Case 2 -

Cutaneous Small Vessel Vasculitis Janis M . Taube John's Hopkins Medical Institution Baltimore, MD

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Clinical History: 12 year-old boy with a low grade fever, headache and joint pains develops a palpable purpura on distal legs and buttocks. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 H&E Case 2 - Figure 2 DIF1 IgA Case 2 - Figure 3 DIF2 IgA Histologic Diagnosis: Henoch-Schonlein purpura Discussion Introduction: Cutaneous vasculitis and its mimickers may demonstrate identical clinical features, such as petechiae, purpura, hemorrhagic bullae, and ulceration. Additionally, similar clinical features are seen in both primary cutaneous vasculitis and secondary cutaneous involvement by systemic vasculitic disorders. Skin biopsy is the gold-standard for determining whether vasculitis is indeed present, and once vasculitis is identified, the recognition of specific features can aid in the classification of a distinct clinical entity [1]. These two steps are the primary goals of the pathologist reviewing such biopsies. To date, there are no formalized criteria for the classification of cutaneous small vessel vasculitis, however, the most common approach is based on the size and location of the vessels affected as well as the predominant cell type in the inflammatory infiltrate [1, 2]. Approximately 90% of biopsies of cutaneous vasculitis demonstrate neutrophil-predominant small-vessel disease, while the remainder include eosinophilic, lymphocytic, or macrophage-predominant small vessel vasculitis or a neutrophil-predominant medium vessel vasculitis, the latter two groups of which have a shorter differential diagnosis and thus tend to be easier to classify into specific clinical entities [3]. The focus of this discussion is the approach to a biopsy with neutrophil-predominant small-vessel vasculitis, and when combined with clinical and laboratory data, the arrival at a more precise diagnosis. Terminology: The clinical and histologic terminology for neutrophil-predominant cutaneous small vessel vasculitis suffers from confusing overlap. Pathologically, the most commonly used terminology for these findings is "leukocytoclastic vasculitis (LCV)". However, when the terminology "LCV" or its alternate designations "cutaneous leukocytoclastic angiitis (CLA)", "hypersensitivity vasculitis/angiitis", or "localized cutaneous vasculitis", are used clinically, it requires that systemic manifestations of vasculitis be absent. This latter determination is obviously not within the purview of the pathologist. Thus the when the pathologist issues a diagnosis of "leukocytoclastic vasculitis", the onus then falls on the clinician to determine whether this is indeed a primary cutaneous small-vessel vasculitis and to subclassify it into a more specific clinical entity such as a localized cutaneous vasculitis/angiitis, connective-tissue disease associated vasculitis, or microscopic polyangiitis (MPA), for example. For the purposes of this discussion, LCV is used as a pathologic descriptor of neutrophil-predominant small vessel vasculitis, while CLA is used as the clinical term indicating isolated cutaneous disease. Pathophysiology: Most neutrophil-predominant small vessel cutaneous vasculitis can be attributed to immune complex deposition, including drug-associated, infection, connective tissue-disease-related and idiopathic cutaneous small-vessel vasculitis. The presence of these immune complexes can be demonstrated by direct-immunofluorescent (DIF) studies performed on a concurrent biopsy specimen. A small proportion of neutrophil-predominant small vessel vasculitis cases are not immune-complex mediated and are mediated by anti-neutrophil cytoplasmic antibodies (ANCA). ANCA status can be assessed by indirect immunofluorescent testing (IIF), and is also sometimes inferred by negative DIF studies. The ANCA-mediated primary systemic vasculitis syndromes include Churg Strauss Syndrome (CSS), MPA, and Wegner's granulomatosis (WG). Biopsy Specimens: The highest diagnostic yield for the evaluation of cutaneous vasculitis is realized when biopsies include the subcutaneous tissue and are taken from symptomatic purpuric lesions that are less than 48 hours old [1]. Biopsies should be obtained from non-ulcerated lesions whenever possible, as ulceration is often associated with incidental vasculitis. Further, a second biopsy specimen submitted for DIF studies is highly recommended, and yield is again improved if the lesion is less than 48 hours old [1]. Performing step-level hematoxylin and eosin-stained sections through the block may be of use, as vasculitis may be focal and segmental [1]. Histologic Criteria for the Diagnosis of Vasculitis: The general criteria for medium and large vessel vasculitis is simply the identification of inflammatory cells within the vessel wall. As small cutaneous vessels are the location for diapedesis of inflammatory cells, additional signs of neutrophil activation and vascular damage are necessary for establishing the diagnosis of cutaneous small vessel vasculitis. Two of the three following criteria are necessary for the diagnosis of cutaneous small vessel vasculitis [1]: 1) Angiocentric and/or angioinvasive inflammatory infiltrates. 2) Disruption and/or destruction of the vessel wall by the inflammatory infiltrate, including collagen degeneration or endothelial necrosis. Indirect evidence of vessel wall damage includes perivascular nuclear dust ('leukocytoclasia') or onion-skinning perivascular fibrosis. 3) Intramural and/or intraluminal fibrin deposition ('fibrinoid necrosis'). Diagnositic Approach [2]: Step 1: Is vasculitis present? (See aforementioned Histologic Criteria) Step 2: Determine the predominant cellular component. For example, a neutrophilic infiltrate raises the differential diagnosis presented in Table 1, while a vasculocentric granulomatous infiltrate suggests a post-herpetic eruption [3]. Step 3: Extent of involvement and vessel size? Superficial perivascular dermal vs. superficial and deep perivascular dermal vs. subcutaneous vessels? For example, the finding of neutrophilic vasculitis accentuated around the plexus of post-capillary venules in the upper part of the dermis (as shown in Figure 1 for the index case) is suggestive of CLA, HSP, drug-induced LCV or MPA while the finding of pandermal neutrophilic vasculitis suggests other systemic diseases, including the other ANCA-positive systemic vasculitides or connective tissue disease (CTD)-associated vasculitis [2]. Step 4: Incorporation of additional histologic findings (such as subcorneal pustules, extravascular granulomas, dermal neutrophlia, etc.) as well as available ancillary testing techniques such as DIF or ANCA, to arrive at a more specific diagnosis when available. While the finding of neutrophilic small vessel neutrophilic vasculitis confined to the upper part of the dermis is suggestive of CLA, Henoch-Schonlein purpura (HSP), drug-induced LCV, or MPA, the diagnosis of HSP is indicated by IgA deposits on DIF (as shown in Figure 2 for the index case), while CLA and drug-induced LCV will demonstrate small granular deposits of IgG, IgM, and complement, and MPA will have a negative DIF. In cases of CTD-associated vasculitis, immune-complex deposition may also be seen at the overlying dermal-epidermal junction. Table 1. Specific vasculitis syndromes implicated by pathologic findings. Adapted from Carlson, JA [1]. Cryoglobulinemic vasculitis (CV), BD=Behcet's disease (BD), rheumatoid vasculitis (RV), lupus vasculitis (LV), systemic lupus erythematosus (SLE), granuloma faciale (GF), erythema elevatum dinutum (EED), urticarial vasculitis (UV). Findings Suspected systemic vasculitis syndrome Histologic examination Deep dermal and/or subcutaneous small and/or muscular vessel vasculitis Systemic vasculitis syndromes (WG, CSS, MPA, CV, BD, RV, LV, septic vasculitis), malignancy associated Extravascular granulomatous dermatitis WG, CSS, LV, RV Tissue neutrophilia SLE, infection Tissue eosinophilia CSS and drug-induced vasculitis Storiform or angiocentric fibrosis GF/EED, WG (rarely) Interface dermatitis + mucin deposition LV, dermatomyositis Pustular dermatosis (sub/intraepidermal pustules) Septic vasculitis, infection Direct Immunofluorescence (DIF) Isolated or predominate IgA vascular deposits HSP Interface dermatitis (IgG, IgM, and/or C3 at the BMZ) LV, UV associated with SLE Predominate IgM and C3 vascular deposits CV, RV Conclusion: Histologic examination focused on the size and extent of vessels involved by vasculitis combined with laboratory studies such as DIF and ANCA status as well as clinical information allows for a more accurate diagnosis of specific primary cutaneous and systemic vasculitic diseases. If supplementary laboratory or clinical information is not available, the main goal of the pathologist is to determine simply whether vasculitis is present or absent. In this scenario, if a neutrophil-predominant small vessel vasculitis involving the superficial dermis is identified, the signout may read "Leukocytoclastic vasculitis. Correlation with a biopsy for direct immunofluorescent and additional laboratory studies, including serologic studies, may allow for a more specific diagnosis". In contrast, when supplementary studies are available, the pathologist can be more specific in reporting. For example, if the same H&E biopsy described above is accompanied by a biopsy for DIF demonstrating predominant IgA deposition in vessels, the report may read "Consistent with Henoch-Schonlein purpura. Histologic sections demonstrate a leukocytoclastic vasculitis, and DIF studies show predominant IgA deposition in the vasculature. Correlation with clinical history and additional laboratory tests are suggested". Lastly, in the instance of our index case when the full clinical history is provided, the report may simply read "Henoch-Schonlein purpura. Histologic sections demonstrate a leukocytoclastic vasculitis, and DIF studies show predominant IgA deposition in the vasculature, supporting the above diagnosis". References and Additional Review Materials: Carlson JA. Review: The histologic assessment of cutaneous vasculitis. Histopathology, 2010;56:3-23. Carlson JA and Chen K. Cutaneous vasculitis update: Small vessel neutrophilic vasculitis syndromes. Am J Dermatopathol, 2006;28:486-506. Carlson JA and Chen K. Cutaneous vasculitis update: Neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes. Am J Dermatopathol, 2007;29:32-43. Jennette JC, Falk RJ. Small-vessel vasculitis. New Eng J Med, 1997:337;1512-1523. Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol, 2003:48;311-40.