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Competing Interests: The author declares no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is a rare systemic vasculitis affecting small- and medium-sized vasculature, associated with asthma and eosinophilia. Different levels of vasculitis in cutaneous lesions have been observed, including dermal small vessel vasculitis and subcutaneous muscular vessel vasculitis. Although the EGPA-associated small vessel vasculitis described as leukocytoclastic vasculitis can be often found in the documented literature, the features of subcutaneous muscular vessel vasculitis in EGPA-associated cutaneous lesions have been rarely demonstrated clinically and histopathologically in English literature. Herein, we report a case of EGPA involving infiltrated erythema on the extremities, with different stages of cutaneous arteritis characterized by eosinophilic arteritis and granulomatous arteritis in the same affected artery. We present this as a unique diagnostic clue for EGPA.

Background: The diverse histopathologic spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) has not been well described., Methods: Fifteen skin biopsy specimens from 9 EGPA patients with histopathologically proven necrotizing vasculitis were reviewed clinicopathologically., Results: Among 8 patients with dermal small vessel vasculitis, neutrophilic vasculitis was observed in 2 myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-positive patients, whereas the remaining 6 MPO-ANCA-negative patients showed eosinophilic vasculitis in 3 and a mixed infiltrate of neutrophils and eosinophils in another 3 patients. Five patients with muscular vessel vasculitis showed vasculitis at different inflammatory stages in separate or coexisting at the same biopsied skin lesions: acute stage (eosinophilic vasculitis), granulomatous stage (granulomatous vasculitis), and healed stage. Coexistent small vessel and muscular vessel vasculitis was found in 4 patients., Conclusions: The histopathologic spectrum of dermal small vessel vasculitis in EGPA ranges from eosinophilic vasculitis with negative MPO-ANCA at one end to neutrophilic vasculitis with positive MPO-ANCA at the other end. The affected vessels ranging from dermal small vessels to subcutaneous muscular vessels in addition to the MPO-ANCA phenotype may account for the many facets of vasculitis in EGPA.

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 Behçet's 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.

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 patient's 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 patient's 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.

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.

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.

Cutaneous pseudovasculitis represents a heterogeneous collection of disorders that are capable of simulating cutaneous vasculitis and can be broadly classified into diseases that produce hemorrhage (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. Hemorrhagic 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), nonvasculitic 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 (eg, thrombocytopenia), and vessel wall trauma. Cyanotic-infarctive pseudovasculitis is due vaso-occlusion by emboli, thrombi, or fibrointimal hyperplasia (endarteritis obliterans) and includes varied conditions such as purpura fulminans, Coumadin necrosis, antiphospholipid antibody syndrome, cardiac myxoma, cholesterol embolization, calciphylaxis, and radiation arteritis. Delayed and inappropriate diagnosis of pseudovasculitis leads to incorrect management and exposure to potentially deleterious treatment modalities such as corticosteroids and cytotoxic agents. 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; absence of histologic evidence of vasculitis, particularly after multiple biopsies, should direct evaluation and diagnosis towards pseudovasculitis.

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 Crohn's 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 broad and diverse spectrum of vasculitic syndromes exists. These syndromes affect the skin with varying levels of associated systemic manifestations, running the gamut from a self-limited, localized, cutaneous phenomenon to rapidly progressive, multiorgan disease. The majority of cases of cutaneous vasculitis will show a neutrophilic small vessel vasculitis that can be either a primary (idiopathic) disorder (eg, cutaneous leukocytoclastic angiitis) or a secondary disorder that is associated with drugs, infection (eg, streptococcal infection, viral hepatitis), or underlying disease (eg, connective tissue disease, malignancy). Biopsy is the gold standard for the diagnosis of cutaneous vasculitis and also necessary for the detection of cutaneous vascular immune complexes by direct immunofluorescence. Based on the type of vessel disrupted by inflammation (small and/or muscular), the distribution of vasculitis in the dermis and subcutis, and predominate inflammatory cell-type mediating vessel wall damage, a list of relevant differential diagnoses can be generated. This histologic information coupled with extravascular findings such as tissue eosinophilia, tissue neutrophilia, and/or granulomas, plus pathophysiologic markers such as direct immunofluorescent examination for immune complexes and serologic evaluation for antineutrophil cytoplasmic antibodies allows for more accurate diagnosis of specific vasculitic entities. Herein, we review both primary and secondary vasculitic syndromes that affect the skin and show a small vessel neutrophilic mediated vasculitis.

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.