A. N. Crowson, MD, Regional Medical Laboratory, St. John Medical Center, 1923 S. Utica, Tulsa, OK 74114, USA Tel: 918-744-2553 Fax: 918-744-3327 e-mail: email@example.com
As the skin is commonly involved in systemic vasculitic disorders as well as those hypersensitivity states whose expression is largely skin-confined, cutaneous vasculitic lesions offer a window to diagnosis and a ready source of accessible tissue for biopsy. In this review, we discuss the pathologic manifestations of chronic vasculitic syndromes such as granuloma faciale and erythema elevatum diutinum; IgA-associated vasculitis including Henoch-Schonlein purpura; vasculitis seen in the setting of cryoglobulinemia and hypergammaglobulinemia of Waldenstrom, hereditary deficiencies of complement, and IgA deficiency; those leukocytoclastic vasculitides resulting from hypersensitivity reactions to drug, chemical and foodstuff ingestion; and those vasculitides seen in patients with systemic diseases such as polyarteritis nodosa, rheumatoid arthritis, mixed connective tissue disease, systemic lupus erythematosus, Sjogren's syndrome, relapsing polychondritis, Behcet's disease, Wegener's granulomatosis, and allergic granulomatosis of Churg and Strauss.
Systemic vasculitides constitute a significant diagnostic challenge in the inpatient and ambulatory care settings. Accurate diagnosis requires a careful integration of clinical findings with the results of serologic, pathologic and diagnostic imaging studies. The skin is commonly involved in vasculitic disorders reflecting systemic disease states as well as in the context of hypersensitivity disorders in which disease expression is largely confined to the skin. The skin therefore offers a window to diagnosis and affords a ready source of accessible tissue for biopsy. With respect to disease mechanisms, the skin manifests a spectrum of vasculitides that reflect injury by circulating immune complexes, antiendothelial cell antibodies, and cell mediated immunity (CMI). Arthus type III reactions occur when antigen complexed to IgG or IgM activates the direct complement cascade sequence; a leukocytoclastic vasculitis (LCV) is the hallmark.1–4 The type II immune mechanism is operative when antibodies directed against endothelial antigenic targets such as in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis, scleroderma and Behcet's disease (BD) generate what is typically a pauci-inflammatory thrombogenic vasculopathy and/or a lymphocytic vasculitis. A type IV (CMI) immune reaction may be the operative mechanism underlying a granulomatous vasculitis in the setting of Crohn's disease, sarcoidosis, postherpetic zosteriform eruptions, tuberculosis and lymphoproliferative disease. Identification of the type and calibre of vessels involved and the pattern of inflammation is integral to isolating the etiology.5 A vasculitis confined to capillaries and post capillary venules of the superficial plexus is typical for LCV related to ingestion or exposure to drugs, chemicals, foodstuffs and low-grade infection.6 Neutrophilic and/or lymphocytic infiltrates with mural necrosis and thrombosis of capillaries and venules throughout the sampled dermis is prototypically seen in cases of acute and chronic septic vasculitis, systemic vasculitic syndromes and connective tissue disease (CTD). Vasculitis confined to the subcutaneous fat may be observed in benign cutaneous polyarteritis nodosa (PAN) and in superficial migratory thrombophlebitis, the latter a manifestation of certain systemic diseases such as BD, Buerger's disease, underlying malignancy and lupus anticoagulant. The vasculitides are broadly classified in Table 1.7
Table 1. Modified Lie classification of vasculitis (after Bonsib, 2001)7
A. Infectious angiitis
B. Noninfectious angiitis
Involving large, medium-sized, and small vessels
Granulomatous (giant cell), Cranial (temporal) and Extracranial giant cell arteritis
Arteritis of rheumatic diseases and spondyloarthropathies
Involving medium-sized and small vessels
Pathergic-allergic granulomatosis and angiitis
Necrotizing sacroid granulomatosis
Vasculitis of collagen vascular disease
Systemic lupus erythematosis
Involving small vessels
Inflammatory bowel disease
Primary biliary cirrhosis
The classification of LCV involving small vessels in the skin is broad. It encompasses serum sickness,6 chronic vascultic syndromes such as granuloma faciale and erythema elevatum diutinum,8–13 IgA-associated vasculitis including Henoch Schonlein purpura (HSP) (Fig. 1),14–22 abnormal serum proteins including cryoglobulinemia and hypergammaglobulinemia of Waldenstrom,23–28 hereditary deficiencies of complement,29–31 IgA deficiency, 32 drug, chemical and foodstuff ingestion,33–35 systemic diseases such as PAN,36–40 RA,13,41–50 mixed connective tissue disease,51 systemic LE,30,52–54 Sjogren's syndrome (SS), relapsing polychondritis,55 BD,56,57 Wegener's granulomatosis (WG),58–61 allergic granulomatosis of Churg and Strauss (AGCS),4,62 inflammatory bowel disease (IBD),34 and infection. With respect to the LCVs of infection-based etiology, one must consider those to include id reactions to non-viable microbial antigens in the context of streptococcus, staphylococcus, hepatitis B and C, influenza, cytomegalovirus, parvovirus B19 and Mycobacterium sp. infection,20,34,65–78 as well as septic vasculitides resulting from hematogenous dissemination of viable microbes. In one study from Spain, where the incidence of hepatitis C seropositivity is 0.8%, some 24% of cases of LCV were related to hepatitis C (19%) or B (5%) infection,34 while 10% reflected underlying malignancy, and 9% an underlying CTD.34
Drug-induced leukocytoclastic vasculitis
Drug-based etiology is implicated in approximately 10–24% of cases of LCV. 34,35 The most frequently implicated agents are propylthiouracil, dilantin, quinidine, sulfonamides, penicillins, and allopurinol.34,35 In addition, roughly six per cent of patients with chronic cyclic neutropenia receiving granulocyte colony stimulating factor develop vasculitis within one week of recovery of their absolute neutrophil count.33 Although some cases of drug-induced LCV manifest a severe pan-dermal and/or pustular vasculitis, such as those associated with calcium channel blockers and carbamazepine, the typical drug-induced LCV is mild in character and is confined to the superficial vascular plexus.
Urticarial vasculitis and serum sickness
Urticarial vasculitis manifests recurrent episodes of raised edematous weals with blanchable erythema, which typically last from 24 to 72 h and are associated with pigmented residua and episodic arthritis.30,79 This condition results from complement activation and may reflect a variety of underlying CTDs, most commonly LE and SS, C1q esterase inhibitor deficiency, underlying malignancy, and circulating immune complexes containing an antigen that may be exogenous, such as a drug, or endogenous, such as a cryoprecipitate.30 The identification of an exogenous antigen does not exclude the possibility that a given patient may have a predisposing CTD diathesis. The syndrome of serum sickness comprises fever, lymphadenopathy, arthralgia, peripheral neuropathy, cutaneous vasculitis, and renal disease, and typically occurs within 10 days of administration of heterologous serum in vaccines or antithymocyte globulin, intravenous and intracoronary streptokinase, drugs such as penicillin, sulfapyridine, sulfonamides, streptomycin, thiouracil and hydantoin and, exceptionally, insults such as mosquito bites.80 Patients may experience pain at the injection site 3 days before onset of the fully expressed syndrome. Urticarial vasculitis and serum sickness both prototypically manifest an interstitial and perivascular neutrophilic infiltrate accompanied by slight leukocytoclasia and mild injurious vascular alterations, although when large amounts of serum are used vasculitis may be intense.
Chronic cutaneous LCV syndromes
Granuloma faciale is a localized craniofacial LCV that presents as recurrent brown-red plaques on the forehead, cheeks, and ears.8 Similar lesions of the upper aerodigestive tract are termed eosinophilic angiocentric fibrosis.81 Angiocentric mixed nodular inflammatory infiltrates with leukocytoclasia and mural fibrin deposition involve the mid dermis and spare the deep, papillary and adventitial dermis and subcutis (Fig. 2). Mononuclear cells and plasma cells may predominate, imparting a pseudolymphomatous appearance to the more florid examples. Laminated angiocentric fibrosis with diminution in the intensity of the inflammation typically ensues with advanced lesional age. In the nasal cavity, this process results in a nodular onion-skin pattern of hyalinization, which produces a distinctive morphology.
Erythema elevatum diutinum
The symmetrical localization of disease in erythema elevatum diutinum (EED) is typically to the extensor surfaces of joints and occasionally the buttocks, and manifests as papules which progress to larger annular lesions. The older lesion is an elevated red, purple, or brown plaque. The cutaneous manifestations and the arthralgia respond dramatically to dapsone and sulphonamides.9,10,12 Early lesions manifest angiocentric neutrophilic infiltrates with leukocytoclasia and only minimal fibrin deposition in the vessels of the upper and mid dermis. Characteristic is a prominent extravascular infiltrate of neutrophils and lymphocytes with a minor population of eosinophils, plasma cells, or lipid-laden histiocytes, thus the alternate designation of extracellular cholesterolosis. Older lesions manifest as a nodular angiocentric eosinophilic fibrous homogenization of the dermis associated with capillary proliferation. One putative antigen source in EED may derive from bacteria of Streptococcus sp., as is suggested by the striking immunoreactivity seen after intradermal skin testing with streptokinase and streptodornase. Lesions of EED are also associated with underlying IgA myeloma, myelodysplasia and acute myelogenous leukemia11 IBD, relapsing polychondritis, and RA. Other syndromes that combine a LCV with prominent extravascular neutrophilia include WG, septic vasculitis, IBD, BD, and RA.41,45,56 The dermal fibrogenesis is postulated to reflect activation of factor XIIIa-expressing dermal dendrocytes.82
Systemic neutrophilic vasculitic syndromes with cutaneous LCV
The principal systemic vasculitic syndromes are PAN, Kawasaki's disease, mixed cryoglobulinemia, LE, RA, BD, WG, and AGCS.4,59,60,62,83 All of these systemic vasculitic syndromes can demonstrate a necrotizing cutaneous LCV and in some cases cutaneous involvement may be their initial manifestation.
The two major forms of systemic systemic polyarteritis nodosa (PAN) are macroscopic PAN (MaPAN) and microscopic PAN (MiPAN). Some authorities prefer to designate the latter as ‘microscopic polyangitis’ and the former as ‘polyarteritis nodosa’ without further modifiers, terminology that reflects the size of the blood vessels involved and that is perhaps, in consequence, more appropriate.84 There is also a distinctive cutaneous vasculitis, benign cutaneous PAN, in which a morphology resembling the extracutaneous small artery disease of MaPAN may be present but in which systemic organ involvement is typically absent.8,36 Kawasaki's disease, an acute vasculitic syndrome of infancy, is considered a variant of MaPAN. 85
Macroscopic polyarteritis nodosa
Macroscopic PAN is a necrotizing segmental vasculitis involving vessels ranging from arterioles to medium-sized arteries, which typically affect men in the 5th decade of life. Typically, MaPAN manifests as a segmental necrotizing vasculitis in which fibrinoid necrosis of the media and destruction of the internal elastic lamina is accompanied by mural infiltration initially by neutrophils and later by mononuclear cells. The result of this vascular insult is intimal fibroblastic proliferation, secondary thrombosis, aneurysmal dilatation and infarction. The reparative response is characterized by replacement of the media by granulation and fibrous tissue. The pathology of this segmental arteriopathy varies with the phase of the process, as the early and late lesions involve different foci of the same artery. In any given area not all vessels are affected, nor are they in the same temporal lesional phase. Skin manifestations are infrequent and comprise a severe pandermal LCV involving venules that frequently extend into the subcutis to involve small arteries and arterioles. A dominant localization to medium-sized vessels of the subcutis defines the histomorphology of benign cutaneous PAN, which is generally unaccompanied by internal organ disease (Figs. 3 and 4).
Kawasaki's disease most commonly affects infants in a seasonal fashion and manifests as fever, conjunctival congestion, reddening of the oropharynx and lips, induration of acral parts, desquamation of the toes and fingers with palmar erythema, a polymorphous rash over bony areas, trunk and extremities, and lymphadenopathy.85 Five of the aforementioned features are required to make the diagnosis. The morbidity and mortality reflects the development of a PAN-like vasculitic syndrome involving coronary, iliac and cerebral arteries. Failure of resultant aneurysmal lesions to regress correlates with longer duration of the acute febrile phase and an age at onset of more than 2 years. There is a subacute form that exhibits myocarditis, arthritis and thrombocytosis. A minority of patients manifest an arteritis that involves the skin. 86 The histopathology of the skin rash is not well defined but includes a psoriasiform dermatitis and an erythema multiforme-like interface injury pattern. Homology between microbial antigens and endogenous heat-shock proteins has been suggested as the possible pathogenetic basis, whereby possible infective triggers include viruses such as Epstein–Barr virus and bacteria including pseudomonas, streptococcus, staphylococcus, and rickettsia.
Skin involvement is frequent in patients with MiPAN, 39,40 which manifests as a necrotizing vasculitis involving capillaries, venules, and arterioles in patients who often have a focal segmental necrotizing glomerulonephritis. Lung and nasopharyngeal involvement is common, characterized clinically in the former instance by hemoptysis as a result of a neutrophilic capillaritis, and in the latter by oral ulceration, sinusitis and epistaxis. The skin pathology comprises a severe pandermal LCV, which differs from that of WG by the absence of extravascular inflammation (Fig. 5). A patient who is seropositive for a perinuclear antineutrophil cytoplasmic antibody (pANCA) with myeloperoxidase specificity and who has a pulmonary/renal vasculitic syndrome almost invariably represents a case of MiPAN. Those patients who have MiPAN with cytoplasmic (c)ANCA positivity and a pulmonary/renal vasculitic syndrome may be difficult to separate from WG clinically. This distinction is based on the absence microscopically of extravascular inflammation including in the context of palisading granulomata. Immune complexes are generally not implicated in idiopathic PAN, although a PAN-like immune complex-based vasculitis has been reported with intravenous drug abuse, CTD, and infection by cytomegalovirus, hepatitis B and Streptococcus sp.
Cryoglobulins, which are normally present in small amounts in serum, may be present in high concentration in the setting of multiple myeloma, Waldenstrom's macroglobulinemia, mycosis fungoides, chronic lymphocytic leukemia, CTDs such as RA, SLE and SS, HSP, and in the setting of infections with pathogens such as hepatitis B, Epstein–Barr virus, cytomegalovirus, Treponema pallidum, and Mycobacterium leprae, as well in patients with poststreptococcal glomerulonephritis. Roughly one-third of cases represent ‘essential mixed cryoglobulinemia’, once attributed to hepatitis B infection24,25,73 but since established to be more often a sequel of chronic hepatitis C (HCV) infection.27,28 The mixed cryoprecipitate comprises polyclonal IgG with specificity against HCV antigen complexed to an IgM rheumatoid factor; HCV particles form part of a cold insoluble immune complex cross-linked to monoclonal IgM rheumatoid factor produced when HCV binds to B cells through interaction between the HCV envelope glycoprotein E2 and the CD81 receptor.9,87 As well, HCV apparently causes low-grade extranodal non-Hodgkin's lymphomas of B-cell phenotype.89 Cryoglobulinemia is classified by the composition of the cryoprecipitate. Type I cryoglobulinemia reflects the presence of a monoclonal immunoglobulin without rheumatoid factor activity, and is usually seen in the setting of lymphoproliferative disease. Type II cryoglobulinemia represents a mixture of monoclonal and polyclonal immunoglobulins and may be seen in association with CTD, infection and essential mixed cryoglobulinemia; the polyclonal protein is usually IgG while the monoclonal protein is typically IgM-ê, which functions as a rheumatoid factor. In type III cryoglobulinemia, the antiglobulin is polyclonal including in the context of an antibody of IgM subtype with rheumatoid factor activity seen in similar clinical settings to those of type II cryoglobulinemia. Types I, II and III represent 25%, 25%, and 50% of cryoglobulinemic states, respectively. Patients are most often women in the 4–5th decades of life whose course is one of relapses and spontaneous recovery. The most common clinical manifestation is lower extremity purpura precipitated by cold, prolonged standing, trauma, or a reaction to a drug or infection. Glomerulonephritis, arthralgia, migratory myalgia and neuropathy may be present. A minority of patients will develop pulmonary vasculitis that manifests as dyspnea and hemoptysis. Monoclonal cryoglobulinemia causes a pauci-inflammatory thrombogenic vasculopathy leading to tissue infarction. A necrotizing systemic PAN-like vasculitis characterizes the type II and type III cryoglobulinemias. Skin biopsies show a severe pandermal LCV extending to subcutaneous arteries and veins. In addition to intraluminal and mural fibrin deposition, eosinophilic globular precipitates are seen in the lumina of the inflamed vessels. Mononuclear cells predominate in chronic lesions and some cases exhibit granulomatous vasculitis. Precipitates of cryoglobulin are easy to distinguish from fibrin by their intense staining reaction with periodic acid-Schiff.
A neutrophilic vascular reaction in association with a spongiform pustulation, at times with acrosyringeal or follicular accentuation, dermatitis herpetiformis (DH)-like microabscesses, and/or a neutrophilic interface dermatitis, defines the entity of pustular vasculitis (Figs. 6 and 7), which encompasses the bowel arthritis dermatosis syndrome,90,91 septic vasculitis, BD,56 acute pustular bacterid,78 IgA-associated vasculitis (particularly infection-related HSP15,20), LCV in patients with a psoriasiform diathesis, Reiter's disease77, following BCG vaccination, and pustular drug reactions.20 Either a Sweet's-like vascular reaction as defined by a neutrophilic vascular infiltrate with leukocytoclasia and hemorrhage but without vascular fibrin deposition or an LCV may be observed.20 The presence of a pustular follicular response may lead to a misdiagnosis of bacterial folliculitis. The latter pattern has been designated sterile neutrophilic folliculitis with perifollicular vasculopathy, and is described in association with acute pustular bacterid, BD, Reiter's disease, tuberculids, hepatobiliary disease, IBD, and CTD.92–94
The clinical expression of a cutaneous LCV associated with vascular IgA deposition is commonly equated with HSP, in which an excessive response to mucosal pathogens is implicated. However, the diagnosis also requires the presence of extracutaneous involvement of renal, gastrointestinal, or musculoskeletal systems. Vascular IgA deposits are also seen in non-lesional skin of patients with DH, IgA nephropathy, and chronic excessive alcohol intake.20 The differential diagnosis of diseases and/or conditions associated with IgA vasculitis (i.e. non-HSP related IgA vasculitis) include underlying IBD, ankylosing spondylitis, SS in the setting of anti-Ro antibodies, RA, prostatic and bronchogenic carcinoma, hypersensitivity reactions to drugs including carbamazepine and calcium channel blockers, and IgA paraproteinemia.20 Most cases of IgA-associated vasculitis that fulfill American College or Rheumatology criteria for HSP are associated with infection in the context of pathogens derived from gut, respiratory, or urinary tract mucosa; all are sites of IgA production.19,20 Implicated microbial antigens include those of Streptococcus sp., Mycoplasma pneumoniae, yersinia, Salmonella hirshfeldii, Pseudomonas aeruginosa, hepatitis A or C, parvovirus B19, denatured microbes, and streptokinase administered following myocardial infarction.19,20 Those patients who develop HSP as a sequel of infection may have underlying immune dysregulation, such as seen in the setting of atopy or RA, a small vessel microangiopathy such as diabetic microangiopathy and/or vascular cofactors including a lupus anticoagulant or anti-Ro antibodies, all of which predispose an individual to the development of vasculitis. 20,95 Although the histology varies with respect to the presence or absence of antecedant infection, extravascular neutrophilia as characterized by epidermal pustulation or DH-like microabscesses is seen in most infectious cases, and almost invariably the patient has other symptoms of HSP.20
An intermittent cutaneous eruption occasionally follows intestinal bypass surgery for morbid obesity or extensive small bowel resection and comprises purpuric macules and papules on trunk and extremities that evolve into necrotizing vesiculo-pustular lesions, sometimes accompanied by polyarthritis, malaise, and fever. Originally termed bowel bypass syndrome, it is similar to that seen in patients with diverticulosis, peptic ulcer disease, and IBD, thus the more appropriate designation bowel arthritis dermatosis syndrome.90,91,94 An LCV may be present, but a Sweet's-like vascular reaction is prototypic. Skin biopsies also show papillary dermal edema, which may lead to subepidermal vesiculation, epidermal pustulation with variable necrosis and marked superficial dermal neutrophilic infiltrates. Most patients manifest demonstrable circulating immune complexes, including those containing cryoproteins. The principle antigenic trigger may be peptidoglycans that derive from intestinal bacteria, many of which are structurally and antigenically similar to those of Streptococcus pyogenes. In addition to direct immunofluorescence testing, which has shown linear and granular deposits of immunoglobulins and complement along the dermoepidermal junction (DEJ) and in vessels, one study demonstrated Escherichia coli antigens in a granular array along the DEJ.96
Skin biopsies from patients with acute septic vasculitis demonstrate a severe pandermal LCV with neutrophil- and bacteria-containing thrombi, extravascular neutrophilia including DH-like microabscesses and neutrophilic exocytosis, and papillary dermal edema. The implicated microbial pathogens include meningococcus, staphylococcus, Group A streptococcus, pneumococcus, pseudomonas, Vibria vulnificus, rickettsia except C. burnetti and candida.71 Vascular injury results from embolization of organisms, whereby bacterial endotoxins provoke complement activation and tumor necrosis factor production rendering the endothelium procoagulant and generating release of tissue factor which promotes thrombosis. In chronic septic vasculitis the luminal thrombi are paucicellular and it is difficult to demonstrate organisms within vessels despite the presence of immune complexes comprising bacterial antigenic components and antibody. The prototypic organisms associated with chronic septic vasculitis are meningococcus and gonococcus.68–72
Systemic vasculitic syndromes with hybrid patterns of vascular injury
Certain CTD and systemic vasculitic syndromes may manifest cutaneous lesions having two or more vascular reaction patterns. In patients with LE, RA, SS, relapsing polychondritis, WG, and AGCS, pauci-inflammatory thrombogenic vasculopathy, lymphocytic thrombogenic vasculopathy and vasculitis, LCV, granulomatous vascultis, and pustular vasculitis may be seen in concert or in isolation.
Clinical manifestations of LE range from a skin rash with arthralgia to progressive multisystem organ failure and death. The diagnosis of SLE is based on the fulfillment of four of 11 criteria established by the American College of Rheumatologists.97 In particular, one arrives at a diagnosis through the association of serological abnormalities with clinical features including a skin rash, arthralgia, arthritis, fever, Raynaud's phenomenon, anemia, leukopenia, serositis, nephritis and central nervous system disease.98,99 The vascular lesions of SLE involve all calibers and types of vessels in all organ systems. The histologic patterns of blood vessel injury encompass a pauci-inflammatory thrombogenic vasculopathy, lymphocytic vasculitis, and neutrophilic vascular reactions including LCV and a systemic MaPAN-like vasculitis. A severe pandermal vasculitis accompanied by thrombosis and resultant infarction is the most common cutaneous manifestation. The mechanism of vascular injury often reflects circulating immune complexes comprising immunoglobulin complexed to endogenous antigens such as cryoglobulins and nuclear components, while the mechanisms of thrombosis include antibodies directed at endothelial antigenic targets,100–103 deposition on endothelium of circulating immune complexes that result in endothelial cell injury with activation of the clotting pathway, and other procoagulant factors such as lupus anticoagulant. In SLE, acute endothelial cell injury has also been implicated in the evolution of a symptom complex mimicking thrombotic thrombocytopenic purpura. The phenomenon of deep blood vessel injury in LE and in other syndromes associated with pro-coagulant states can effect deep vascular occlusion, particularly in the lower extremities. The result is a livedoid pattern (Fig. 8).
Rheumatoid arthritis is a chronic inflammatory disorder that results in destruction of joints, articular cartilage and adjacent structures, with extra-articular manifestations including subcutaneous and dermal rheumatoid nodules and papules, episcleritis, interstitial lymphocytic pneumonitis, hypersplenism and vasculitis.13,41–50, 95, 104 Those patients with extra-articular disease usually have a positive rheumatoid factor. The skin manifestations of vascular injury include the rheumatoid nodule and papule, palpable purpura, recurrent urticaria, superficial ulcers, livedo reticularis, digital infarcts around the nail fold, segmental infarcts of the hands, feet, and legs, erythema nodosum-like nodules, granuloma annulare-like lesions that occur particularly overlying the elbow and metacarpal phalangeal joints, necrobiosis lipoidica (NL)-like lesions, and pyoderma gangrenosum.13,41–50,104 Other manifestations of vasculitis include visceral and cerebral infarcts and mononeuritis multiplex. The vasculitis involves all types and calibers of vessels with frequent thrombosis and a variably dense inflammatory infiltrate that may be lymphocytic, granulomatous or neutrophil-predominant (Fig. 9). When neutrophils predominate, the vasculitic lesions may resemble either systemic PAN if larger caliber vessels are affected or LCV if there is involvement of capillaries and venules; a Sweet's-like vascular reaction may be seen. The vasculitis may have as its epicenter a necrotizing suppurative folliculitis92 or there may be large areas of collagen necrobiosis resembling GA,44 NL44 or chondrodermatitis nodularis helicus (personal observation). Other authors have used the appellations rheumatoid papule and superficial ulcerating rheumatoid necrobiosis104 to describe the phenomenon of palisading necrobiosis accompanied by vasculitic alterations. The systemic disorders that generate this pattern of palisading granulomatous inflammation with vasculitis include WG, LE, IBD, a paraneoplastic syndrome in the setting of malignant lymphoma, and infection with HIV, HCV, and parvovirus B1944,65 There is a correlation between the NL tissue reaction in the setting of RA and the presence of antiphospholipid antibodies, similar to the association observed between antiphospholipid antibodies and the rheumatoid nodule.49, 95 In those lesions of pyoderma gangrenosum in the setting of RA, a dichotomous tissue reaction with central neutrophil-rich tissue pathergy and a peripheral non-necrotizing lymphocytic vascular reaction is observed. Older vasculitic lesions may manifest endarteritis obliterans with intimal fibrosis. Two other cutaneous manifestations of RA are the rash of Still's disease, characterized histologically by a sparse neutrophilic infiltrate with spotty keratinocyte necrosis, and rheumatoid neutrophilic dermatosis,50 which comprises symmetrical urticarial plaques over joints and extensor surfaces from which skin biopsies show dense neutrophilic infiltrates, leukocytoclasia, and intraepidermal and DH-like pustulation in the absence of vasculitis.
Aphthosis (Behcet's disease)
Behcet's disease is a symptom complex of oral and genital ulceration and iritis that has a global distribution but is preponderant in the Pacific rim and eastern Mediterranean. Oral ulcers plus any two of genital ulcers, skin and eye lesions is diagnostic.56 Oral aphthosis that recurs at least three times over a 12-month period is essential to the diagnosis. The extracutaneous manifestations are categorized as oral and/or genital aphthae, vasculo-, ocular, entero- or neuro-BD, renal disease, and arthritis. The disease may be complicated by aneurysms and by occlusive large vein and artery disease. The ocular manifestations include uveitis, hypopyon iritis, optic neuritis and choroiditis. The intestinal manifestations of entero-BD include diarrhea, constipation, abdominal pain, vomiting, and melena, while neuro-BD comprises brain stem dysfunction, meningoencephalitis, organic psychiatric symptoms, and mononeuritis multiplex. Renal disease is expressed as asymptomatic microhematuria and/or proteinuria, while an oligoarthritis may involve the wrist, elbow, knee, or ankle joints.56 The skin lesions include erythema nodosum-like nodules, vesicles, pustules, pyoderma gangrenosum, Sweet's syndrome, a pustular pathergic tissue reaction to needle trauma, superficial migratory thrombophlebitis, ulceration, infiltrative erythema, acral purpuric papulonodular lesions, and acneiform folliculitis.7,56
The histopathology of the skin lesions has three main expressions: vascular, extravascular with or without vasculopathy, and acneiform. The cutaneous vasculopathy comprises a lymphocytic or granulomatous vasculitis with or without thrombosis, necrosis, or mural fibrin deposition, a paucicellular thrombogenic vasculopathy, and a neutrophilic vascular reaction that involves capillaries as well as arteries and veins of all calibers. Neutrophilic vasculopathies include an LCV and a Sweet's-like reaction. With or without blood vessel injury, one may see extravascular mononuclear cell- or neutrophil-predominant inflammation of the dermis and/or panniculus. A histiocytic panniculitis may be seen, while suppurative or mixed suppurative and granulomatous folliculitis characterizes the acneiform lesions.56 Acral purpuric papulonodular lesions show a lymphocytic interface dermatitis with lymphocytic exocytosis, dyskeratosis and a perivascular lymphocytic infiltrate that recapitulates the mucosal histology;57 the extracutaneous pathology tends to mirror that found in the skin. For example, while the centers of oral aphthae manifest a dense neutrophilic infiltrate with necrosis of the epithelium and connective tissue pathergy of the submucosa, the peripheries show dense lymphocytic infiltration of the submucosa, lymphocytic exocytosis and epithelial degeneration; genital aphthae have the same appearance. The large vessel arteriopathy is an ischemic sequel of a mononuclear cell vasculitis of the vasa vasorum, while venous thrombosis may partly reflect hypercoagulability. The renal manifestations include IgA nephropathy, focal and diffuse proliferative glomerulonephritis, and amyloidosis. The lymphocytic vasculitis recapitulates that seen with the CTDs, Degos' disease, and paraneoplastic vasculitis. A granulomatous vasculitis may also be observed in WG, AGCS, Crohn's disease, sarcoidosis, acquired hypogammaglobulinemia, a post-Herpetic eruption, paraneoplastic syndromes, RA, hypersensitivity to certain infections including syphilis and tuberculosis, scleroderma, and the late-stage lesions of MiPAN. The combination of vasculitis and folliculitis is seen in pyoderma gangrenosum, mixed cryoglobulinemia, BD, IBD, RA (personal observation) and pyodermatous eosinophilic folliculitis.92,105 Vascular thrombosis attributable to antibody mediated endothelial injury, protein C or S deficiency, factor XII deficiency, inhibition of plasminogen activator, and circulating lupus anticoagulant has been described.
Cutaneous lesions of Wegener's granulomatosis include subcutaneous nodules, ulcerating lesions producing a ‘malignant pyoderma’ mainly in the head and neck, hemorrhagic bullae, pustules, papules, ulcers, vesicles, petechiae, and palpable purpura. Limited WG encompasses pulmonary disease with or without skin or gut lesions in the absence of upper respiratory tract and kidney involvement. Superficial limited WG confined to the skin or oral mucosa has been described. The cutaneous manifestations of WG encompass collagen degeneration, extravascular inflammation, and vasculitis. In cases of WG limited to the skin, upper respiratory tract, mediastinum and/or retropertitoneum, extravascular inflammation without vasculitis may be seen. The extravascular inflammation includes suppurative or suppurative and granulomatous inflammation with pseudoepitheliomatous hyperplasia and intraepithelial microabscess formation; palisading granulomata of Churg Strauss, GA or NL subtypes; and foreign body giant cells with or without extravascular neutrophilia. The vasculitic lesions involve capillaries, venules, arterioles, small arteries and veins which show necrosis with an angiocentric infiltrate ranging from a granulomatous to a neutrophil-predominant pattern. Any of neutrophilic capillaritis, LCV or a PAN-like vasculitis may be seen, usually in concert with extravascular inflammation and collagen degeneration. Patients presenting with cutaneous LCV often have widespread disease whereas those presenting with granulomatous inflammation without LCV less often have pulmonary and renal manifestations. Some patients with cutaneous LCV may have a protacted superficial form of WG of skin and upper respiratory tract, developing lung or kidney involvement years later.59,60
Allergic granulomatosis of Churg and Strauss
Allergic granulomatosis of Churg-Strauss (AGCS) is a systemic vasculitis in the setting of an atopic diathesis comprising allergic rhinitis and/or asthma along with marked peripheral blood eosinophilia. In some patients vasculitis develops 30 years after the onset of asthma, the latter abating with the onset of vasculitis. The vasculitis closely resembles WG or MiPAN and mainly involves small arteries and veins with a few cases showing medium-sized vessel disease reminiscent of MaPAN. Some authors consider AGCS to represent PAN or WG in a patient with atopy, but unlike WG, gastrointestinal disease and heart involvement are common in AGCS, while renal disease and obstructing aneurysmal medium vessel lesions are rare. Unlike PAN, hepatitis B is not implicated in the pathogenesis of AGCS; in contrast, drug allergy or allergy shots may be precipitating events. In WG and PAN, vascular immune complex deposition is not observed, in contrast to a high percentage of AGCS cases showing vascular IgE immune complex deposits.
In the skin, AGCS manifests as a severe LCV that extends to subcuticular vessels. The vasculitis in the lung resembles that of WG or MiPAN with tissue eosinophilia, which, in the lung, may produce a picture cognate to eosinophilic pneumonia. In other organs the vasculitis resembles that of MaPAN. A distinctive finding is the palisading granuloma of Churg and Strauss (PGCS), which comprises collagen necrobiosis with a palisading histiocytic infiltrate and disintegrating eosinophils within the necrobiotic zones, the granules of which encrust degenerating collagen fibers (Fig. 10). In contrast, neutrophils infiltrate the necrobiotic collagen in the PGCS seen in WG, subacute bacteria endocarditis, and hematopoietic malignancy. The most common cause of death in AGCS is an eosinophilic cardiomyopathy, albeit only a minority of patients die from coronary or myocardial vasculitis or a restrictive cardiomyopathy resembling Loffler's eosinophilic endocarditis. Involvement of the skin is common and characteristically presents as nodules on the scalp and/or extensor surfaces of the arms. Other features of the disease include eosinophilic gastroenteritis and mononeuritis multiplex. Many patients with AGCS have ANCAs similar to WG and MiPAN and there are morphologic similarities between these three conditions, which principally affect smaller blood vessels.4,62 The ANCAs are antibodies targeted against constituents of neutrophil primary granules and monocyte lysosomes, seen in approximately 90% of patients with WG, AGCS and MiPAN; these ANCAs react with either myeloperoxidase (pANCA) or proteinase-3 of the α-granules (cANCA).106,107 An IgA cANCA is detectable in 10% of HSP cases, as well as in select cases of IBD, SS, EED and bacterial endocarditis.22 An atypical pANCA, termed ‘xANCA’, with a specificity for a 50-kDa myeloid envelope protein,108 is seen in patients with IBD, autoimmune hepatitis and 1° sclerosing cholangitis108,109 (see Table 3).
Table 3. Frequency of anti-neutrophil cytoplasmic antibody (ANCA) with specificity of proteinase 3 or myeloperoxidase in patients with active untreated microscopic polyarteritis, Wegener's granulomatosis, and Churg–Strauss syndrome
Sjogren's syndrome is an autoimmune syndrome with a lymphocytic CMI reaction directed against the lacrimal and/or salivary glands. The sequel include, inter alia, dry eyes and mouth and a 40-fold increased risk of lymphoid malignancy. Antibodies to SSB/La are typically seen in cases of SS, except for those examples mediated by viruses such as HIV or HCV; SS may be a 1°CTD or a 2° syndrome complicating SLE or RA. Vasculitis seen in patients with SS may either be lymphocytic or neutrophilic or manifest a hybrid pattern. Cutaneous vasculitis may be associated with mononeuritis multiplex or neuroaxial involvement; such patients often have anti-Ro antibodies,110 a positive rheumatoid factor, and mixed cryoglobulinemia included in the context of Waldenstrom's macroglobulinemia. Young women with recurrent leg purpura and polyclonal hyper-γ-globulinemia may represent a possible forme fruste of SS termed ‘hypergammaglobulinemia of Waldenstrom’, in whom vascular IgA deposition may be seen.
Systemic vasculitides represent a diagnostic challenge in the inpatient and ambulatory care settings, with accurate diagnosis requiring a careful integration of clinical findings with the results of serologic, pathologic and diagnostic imaging studies. The pathologist must be cognizant of the limitations of morphology when attempting to support his or her clinicians, and must also know what questions to ask in order to formulate a biopsy report that is contributory to patient care.