatic ulceration or diffuse neutrophilic infiltrates. Clinically, cutaneous vasculitis can present with a panoply of morphologies that include urticaria, purpura, haemorrhagic vesicles, ulcers, nodules, livedo, infarcts, and/or digital gangrene. Palpable purpura may represent the cutaneous manifestation of systemic disease, or, in most instances, a benign self-limited, single episode phenomenon – CLA (hypersensitivity vasculitis). Given this broad range of presentations for cutaneous vasculitis and the numerous disorders that can mimic vasculitis,6 it is not surprising that it is difficult to recognize and correctly, confidently classify patients presenting with cutaneous vasculitis. In this review, the histological spectrum of cutaneous vasculitis will be presented, how cutaneous histological patterns can be used to generate relevant clinical differential diagnoses, and, when coupled with clinical and laboratory data, allow more precise and accurate diagnosis of vasculitic syndromes.
Classification of vasculitis
Currently, the most widely adopted vasculitis classification system is that of Chapel Hill Consensus Conference (CHCC), which is based on pathological criteria.7 The other widely used system is that of the American College of Rheumatology (ACR), which is based predominately on clinical findings.8–15 Both schemes were developed to compare groups of vasculitis patients, not as diagnostic criteria for individual patients. For example, when CHCC or ACR criteria are applied to individual patients, shortcomings are apparent with lack of recognition of specific disorders and overlap amongst primary vasculitides.1 For example, systemic polyarteritis nodosa (PAN) is rare by CHCC criteria, but relatively common by ACR criteria.16 Patients diagnosed with hypersensitivity vasculitis by ACR criteria can also be classified as Henoch–Schönlein purpura (HSP). These latter patients can also be classified as MPA by CHCC criteria,17 particularly if any sign of systemic disease is present. Therefore, a more useful scheme is necessary for the evaluation of individual patients.
The role of skin biopsy
Few vasculitic syndromes have pathognomonic clinical, radiographic and/or laboratory findings; thus, confident and accurate diagnosis of vasculitis requires histological confirmation. On the other hand, a biopsy diagnosis of vasculitis cannot stand alone, as it must be correlated with clinical history, physical and laboratory findings and/or angiographic features to arrive at specific diagnosis. For example, a diagnosis of localized cutaneous vasculitis [also known as CLA, hypersensitivity vasculitis or leukocytoclastic vasculitis (LCV)] requires that evidence of systemic manifestations of vasculitis be found to be absent. If systemic vasculitis is present, imaging studies can provide a useful means to determine disease extent and activity, and serology, such as C-reactive protein and anti-neutrophil cytoplasmic antibody (ANCA) levels and type, can be used to monitor disease activity and predict mortality risk, respectively. Hence, the classification of cutaneous vasculitis into specific syndromes is best approached morphologically by determining vessel size and principal inflammatory response. These histological patterns roughly correlate with pathogenic mechanisms that, when coupled with direct immunofluorescent examination, ANCA status and findings from work-up for systemic disease, allow for specific diagnosis, and ultimately, more effective therapy.1,2,5 In the evaluation of cutaneous vasculitis, accurate histological classification is the first step in arriving at a reproducible diagnosis of a specific vasculitic syndrome (see Figures 1 and 2, and Table 1). For example, a neutrophil predominant small vessel vasculitis primarily affecting upper dermal blood vessels and showing papillary IgA deposits is diagnostic of HSP, whereas a neutrophil predominant small vessel vasculitis affecting dermal and subcutaneous blood vessels and showing predominance of IgM vascular deposits would implicate cryoglobulinaemic vasculitis (CV) or rheumatoid vasculitis (RV).
Table 1. Working pathological classification of cutaneous vasculitis
ANCA, anti-neutrophil cytoplasmic antibody; DIF+, direct immunofluorescence examination of skin lesions shows vessel wall immune complexes and/or complement deposition. Modified from Carlson and Chen.3
Lymphocytic thrombophilic arteritis51 [Macular arteritis, possible PAN variant47]
Epidemiology and clinical features
The incidence of cutaneous vasculitis ranges from 15.4 to 29.7 cases per million per year, and it affects all ages, slightly fewer males than females, and adults more often than children, with 90% of the latter having HSP.1 Almost half of all patients presenting with cutaneous vasculitis have self-limited disease localized to the skin without any attributable cause, trigger or associated systemic disease (idiopathic) CLA.1,18 The remainder of localized cutaneous vasculitis cases can be attributed to recent infection and/or drug ingestion LCV secondary to drugs or infection (also known as hypersensitivity vasculitis or allergic vasculitis). However, a minority of cases of ANCA-associated primary systemic vasculitis syndromes (PSV) such as CSS, MPA and WG may first present with cutaneous vasculitis.16 In other patients, the onset of cutaneous vasculitis signals increased systemic disease activity, as is the case for vasculitis occurring in systemic lupus erythematosus (SLE) [lupus vasculitis (LV)].19 Vasculitis secondary to CTD, malignancy or infections such as hepatitis B and C is infrequent; for example, only 2.1% of patients with rheumatoid arthritis (RA) develop RV.20
In adults, the mean age of onset of vasculitis is 47 years, and amongst children the mean age of onset is 7 years.1,2 The onset of vasculitis after exposure to a trigger such as a drug or infection is at 7–10 days. A mean interval of 6 months, range weeks to years, exists between the onset of symptoms and signs of systemic disease and the onset of secondary cutaneous vasculitis. Three patterns of disease evolution occur in cutaneous vasculitis: (i) single acute, self-limited episode (resolved in ≤6 months) of vasculitis typically associated with a drug or infectious trigger (∼60% of all cases); (ii) relapsing disease with symptom-free periods usually found in patients with HSP and cryoglobulinaemia (∼20%); and (iii) a chronic, unremitting disease often associated with PSV, CTD-associated vasculitis (including cryoglobulinaemia) and malignancy (∼20%).1 The duration of vasculitis can range from 1 week to 318 months, with mean and median durations of 28 months and 3.7 months, respectively. Less than 20% of cutaneous vasculitis patients will have extracutaneous (visceral) vasculitis. Fatal disease occurs in a minority of patients (<7%).1,18
Clinical pathological correlation
In general, systemic symptoms accompany all cutaneous vasculitic syndromes, and these symptoms include fever, malaise, weight loss, arthritis and/or arthralgias.1,2 In the majority of patients, vasculitic lesions will affect the lower extremities, mostly at dependent sites or underlying tight-fitting clothes. Upper extremity, trunk and head and neck involvement are infrequent and often signal the presence of more severe disease or coexisting systemic vasculitis. The type of cutaneous lesions closely correlates with the size of vessel affected by vasculitis. Sparse superficial perivascular neutrophilic infiltrates associated with nuclear debris and extravasated red blood cells result in urticarial papules and plaques, which last >24 h, burn rather than itch, and resolve with residual pigmentation. Small, predominately superficial vessel involvement results in purpuric macules and infiltrated erythema, whereas deeper dermal small vessel vasculitis correlates with palpable purpura and/or vesiculobullous lesions. Ulcers, nodules, pitted scars, or livedo reticularis are associated with arterial-muscular vessel involvement, which will be located at the dermal–subcutis interface or within the subcutis.2
Biopsy: timing, technique and choice of lesions
Choice of clinical lesions and type of pathological assessment has great impact on the diagnostic yield of cutaneous biopsies.1,2 Choice of a shave biopsy, punch biopsy or excisional biopsy will affect which vessels are examined, as the type of vessel is dependent on location within the skin and subcutis, i.e. the deeper the location, the larger the vessel (see Figure 1). Therefore, if a medium vessel vasculitis such as cutaneous PAN is suspected, the biopsy must include the subcutaneous fat where medium-sized vessels are situated.
In general, a biopsy extending to subcutis taken from the most tender, reddish or purpuric, lesional skin is the key to obtaining a significant diagnostic result.2 The optimal time for skin biopsy is <48 h after the appearance of a vasculitic lesion. If the biopsy is poorly timed, the pathological features of vasculitis may be absent, a fact that must be considered when interpreting a negative biopsy from a patient whose clinical findings suggest vasculitis. A punch biopsy of a lesion at the appropriate stage will enable histological confirmation of most small-vessel vasculitic syndromes. Purpuric lesions obtained in the first 24 h are characterized by fibrin deposits within the vessel wall accompanied by neutrophilic infiltration of the wall and surrounding haemorrhage and nuclear debris. After 24 h, neutrophils begin to be replaced by lymphocytes and macrophages. Thus, biopsy of lesions >48 h old, regardless of the underlying form of vasculitis, may show lymphocyte-rich infiltrates (see Figure 3). In the case of assessing the cause of livedo racemosa, a deep biopsy specimen extending to the subcutis should be taken from the centre of the circular livedo segment (the ‘white’ centre, not the ‘red’ periphery), because this is where the stenosed vessel responsible for the cyanotic periphery is located. In this setting, level sections thoroughly sampling the biopsy specimen are often required to find the focus of vasculitis, which is typically focal and segmental. Biopsy specimens should also be obtained from non-ulcerated sites due to frequent finding of incidental vasculitis seen underlying an ulcer bed. If only superficial ulcers are present, biopsy of the edge is advisable. In the case of deep, ‘punched out’ ulcers, biopsy of the subcutis including the central ulcerated area increases diagnostic yield and recognition of a arterial vasculitis (e.g. PAN).21
Lastly, omission of a biopsy for direct immunofluorescent (DIF) studies wastes an opportunity to collect potentially valuable information; moreover, the finding of IgA vascular deposits is the sine qua non of HSP and adult IgA vasculitis. Similar to haematoxylin and eosin (H&E) evaluation, the presence of diagnostic immunofluorescence patterns is inversely related to the age of the lesion biopsied. In cases of immune complex (IC)-mediated vasculitis, 100% of biopsies will harbour immunoglobulins within the first 48 h, 70% will be positive at 48–72 h, and after 72 h immunoglobulins will not be detected; however, complement can still be detected in >50% vasculitic lesions after 72 h.22
Histological findings of vasculitis
Many different types of injury, immune mediated (e.g. IC deposition), toxin mediated or due to direct infection, can cause identical responses in the vessel wall resulting in the morphologic pattern of fibrinoid necrosis, diagnostic of vasculitis.1,23 Common to all these aetiologies is activation of neutrophils and abnormal neutrophil diapedesis. Other morphological patterns of vasculitis include lymphocytic endarteritis and endarteritis obliterans of transplant vascular rejection, which are not generally associated with abundant fibrin deposits and destruction of the vessel wall with loss of the elastic lamina.24,25 Adding to the difficulties in histological evaluation of vasculitis is that vasculitis is a dynamic process where the characteristics of the initial insult are lost during the process of repair. This evolution also probably represents a final common morphological pathway that includes transformation from active, acute inflammatory lesions into older, often sclerotic lesions where T cells and macrophages predominate and neovascularization has transpired to compensate for the ischaemic insult. Nonetheless, the type of inflammatory cell mediating vessel damage and vessel size affected roughly correlates with pathogenic mechanisms. (For review of pathogenesis of cutaneous vasculitis see Carlson et al.1
The diagnosis of cutaneous vasculitis of small and medium-sized/muscular vessels is made primarily by biopsy and examination of H&E-stained sections1Table 2 lists criteria for diagnosis of cutaneous vasculitis. Fibrinoid necrosis (fibrin deposition within and around the vessel wall) is a common histological feature of nearly all early vasculitic lesions and is due to the accumulation of plasma proteins, including coagulation factors that are converted to fibrin, at sites of vessel wall destruction. The diagnosis of vasculitis can be unequivocally be made if there are inflammatory infiltrates within and around the walls of vessels accompanied by fibrin deposition (see Figure 4). These changes commonly coexist with signs of endothelial damage in the form of endothelial swelling, shrinkage (apoptosis) and/or sloughing (see Figure 5). As the media of muscular vessels is not the site of inflammatory diapedesis, the finding of inflammatory cells infiltrating the adventia and media, or disrupting the endothelium (endothelialitis) are de facto signs of vasculitis (see Figure 6). Recently, the evolution of cutaneous PAN, a neutrophilic muscular vessel vasculitis, has been divided into four stages26: (i) the acute stage shows endothelial loss and fibrin thrombi with neutrophil infiltration without obvious internal elastic lamina disruption or medial fibrinoid necrosis; (ii) the subacute stage has mixed neutrophilic, macrophage and lymphocytic infiltrates associated with an intimal target-like fibrinoid necrosis, which also extends through disrupted regions of internal elastic lamina into the media; (iii) the reparative stage shows intimal fibroblastic proliferation and perivascular neovascularization with predominant infiltrates of macrophages and lymphocytes; and (iv) the final, healed stage has minimal inflammation and shows fibrointimal occlusion of the lumen (endarteritis obliterans) (see Figure 7). This last stage typically shows a sharply defined region of loss of the internal elastic lamina. This finding of lamina disruption, in the absence of inflammation and associated with acellular scar tissue, indicates the healed stage of muscular vessel vasculitis. When endarteritis obliterans (fibrointimal stenosis or occlusion) is associated with an intact elastic lamina, the differential diagnosis includes vasculitis (lymphocytic type) and non-vasculitic disorders such as atherosclerosis, diabetes, hypertension, radiation or toxin exposure, thrombotic disorders, and embolic disorders1,6,27 (see Figure 8). Healed lesions of muscular vessel vasculitis can be associated with either progressive luminal stenosis or aneurysm formation if there is persistence of vessel wall inflammation.
Table 2. Histological diagnostic criteria for cutaneous vasculitis and associated histologies
Secondary changes of active vasculitis (suggestive of, but not diagnostic of vasculitis)†
RBC extravasation (petechiae, purpura, hematoma)
Nuclear dust, perivascular (leukocytoclasia)
Endothelial swelling, sloughing or necrosis
Eccrine gland necrosis (or regeneration with basal cell hyperplasia)
Histological sequelae of vasculitis (chronic signs and healed lesions of vasculitis)
Lamination (onion-skinning) of vessel wall constituents†
Luminal obliteration (endarteritis obliterans)†
Segmental or complete loss of elastic lamina in medium and large vessels associated with acellular scar tissue*
Neovascularization of adventitia
Histological patterns associated with systemic vasculitis and/or indicative of aetiology
Lamellar or storiform fibrosis
Palisaded and neutrophilic granulomatous dermatitis (red or blue collagenolytic granuloma)
Vacuolar interface dermatitis (sometimes with dermal mucin deposition)
‘Pustular’ dermatosis with intraepidermal or subepidermal neutrophilic abscesses
Most of the pathology described above occurs relatively acutely, over days, weeks or months. However, in some cases of endarteritis obliterans due to vasculitis, the luminal stenosis and eventual occlusion probably occurs over years. The stages of this slowly progressive vessel destruction have been documented by examining the natural history of Sneddon’s syndrome, an ischaemic, neurocutaneous disorder.28,29 Initially, a lymphocytic endothelialitis (endarteritis) is evident that is followed by the formation of a sponge-like plug composed of mononuclear cells, fibrin, and red blood cells that results in partial to complete obstruction. A perivascular lymphohistiocytic (non-neutrophilic) inflammatory infiltrate develops around affected arteries, which is then followed by formation of dilated capillaries in obstructed vessels’ adventitia (i.e. neovascularization). Smooth muscle cells immigrate and proliferate in the subendothelial zone, organizing the occluding plug during the intermediate stage. The final stage is characterized by fibrosis, shrinkage, and atrophy of the occluded artery.
Secondary changes in which vascular damage can be inferred are the histological findings of extravasation of red blood cells (purpura), necrosis (infarct) and ulceration secondary to the ischaemia from vessel obstruction or destruction by the inflammatory insult. These findings are not specific to vasculitis as they frequently occur in vaso-occlusive disorders6 (see Figure 9). Other indirect evidence of vessel wall damage, thus vasculitis, includes perivascular nuclear dust (leukocytoclasia) without fibrin deposits found in early lesions of LCV and urticarial vasculitis (UV) (Figures 3 and 10); concentric (so-called onion skinning) or patterned (storiform or lamellar) fibrosis seen in chronic localized forms of cutaneous LCV (e.g. granuloma faciale, erythema elevatum dinutum and inflammatory pseudotumours)30 and found in some lesions of WG31,32 (Figure 11); and neovascularization of the adventitia, which is a prominent feature of mature and older lesions of medium vessel vasculitis such as PAN and giant cell arteritis (Figure 12). Reactive angioendotheliomatosis is part of the spectrum of neovascularization and can be seen secondary to medium vessel vasculitis such as PAN or vaso-occlusive disorders.33 It is characterized by diffuse or lobular proliferations of capillaries in the dermis, often with fibrin microthrombi, reactive, fasciitis-like dermal alterations, and foci of epithelioid endothelium (see Figure 13). The livedoid pattern or atrophie blanche pattern overlying cutaneous PAN34 may represent a variant of reactive angioendotheliomatosis.
It is not uncommon to find changes of neutrophilic small vessel vasculitis underlying an ulcer formed by another process (trauma or surgery) (see Figure 14). This is incidental vascular injury and can usually be differentiated from primary vasculitis by correlation with history and the focal nature of the vessel damage that is restricted to the area of trauma, scarring or ulceration; the vessels in the surrounding skin will be unaffected. [The term secondary vasculitis is not used as it refers to vasculitis developing secondarily in a systemic disease, e.g. lupus vasculitis (LV) developing in longstanding SLE]. Neutrophilic dermatoses [e.g. neutrophilic dermatosis of the dorsum of hands (also known as pustular vasculitis)] can also exhibit neutrophil-mediated vessel damage that can resemble LCV in a minority of cases.1,35 In these instances, the foci of incidental vasculitis typically affect vessels within the diffuse dermal neutrophilic infiltrate in contrast to the angiocentric neutrophilic infiltrate of authentic LCV.
Other histological findings associated with vasculitis
Some cutaneous vasculitis patients with systemic disease will exhibit histological findings concomitant to the vasculitis that will point to aetiology and or diagnosis, such as granulomatous dermatitis, dermal eosinophilia, or dermal neutrophilia (see Table 3 and Figure 15). Eosinophilic or ‘red’ extravascular granulomas (palisaded neutrophilic granulomatous dermatitis with eosinophils) are found in the papular and nodular extremity lesions of CSS. Early ‘blue’ extravascular granulomas (palisaded neutrophilic granulomatous dermatitis) are found in some papular and nodular lesions in RV and WG. Sub- and intraepidermal pustules are seen in the case of cutaneous vasculitis triggered by bacterial pharyngitis as well as in septic vasculitis.
Table 3. Specific vasculitis syndromes implicated by clinical and pathological findings
Suspected systemic vasculitis syndrome
*Purpura plus ulcers, nodules, bullae, and/or livedo reticularis.
The absence of ICs, or minimal IgG and/or C3, so-called pauci-immune vasculitis, is the expected finding in WG, CSS and MPA. Deposition of IgG, IgM, IgA and/or C3 in or around the vessels characterizes IC-mediated vasculitis such as CV and most cases of CLA. The most common immunoreactant found in vessels by DIF is C3, followed by IgM, IgA and IgG.1,2 Fibrinogen vascular deposits are also commonly found. The type of immunoglobulin and pattern of deposits in DIF examinations can add diagnostic value: predominate IgA vascular deposits are found in HSP (Figure 2) and renal involvement should be evaluated. Basement membrane zone or keratinocyte nuclear [in vivo antinuclear antibodies (ANA)] immunoreactants, mostly IgG, can be found in CTD vasculitis such as lupus vasculitis. In the evaluation of UV, the finding of basement membrane zone immunoreactants may be seen in patients with hypocomplementaemic states and who have CTD. In addition, IgM deposition in blood vessels may be readily seen in cases of vasculitis with a circulating rheumatoid factor (RF) or with monoclonal production of IgM, as found in CV or RV.
Anti-neutrophil cytoplasmic antibody testing
ANCA testing has been established as a useful adjunctive tool for the diagnosis of small vessel vasculitis.1,2 In addition, serial measurement of ANCA levels can be used to monitor disease activity or to predict the risk for relapse.36 ANCA-associated vasculitides include WG, MPA, CSS and some drug-related vasculitis, but ANCA can be also found in patients with inflammatory bowel disease, CTD and other chronic inflammatory diseases, some of whom may have vasculitis. Positive ANCA patterns should be separated into perinuclear (p)-ANCA and cytoplasmic (c)-ANCA. p-ANCA may be seen with myeloperoxidase (MPO) antibodies as well as others (e.g. lactoferrin, cathepsin) and is found in MPA and CSS. c-ANCA are mostly anti-proteinase-3 (PR3), which is strongly associated with WG. However, the presence of ANCA is not diagnostic of systemic vasculitis, as some cases of cutaneous LCV have a positive ANCA and limited skin disease, and ANCA are found at low levels in many systemic inflammatory and pulmonary disorders that mimic vasculitis. In this latter group, atypical indirect immunofluorescent patterns are present and antibodies to PR3 and MPO are rare by antigen-specific enzyme-linked immunosorbent assay testing.
Differential diagnosis (pseudovasculitis)
As the clinical manifestations of vasculitis are protean, and diagnosis is based on a constellation of clinical, histological, imaging and laboratory features, it is not surprising that non-vasculitis disorders can mimic vasculitis.6 Cutaneous pseudovasculitis represents a heterogeneous collection of disorders that are capable of simulating cutaneous vasculitis and can be broadly classified into diseases that produce haemorrhage (petechiae, purpura and ecchymoses) or vessel occlusion with resultant livedo, cyanosis, ulcers, digital necrosis and/or gangrene. Overlap is not uncommon, but, if present, one mechanism dominates. Haemorrhagic pseudovasculitis is due to vessel wall dysfunction (incompetence), which can be related to diverse factors that include vessel wall deposition of metabolic substances (amyloid, calcium), nutritional deficiencies (scurvy), non-vasculitic inflammatory purpura (pigmented purpuric dermatitis, arthropod, viral and drug reactions, degeneration of the vessel wall and supporting stroma (senile/solar purpura), direct vessel wall invasion of infective organisms, coagulation-fibrinolytic disorders (e.g. thrombocytopenia), and vessel wall trauma. Cyanotic-infarctive pseudovasculitis is due vaso-occlusion by emboli, thrombi, or fibro-intimal hyperplasia (endarteritis obliterans) and includes varied conditions such as purpura fulminans, Coumadin necrosis, antiphospholipid antibody syndrome, cardiac myxoma, cholesterol embolization, calciphylaxis, and radiation arteritis. Table 4 lists common, uncommon and rare pseudovasculitic disorders. The diagnosis of a pseudovasculitic disorder requires a high index of suspicion and should always be part of the differential diagnosis of vasculitis. Skin biopsy is a crucial step in differentiating pseudovasculitis from authentic vasculitis (Figure 9); absence of histological evidence of vasculitis, particularly after multiple biopsies, should direct evaluation and diagnosis towards a pseudovasculitis. Other signs that that should raise suspicion for pseudovasculitis are the presence of severe atherosclerosis, cardiac murmur, livedo racemosa, the absence of inflammatory markers (e.g. normal erythrocyte sedimentation rate), abnormal eating habits (e.g. chronic alcoholism) and isolated vascular lesions on imaging studies6 (see Figure 9).
Table 4. Mimickers of cutaneous vasculitis (pseudovasculitis)
Adapted from Carlson and Chen6 and Chen and Carlson.2
Lucio’s phenomenon (endothelial swelling due to mycobacteria leprae)
Antiphospholipid antibody syndrome (APS)
Thrombotic thrombocytopenic purpura
Less frequent than vasculitis
Warfarin (coumarin)-induced skin necrosis
Disseminated intravascular coagulation
Monoclonal gammopathy (1° cryoglobulins)
Less frequent than vasculitis
Sickle cell disease
Vasospasm (drug induced)
Hypothenar hammer syndrome
Less frequent than vasculitis
Vessel wall pathology
Histology of cutaneous vasculitis syndromes
Cutaneous leukocytoclastic angiitis
The diagnosis of idiopathic CLA is based on the exclusion of predominant IgA vascular deposits, visceral disease, co-existing systemic disease, and antecedent infection or drug ingestion.1–3 On biopsy, a small vessel neutrophilic vasculitis affecting the superficial dermal plexus will be found, and DIF examination will show both complement and immunoglobulins in vessel walls (typically small granular deposits of IgG, IgM and C3). Rarely, CLA exhibits shows necrotizing venulitis throughout the mid- and deep dermis manifested as indurated erythema, and haemorrhagic bullae on the lower legs; some of these patients may have systemic disease, renal or gastrointestinal (<10%).37,38 It has been suggested to classify this variant of systemic vasculitis as ‘LCV with perivascular deposition of IgG/IgM with systemic involvement’.39
IgA-associated vasculitis, HSP, compromising about 10% of all cases of cutaneous vasculitis, is the most common vasculitis in children (∼90% of all cases).1–3 On biopsy, most patients will show a small-vessel neutrophilic vasculitis restricted to the superficial dermis, although whole dermis will be involved occasionally.40 Features with high sensitivity and specificity for the diagnosis of HSP are isolated or predominant IgA vascular deposits, and two or more of these clinical features: age ≤20 years, gastrointestinal involvement (colicky pain or haematochezia), upper respiratory tract infection prodrome, and/or haematuria or renal biopsy showing mesangioproliferative glomerulonephritis with or without IgA deposits.
About a fifth of all episodes of cutaneous vasculitis represent an adverse drug eruption (i.e. hypersensitivity vasculitis), which on biopsy will show a superficial dermal small-vessel neutrophilic or lymphocytic vasculitis.1–3,41 Concurrent tissue eosinophilia is a clue to a drug aetiology.42
About 20% of patients presenting with chronic urticaria will have UV. UV patients have painful, tender, burning or pruritic papules and plaques affecting any cutaneous surface, and which persist >24 h and <72 h, and in some cases leave residual purpura or hyperpigmentation.1–3 UV patients do not have fully developed lesions of LCV; either focal nuclear debris or vascular fibrin deposits, with or without extravasated red blood cells, will be evident3,43 (see Figure 10). Tissue neutrophilia and DIF showing a positive lupus band test point to hypocomplementaemic UV, a condition associated with CTD, frequently SLE or Sjögren’s syndrome.
All types of infectious agents have been associated with the development of vasculitis (viruses, bacteria, fungi, protozoa, and helminthes).1–3 The cutaneous pathology most often found in these cases is a small-vessel neutrophilic vasculitis affecting superficial dermal vessels. Infection-triggered LCV is suspected to show a greater frequency of subcorneal, intraepidermal and subepidermal neutrophilic pustules, tissue neutrophilia, predominant IgA vascular deposits, and have relatively less eosinophils and lymphocytes compared with idiopathic CLA and drug-related cutaneous LCV.40
Septic vasculitis is a variant of small-vessel neutrophilic vasculitis that is typically IC – and is caused by infective endocarditis and septicaemia.1–3 On biopsy, mixed neutrophilic small and muscular vessel vasculitis with deep dermal and subcutaneous vessel involvement is found and associated with scant perivascular fibrin or fibrin thrombi, and no or little nuclear debris; these features help differentiate between septic vasculitis and conventional CLA.
Cutaneous vasculitis occurring in the presence of cryoglobulins is classified as CV, either associated with hepatitis C infection or less frequently CTD.1–3 In most cases, skin biopsy will show a small vessel neutrophilic vasculitis equally affecting superficial dermal and subcutis vessels, and in a minority of cases neutrophilic muscular vessel vasculitis (PAN-like). DIF demonstrates vascular immunoglobulins, mostly IgM, and/or complement deposits.
Connective tissue disease vasculitis
Secondary vasculitis due to CTD should be considered in patients presenting with biopsy-proven cutaneous vasculitis who have signs and symptoms of dry eyes or mouth, arthritis, sclerosis, photosensitivity, or serological evidence of ANA, RF, antiphospholipid antibodies, or anti-DNA, Ro or La antibodies;1–3 CTD vasculitis occurs frequently in SLE, RA and Sjögren’s syndrome, and less commonly in dermatomyositis, scleroderma, and polychondritis.1,3,20 In general, CTD vasculitis shows more widespread organ involvement and mixed small and muscular vessel involvement. Arterioles and post-capillary venules are the most commonly affected by vasculitis, manifested as purpura, vesiculobullous lesions, urticaria, and splinter haemorrhages. One should suspect arterial involvement if cutaneous ulcers, nodules, digital gangrene, (necrotizing) livedo racemosa, punctate acral scars, or pyoderma gangrenosum-like lesions are present; these patients have a higher probability of visceral vasculitis. Skin biopsy shows a mixed, mostly small and, less commonly, muscular vessel neutrophilic vasculitis with lesions that can resemble either typical CLA or PAN; the coexistence of small and muscular vessel vasculitis in the same biopsy specimen or different lesional skin is a characteristic feature of CTD vasculitis. Extravascular histologies can provide a clue to diagnosis of CTD vasculitis, such as the presence of interface dermatitis (e.g. SLE and dermatomyositis), dermal and/or subcutaneous sclerosis in scleroderma, palisaded neutrophilic and granulomatosis dermatitis in RV or LV, and tissue neutrophilia (neutrophilic urticaria) in SLE and Sjögren’s syndrome.
ANCA + primary systemic vasculitis
Approximately 5% of all patients presenting with cutaneous vasculitis will have PSV: mostly WG, CSS or MPA.1–4,44 Histologically identical small-vessel neutrophilic vasculitis is the most prominent feature of these PSV, which can all manifest as palpable purpura, pulmonary haemorrhage, mononeuritis and/or glomerulonephritis of varying severity. ANCA, p-ANCA and/or c-ANCA are identified in most cases. From one-third to one-half of patients presenting with palisaded and neutrophilic granulomatous dermatitis have co-existing primary systemic vasculitis; small-vessel neutrophilic vasculitis is often found in the same sample, implicating a relationship between vasculitis and granulomatous inflammation.
Less than 15% of WG will present with cutaneous disease; however, up to 50% will develop cutaneous lesions during the course of disease.1–3 Three categories of cutaneous disease exist in WG3: (i) palpable or non-palpable purpura due to LCV found in 60% of WG with cutaneous disease; (ii) subcutaneous nodules, ulcers and digital infarcts (gangrene) secondary to medium-vessel vasculitis in 31%; and (iii) polymorphic lesions, produced by neutrophilic and/or granulomatous infiltrates, consisting of rheumatoid papules [papules and nodules (necrotic over extensor surfaces, often the elbows)], pyoderma gangrenosum-like ulcers (also known as malignant pyoderma), urticaria, vesiculobullous lesions, and gingival hyperplasia (strawberry gingivitis) in 17%. Proposed criteria for the diagnosis of WG include biopsy or surrogate marker (infiltrates or cavities) for granulomatous inflammation of the respiratory tract, biopsy-verified necrotizing vasculitis in small to medium-sized vessels or biopsy/surrogate marker for glomerulonephritis/proteinuria and haematuria, and/or positive c-ANCA.
CSS is characterized by the presence of asthma, usually of adult onset, and other allergic symptoms (allergic rhinitis), peripheral and tissue eosinophilia, and systemic vasculitis.1–3 Cutaneous biopsy reveals three broad categories of changes, which can frequently be identified together: (i) palpable purpura, petechiae, ecchymoses, livedo racemosa and/or haemorrhagic bullae vasculitis due to small-vessel eosinophil-rich neutrophilic vasculitis affecting both dermal venules and arterioles and, less commonly, muscular vessel eosinophil-rich arteritis or histiocyte-rich granulomatous arteritis in dermo–subcutaneous junction or subcutis; (ii) urticarial plaques due to dermal eosinophilia; and (iii) dermal and subcutaneous papules and nodules often located on the scalp or symmetrically distributed over the extremities produced by palisading neutrophilic and granulomatous dermatitis with either neutrophilic debris among basophilic degenerated collagen bundles, or abundant eosinophils and eosinophilic granules and debris coating degenerated collagen bundles (‘red’ granulomas).3,45,46
MPA is defined as systemic neutrophilic small-vessel vasculitis without extravascular granulomas or asthma. The skin lesions found in MPA include palpable purpura and petechiae in more than three-quarters of patients, and in the remainder splinter haemorrhages, nodules, palmar erythema and/or livedo. The criteria for diagnosis of MPA are the findings of lack of biopsy or surrogate markers of granulomatous inflammation (e.g. lung cavities or infiltrates of >1 month’s duration), biopsy confirmation of neutrophilic small-vessel vasculitis and/or glomerulonephritis with few or no immune deposits, and involvement of more than one organ system documented by biopsy or surrogate marker such as proteinuria and haematuria for glomerulonephritis.
Cutaneous polyarteritis nodosa
Cutaneous polyarteritis nodosa (CPAN) should be suspected in patients presenting with tender nodules, livedo vasculopathy, livedo racemosa, ulcers, acral gangrene and/or neuropathy.1,2,4 Deep punch or incisional biopsy to fascia will demonstrate neutrophilic muscular vessel vasculitis at arterial branch points, located either at the dermal–subcutis junction or within the subcutis. Recently, two entities have been described that show clinical features of CPAN, but a lymphocytic arteritis on biopsy: macular arteritis47–50 and lymphocytic thrombophilic arteritis.51 These variants of vasculitis may simply represent latent or late evolutionary stages of CPAN.47
Nodular vasculitis (erythema induratum of Bazin) and thrombophlebitis can be clinically or pathologically mistaken for CPAN.1,2,4 Nodular vasculitis is a lobular panniculitis and vasculitis affecting mostly venules or septal veins and less commonly arteries.52 In contrast, CPAN is an arterial vasculitis with minimal extension of its inflammation into the adjacent subcutis. To differentiate between venous and arterial vasculitis, the pattern of elastic tissue distribution and vessel silhouette is a diagnostic aid.53,54 Veins are oval blood vessels, which lack an internal elastic lamina, and have collagen intermixed with smooth muscle bundles and elastic fibres; in contrast, an artery is a round muscular vessel with a continuous wreath of smooth muscle fibres intermixed with few or no elastic fibres, and will show an intact, fragmented or discontinuous internal elastic lamina.
Vasculitis presents with protean clinical manifestations; has a wide spectrum of clinical presentations ranging from benign, single episode, cutaneous vasculitis to progressive, lethal, systemic, multiorgan vasculitis (Table 1); has numerous mimics (Table 4); and can occur as a primary or secondary disorder to various medical conditions, the treatment of which differs. It follows that a rational approach is required for the evaluation of patients with suspected vasculitis.1,2,5,6,55 Therefore, in the assessment of a patient presenting with cutaneous vasculitis, histological verification and accurate histological classification are the first steps in arriving at a reproducible diagnosis of specific vasculitis syndrome. DIF and indirect IF serological evaluation to detect and identify vascular immunoglobulins and/or ANCA, respectively, are the next steps. The final steps involve correlating these data with clinical evaluation for systemic disease and pertinent laboratory studies to classify accurately the type of cutaneous vasculitis. Accurate and reproducible diagnosis will result in efficacious management of cutaneous vasculitis patients.1,2,5