Cutaneous arteriolitis: A novel cutaneous small vessel vasculitis disorder clinicopathologically different from cutaneous polyarteritis nodosa and cutaneous venulitis.

Cutaneous vasculitis can be classified into two types based on the affected vessel size: small vessel vasculitis predominantly affecting dermal venules, and muscular vessel vasculitis as found in cutaneous arteritis predominantly affecting arteries located at the dermal-subcutaneous junction. We describe two cases with a novel small vessel vasculitis disorder, which exclusively affected arterioles in the mid-dermis, and show clinical and pathological difference distinct from cutaneous polyarteritis nodosa and cutaneous venulitis. Both patients were male, and presented with painful infiltrative plaques, involving the palms, soles, and thighs without extracutaneous involvement except for fever and arthralgia. Histopathological examination revealed vasculitis in the mid-dermis characterized by a predominant infiltration of neutrophils with vessel wall fibrinoid necrosis and leukocytoclasia identical to the features of leukocytoclastic vasculitis, except that the affected vessels were arterioles rather than venules. Serological examinations showed normal levels of serum complements, immune complexes, and antineutrophil cytoplasmic antibodies, and vasculitis disorders associated with systemic diseases were excluded in both patients. The patients showed a good response to short-term treatment with prednisolone up to 30 mg. This novel cutaneous arteriolitis clinicopathologically different from both cutaneous venulitis and cutaneous arteritis appears to be a skin-limited disorder.

A Case of Cutaneous Arteritis Presenting as Infiltrated Erythema in Eosinophilic Granulomatosis With Polyangiitis: Features of the Unique Morphological Evolution of Arteritis as a Diagnostic Clue.

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.

Reappraisal of histopathology of cutaneous polyarteritis nodosa.

BACKGROUND: There is controversy on whether lymphocytic thrombophilic arteritis (LTA) and macular arteritis (MA) are a different entity from cutaneous polyarteritis nodosa (C-PAN). OBJECTIVE: To evaluate the controversy on LTA/MA by examining the morphologic changes during the dynamic inflammatory process. MATERIALS AND METHODS: A clinical and histopathological investigation of 46 biopsy specimens from 21 histopathologically proven C-PAN patients at our hospital was performed. RESULTS: Most of the biopsy findings revealed arteritis in the subacute and reparative stages. Coexistence of different stages was found in over half of the specimens. Two biopsy specimens consistent with LTA/MA showed coexisting histologically proven (subacute stage) C-PAN in other lesions. Analyses of the longitudinal sections showed focal and segmental arteritis. Patients overall improved well with compression stockings, anti-inflammatory agents, a prostaglandin analog and antiplatelet agents. Currently, three patients are medication free and only require compression stockings. CONCLUSION: LTA/MA seems to be part of the spectrum of C-PAN. The vasculitic lesions of C-PAN are segmental and focal, and coexist in different stages. As the chronic stage of C-PAN can be mistaken as LTA/MA, it is necessary to perform multiple biopsies, serial sections and analyses of longitudinal sections to confirm the main finding of vasculitis.

Evaluation of histopathological findings at the injection site following degarelix administration.

PURPOSE: The aims of the present study were to investigate the incidence of injection site reactions (ISRs) following administration of 240 mg degarelix and identify the risk factors for ISRs. METHODS: This study was conducted in 50 consecutive men treated with degarelix for the first time. ISRs after an initial degarelix dose of 240 mg (administered subcutaneously as two 3 ml subcutaneous injection) were evaluated using the five categories of the Common Terminology Criteria for Adverse Events Version 4 of the National Cancer Institute. We also assessed the differences in patient background between patients with and without an ISR. RESULTS: The mean age of patients and prostate-specific antigen (PSA) level just before degarelix administration were 75.6 and 198.4 ng/ml, respectively. Hormonal therapy with degarelix was administered for the first time to 33 patients; 11 of the 50 patients were receiving an oral steroid, 6 for prostate cancer, 1 for hematological disease, and 4 for allergic conditions. ISRs were observed in 25 patients, and all of the ISRs were categorized as grade 1 or 2; however, 2 patients discontinued this procedure due to the ISR. Significant differences in the first experience with subcutaneous therapy (p = 0.007) and rate of combination with a steroid (p = 0.017) were observed between patients with and without ISRs. CONCLUSION: The incidences of ISRs in patients receiving subcutaneous therapy for the first time and in patients also receiving an oral steroid were 64 and 18 %, respectively. Patients should be provided with information concerning the possible occurrence of ISR due to degarelix prior to the administration, particularly patients who are not receiving steroids and patients who have no experience with subcutaneous injections.

Spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): a case series.

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.

Cutaneous vasculitis in autoinflammatory diseases.

Autoinflammatory diseases (AIDs) characterized by recurrent episodes of localized or systemic inflammation are disorders of the innate immune system. Skin lesions are commonly found in AIDs and cutaneous vasculitis can coexist with AIDs and even present as the most striking feature. This review aims to focus on the frequent cutaneous vasculitis association in three monogenic AIDs including familial Mediterranean fever (FMF), deficiency of adenosine deaminase type 2 (DADA2), and the recently identified adult-onset VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Cutaneous vasculitis in FMF is characterized by: (1) small-vessel vasculitis similar to IgA vasculitis with palpable purpura but increased intussusception complication and less vascular IgA deposit, and (2) cutaneous arteritis-like vasculitis presenting as subcutaneous nodules most often with higher glomerular involvement. DADA2 has a wide spectrum of clinical presentations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. DADA2 shares similar clinical and histopathological features with polyarteritis nodosa (PAN). As a result, DADA2 is commonly initially misdiagnosed as childhood PAN. Livedo racemosa reveals the most common cutaneous manifestation of cutaneous vasculitis in patients with DADA2. VEXAS syndrome is a life-threatening disease. A diagnosis of VEXAS syndrome should be strongly considered or could be made in patients with skin lesions characterized by Sweet syndrome-like eruption, livedo racemosa, concomitant relapsing polychondritis, deep venous thrombosis, pulmonary involvement, and progressive hematologic abnormalities such as myelodysplastic syndrome with a unique finding of cytoplasmic vacuoles in myeloid and erythroid precursor cells from bone marrow aspirate smear. As skin involvement is common in AIDs and may present as the most frequent manifestation, especially in DADA2 (70% to 90%) and VEXAS syndrome (83% to 91%), dermatologists play a crucial role in contributing to the early diagnosis of these AIDs with early initiation of the appropriate therapy to avoid progressing fatal outcomes.

Skin involvement in ANCA-associated vasculitis.

The skin is a common target organ in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Skin lesions may present as the initial manifestation or as the associated cutaneous manifestations in ANCA-associated vasculitis. Visually assessing the cutaneous manifestations and performing a biopsy of skin lesions to facilitate histopathologic confirmation are highly valuable diagnostically. Vasculitis (which affects dermal small vessels and subcutaneous muscular vessels) and nonvasculitic inflammation cause various types of skin lesions. The coexistence of different levels of vasculitis and nonvasculitis can occur in one or in several lesions or on different occasions. These puzzling clinical and histopathologic features may be closely related to the disease activity. Understanding the complicated clinical and histopathologic spectrum of skin lesions will contribute to the early diagnosis of ANCA-associated vasculitis with cutaneous complications.

Histopathological characteristics of stenosing flexor tenosynovitis in diabetic patients and possible associations with diabetes-related variables.

PURPOSE: To compare the histopathological findings of stenosing flexor tenosynovitis (SFTS) in diabetic patients with those in nondiabetic patients and to analyze the predominant characteristics of SFTS in diabetic patients by statistical methods. METHODS: We included 63 patients (63 specimens) who underwent excision of A1 pulleys for SFTS. A total of 38 patients (38 digits) were diabetic and 25 (25 digits) were nondiabetic. We obtained specimens from the proximal one-third of each A1 pulley and analyzed them by histological and immunohistochemical methods. After we identified the predominant histopathological characteristics of SFTS in patients with diabetes, we performed multiple logistic regression analysis to examine the possible associations between the histopathological characteristics and diabetes-related variables. RESULTS: We divided histopathological findings into 3 types in both diabetic and nondiabetic groups. Types 1 and 2 showed fibrocartilage metaplasia including fibrocartilage-like cells surrounded by basophilic extracellular substances. Type 2 was characterized by the presence of granulation tissue in the middle layer, which was not recognized in type 1. The granulation tissue contained newly formed microvessels, stromal cells, a small number of inflammatory cells, and extracellular matrix that showed myxomatous degeneration. Type 3 showed a decrease in fibrocartilage-like cells with surrounding extracellular eosinophilic substances, which was similar to hyaline degeneration. The histopathological features of type 2 were found in 68% of the diabetic group and in 28% of the nondiabetic group. This difference was statistically significant. The findings of type 2 were significantly associated with the severity of diabetic retinopathy and hemoglobin A1c values in the diabetic group. CONCLUSIONS: Type 2 findings were more frequent in the diabetic group than in the nondiabetic group. A pathomechanism to accelerate neovascularization and hypercellularity in the granulation tissue in the middle layer of A1 pulley may exist, especially in diabetic patients with severe retinopathy and poorly controlled hyperglycemia.

A case of microscopic polyangiitis with skin manifestations in a seven-year-old girl.

A case of a 7-year-old girl with microscopic polyangiitis (MPA) with a skin eruption characterized by maculopapular, erythematous and purpuric lesions on the face, elbows, and knees is presented. Anti-neutrophil cytoplasmic autoantibodies (ANCA) with myeloperoxidase specificity (MPO-ANCA) were identified. Chest X-ray and computed tomography scan revealed diffuse infiltrates in both lung fields, suggesting alveolar hemorrhage. Microscopic hematuria was detected but a renal biopsy showed no abnormalities. Histological examination of a skin biopsy from a purpuric papule showed leukocytoclastic vasculitis of the small vessels in the entire dermis. The patient was treated with prednisolone and mizoribine, resulting in an improvement in the skin lesions except for those on the knee.

Coexistence of Superficial Thrombophlebitis and Cutaneous Venulitis in Behçet's Disease: Report of 5 Cases.

Previous studies have shown that erythema nodosum-like lesions in patients with Behçet's disease show cutaneous vasculitis of either phlebitis or dermal venulitis. To analyse the clinicopathological characteristics of superficial thrombophlebitis as well as cutaneous venulitis in Behçet's disease. We re-evaluated the histopathological features of superficial thrombophlebitis in patients with Behçet's disease. Five patients, one man and four women, developed superficial thrombophlebitis on the lower extremities. Two of the patients had vascular Behçet's disease, both also developed deep vein thrombosis. One patient had intestinal Behçet's disease. In all cases, venulitis in the overlying lower dermis or adjacent subcutis spreading from the main affected subcutaneous thrombophlebitis lesions was observed. Both neutrophilic venulitis (n = 2) and lymphocytic venulitis (n = 3) were observed at the same depth level or upper/lower location of the thrombophlebitis in the same specimens. In addition, concurrent venulitis with fibrin thrombus and fibrinoid necrosis was observed in one case, suggesting that fibrin thrombus affected both venules and muscular veins. By contrast, arteritis or arteriolitis at the same depth level was not observed. Our results showed histopathological features of coexistent thrombophlebitis and venulitis without involvement of either arteries or arterioles in the biopsied specimens of superficial thrombophlebitis. Further studies are necessary to support that those unique histopathological findings are the characteristic features and significant diagnostic indicators of Behçet's disease.

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.

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 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.

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 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.