Ko-Ron Chen

Clinical Approach to Cutaneous Vasculitis

Vasculitis is an inflammatory process affecting the vessel wall and leading to its compromise or destruction and subsequent hemorrhagic and ischemic events. Vasculitis can be classified as a primary phenomenon (e.g. idiopathic cutaneous leukocytoclastic angiitis or Wegener granulomatosis) or as a secondary disorder (connective tissue disease [CTD], infection, or adverse drug eruption-associated vasculitis). Cutaneous vasculitis may present as a significant component of many systemic vasculitic syndromes such as rheumatoid vasculitis or anti-neutrophil cytoplasmic antibody (ANCA)-associated primary vasculitic syndromes (Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis). Cutaneous vasculitis manifests most frequently as palpable purpura or infiltrated erythema indicating dermal superficial, small-vessel vasculitis, and less commonly as nodular erythema, livedo racemosa, deep ulcers, or digital gangrene implicating deep dermal or subcutaneous, muscular-vessel vasculitis. A biopsy extending to the subcutis taken from the most tender, reddish or purpuric lesional skin is the key to obtaining a significant diagnostic result and serial sections are often required for identifying the main vasculitic lesion. Coexistence of pan-dermal small-vessel vasculitis and subcutaneous muscular-vessel vasculitis usually indicates CTD, ANCA-associated vasculitis, Behçet disease, or malignancy-associated vasculitis. A concomitant biopsy for direct immunofluoresence evaluation contributes to accurate diagnosis by distinguishing IgA-associated vasculitis (Henoch-Schönlein purpura) from IgG-/IgM-associated vasculitis, which has prognostic significance. Treatment for cutaneous vasculitis should include avoidance of triggers (excessive standing, infection, drugs) and exclusion of vasculitis-like syndromes (pseudovasculitis) such as thrombotic disorders (e.g. anti-phospholipid antibody syndrome). In most instances, cutaneous vasculitis represents a self-limited condition and will be relieved by leg elevation, avoidance of standing, and therapy with NSAIDs. For mild recurrent or persistent disease, colchicine and dapsone are first-choice agents. Severe cutaneous disease requires treatment with systemic corticosteroids or more potent immunosuppression (azathioprine, methotrexate, cyclophosphamide). A combination of corticosteroids and cyclophosphamide is required therapy for systemic vasculitis, which is associated with a high risk of permanent organ damage or death. In cases of refractory vasculitis, plasmapheresis and intravenous immunoglobulin are viable considerations. The new biologic therapies that act via cytokine blockade or lymphocyte depletion, such as the tumor necrosis factor-α inhibitor infliximab and the anti-B-cell antibody rituximab, respectively, are showing benefit in certain settings such as CTD and ANCA-associated vasculitis.

Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis.

Vasculitis, inflammation of the vessel wall, can result in mural destruction with hemorrhage, aneurysm formation, and infarction, or intimal-medial hyperplasia and subsequent stenosis leading to tissue ischemia. The skin, in part due to its large vascular bed, exposure to cold temperatures, and frequent presence of stasis, is involved in many distinct as well as un-named vasculitic syndromes that vary from localized and self-limited to generalized and life-threatening with multi-organ disease. To exclude mimics of vasculitis, diagnosis of cutaneous vasculitis requires biopsy confirmation where its acute signs (fibrinoid necrosis), chronic signs (endarteritis obliterans), or past signs (acellular scar of healed arteritis) must be recognized and presence of extravascular findings such as patterned fibrosis or collagenolytic granulomas noted. Although vasculitis can be classified by etiology, many cases have no identifiable cause, and a single etiologic agent can elicit several distinct clinicopathologic expressions of vasculitis. Therefore, the classification of cutaneous vasculitis is best approached morphologically by determining vessel size and principal inflammatory response. These histologic patterns roughly correlate with pathogenic mechanisms that, when coupled with direct immunofluorescent examination, anti-neutrophil cytoplasmic antibody (ANCA) status, and findings from work-up for systemic disease, allow for specific diagnosis, and ultimately, more effective therapy. Herein, we review cutaneous vasculitis focusing on diagnostic criteria, classification, epidemiology, etiology, pathogenesis, and evaluation of the cutaneous vasculitis patient.

Cutaneous Vasculitis Update: Neutrophilic Muscular Vessel and Eosinophilic, Granulomatous, and Lymphocytic Vasculitis Syndromes

Most biopsies of cutaneous vasculitis will exhibit a small vessel neutrophilic vasculitis [leukocytoclastic vasculitis (LCV)] that is associated with immune complexes on direct immunofluorescence examination or, less commonly, antineutrophilic cytoplasmic antibodies (ANCA) by indirect immunofluorescence testing. Is in uncommon for skin biopsy to reveal solely a neutrophilic arteritis signifying the presence of cutaneous polyarteritis nodosa or, if accompanied by significant lobular panniculitis, nodular vasculitis/erythema induratum. In other cases, cutaneous vascular damage (fibrinoid necrosis, muscular vessel wall disruption, or endarteritis obliterans) will be mediated by a nonneutrophilic inflammatory infiltrate. Eosinophilic vasculitis can be a primary (idiopathic) process that overlaps with hypereosinophilic syndrome, or it can be a secondary vasculitis associated with connective tissue disease or parasite infestation. Authentic cutaneous granulomatous vasculitis (versus vasculitis with extravascular granulomas) can represent a cutaneous manifestation of giant cell arteritis, an eruption secondary to systemic disease such as Crohns disease or sarcoidosis, or a localized disorder, often a post-herpes zoster (HZ) phenomenon. Lymphocytic vasculitis is a histologic reaction pattern that correlates with broad clinical differential diagnosis, which includes connective tissue disease-mostly systemic lupus erythematosus (SLE), endothelial infection by Rickettsia and viruses, idiopathic lichenoid dermatoses such as perniosis or ulcerative necrotic Mucha-Habermann disease, and angiocentric cutaneous T-cell lymphomas. Skin biopsy extending into the subcutis, identifying the dominant inflammatory cell and caliber of vessels affected, extravascular histologic clues such as presence of lichenoid dermatitis or panniculitis, and correlation with clinical data allows for accurate diagnosis of these uncommon vasculitic entities.

A Morphological Study of Evolution of Cutaneous Polyarteritis Nodosa

Morphologic changes including formation of vessel wall fibrinoid necrosis in evolution of cutaneous polyarteritis nodosa (C-PAN) have not been described in detail. Therefore, an investigation of 18 skin biopsy specimens from 14 cases of clinicohistologically proven C-PAN was performed. The results indicated that evolution of arteritis can be classified into 4 stages. Coexistence of different stages was common (50%) in the same or different specimens. The initial (acute) stage shows endothelial loss and fibrin thrombi with neutrophil infiltration without obvious internal elastic lamina disruption and medial fibrinoid necrosis. The second (subacute) stage has mixed cell infiltrates showing a unique intimal target-like fibrinoid necrosis with fibrinoid leakage extending through the disrupted sites of the internal elastic lamina to the media. The third (reparative) stage shows intimal fibroblastic proliferation and perivascular neovascularization with predominant infiltrates of histiocytes and lymphocytes. The final (healed) stage has minimal cellular inflammation with occlusive intimal thickening. Overall, our results show that there are 4 stages in the evolution of C-PAN. The initial change occurs in the intima, and the role of internal elastic lamina in preventing intimal fibrinoid necrosis from discharging into the media may account for the development of target-like fibrinoid necrosis in C-PAN.

The misdiagnosis of superficial thrombophlebitis as cutaneous polyarteritis nodosa: features of the internal elastic lamina and the compact concentric muscular layer as diagnostic pitfalls.

The presence of an internal elastic lamina and a compact concentric muscular layer are the cardinal histologic clues for distinguishing a small muscular artery from small muscular vein. However, the subcutaneous muscular veins in the lower legs usually have thick muscular layers with the proliferation of concentric intimal elastic fibers, which resembles the internal elastic lamina of an artery. Moreover, vertical biopsy specimens of the muscular veins can reveal a compact concentric muscular layer with a round luminal appearance, which also resembles the muscular layer in an artery. As these 2 histologic features are commonly accepted as crucial clues for identifying small to medium-sized muscular arteries, it seems that many cases that are histopathologically proven to be deep dermal or subcutaneous arteritis-including cases documented in numerous dermatology, rheumatology, and dermatopathology-related journals as cutaneous polyarteritis nodosa in Behçets disease and relapsing polychondritis or granulomatous arteritis in nodular vasculitis-are actually consistent with the features of phlebitis or thrombophlebitis. Cutaneous polyarteritis nodosa and subcutaneous thrombophlebitis are usually found in the lower legs and may present with the same cutaneous manifestation of widespread tender or painful nodular erythema. This also accounts for the difficulty in clinically and histopathologically distinguishing between these 2 disorders. Nevertheless, it is important to make a distinction between arteritis and phlebitis because misdiagnosing subcutaneous thrombophlebitis as polyarteritis nodosa may lead to overtreatment with high doses of systemic steroids. Although the veins in the lower legs may have a compact concentric smooth muscle pattern with a round lumen and the intimal elastic fiber proliferation mimicking the characteristic features of arteries, the elastic fibers in the muscular layer are distributed between the bundled smooth muscle in veins, whereas the elastic fibers are scantly distributed in the medial muscular layer in arteries. A diagnostic assessment that is based on the amount of the elastic fibers in the muscular vessel wall more reliably distinguishes a vein from an artery than does the presence or absence of the internal elastic lamina or a smooth muscle pattern.

Mantle Cell Lymphoma With Skin Invasion Characterized by the Common Variant in the Subcutis and Blastoid Transformation in the Overlying Dermis

We report a case of common mantle cell lymphoma (MCL) with subcutis infiltration and transformation to blastoid MCL in the overlying dermis. The patient was initially diagnosed as having chronic lymphocytic leukemia and treated with chemotherapy. Eight months after the diagnosis of MCL with bone marrow involvement, subcutaneous nodules developed on the patients left thigh and forearm. A skin biopsy showed a massive infiltration of neoplastic lymphocytes throughout the dermis and subcutaneous tissue. In the upper dermis, there was a perivascular mixed infiltrate of atypical large lymphoid cells and small-sized cells. In the mid to lower dermis, the infiltrate was dense with a nodular growth pattern and was composed of atypical large lymphoblast-like cells with large nuclei, dispersed chromatin, and numerous mitoses. In the subcutaneous tissue, there was a diffuse infiltration of neoplastic cells with common MCL cytologic features characterized by small- to medium-sized lymphoid cells. Cells in the common and blastoid variants of MCL were immunohistochemically positive for CD20 and cyclin D1 but negative for CD5. Neoplastic lymphocytes from the patients bone marrow had the typical morphologic features and the immunophenotype of MCL (ie, CD5, CD20, cyclin D1, CD10, and CD23). Other case reports in the medical literature indicate that an MCL with skin invasion tends to have a poor prognosis. Our patient died 3 months after the appearance of skin invasion.

Dermatological Addendum to the 2012 International Chapel Hill Consensus Conference Nomenclature of Vasculitides

To prepare a dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) to address vasculitides affecting the skin (D‐CHCC). The goal was to standardize the names and definitions for cutaneous vasculitis.

Churg-Strauss syndrome with coexistence of eosinophilic vasculitis, granulomatous phlebitis and granulomatous dermatitis in bullous pemphigoid-like blisters

The main histopathological features in the cutaneous lesions of Churg‐Strauss syndrome (CSS) are dermal leukocytoclastic vasculitis with a variable eosinophilic infiltrate and non‐vasculitic tissue eosinophilia with granuloma formation. This wide histopathological spectrum may account for the various skin manifestations of CSS. However, the unique histopathological combination of dermal eosinophilic vasculitis and subcutaneous granulomatous phlebitis accompanied by bulla formation has not been previously described. We report an unusual CSS case showing dermal necrotizing eosinophilic vasculitis and granulomatous phlebitis in purpuric lesions coupled with subepidermal blistering. The blisters showed dermal granulomatous dermatitis and eosinophilia without evidence of vasculitis. Dermal necrotizing eosinophilic vasculitis was characterized by fibrinoid alteration of the vessel wall, a prominent perivascular eosinophilic infiltrate, a few infiltrating histiocytes along the affected vessel wall, and the absence of neutrophilic infiltration. The underlying subcutaneous granulomatous phlebitis was characterized by an angiocentric histiocytic infiltrate surrounded by marked eosinophilic infiltrate. Deposition of cytotoxic proteins and radicals derived from eosinophils in the vessel walls and papillary dermis followed by a secondary granulomatous response may account for the unique clinical and histopathological features in this case.

Livedoid vasculopathy with underlying subcutaneous necrotizing venulitis in an asymptomatic hepatitis B virus carrier: is livedoid vasculopathy a true nonvasculitic disorder?

Livedoid vasculopathy has been accepted as a nonvasculitic disorder, but authentic vasculitis in the underlying subcutis can occur in cases of collagen disease and polyarteritis nodosa. We report a case of livedoid vasculopathy with underlying subcutaneous necrotizing venulitis in a 42-year-old carrier of hepatitis B virus. The patient also had a 15-year history of ankylosing spondylitis that was currently in remission. Skin lesions revealed superficial ulceration, purpura, atrophie blanche, and reticulate erythema on the lower extremities, and a skin biopsy showed a minimal dermal perivascular lymphocytic infiltrate with marked fibrin thrombi and fibrin deposits along luminal vessel walls, consistent with features of livedoid vasculopathy. However, necrotizing venulitis characterized by a predominant lymphocytic infiltrate in and around the vessel wall with marked fibrinoid vessel wall necrosis was found in the underlying subcutaneous tissue. A direct immunofluorescence study detected immunoglobulin M and C3 deposits in the papillary dermis. The patient responded well to oral aspirin and a prostaglandin analogue and was well controlled with a compression bandage. Vasculitic lesions in the underlying subcutis may have been overlooked in cases in which livedoid vasculopathy has been considered as a nonvasculitic disorder because our case demonstrates that livedoid vasculopathy can be accompanied by subcutaneous vasculitis.

Reappraisal of histopathology of Cutaneous Polyarteritis Nodosa

There is controversy on whether lymphocytic thrombophilic arteritis (LTA) and macular arteritis (MA) are a different entity from cutaneous polyarteritis nodosa (C‐PAN).