[Cutaneous vasculitis and vasculopathy : Differential diagnosis in biopsies of the lower extremities]. / Kutane Vaskulitis und Vaskulopathie : Differenzialdiagnosen an der unteren Extremität.

The skin is one of the most frequently involved organs in primary systemic and secondary vasculitis; moreover, a vasculitis can occur as single organ vasculitis, limited to the skin. For most types of vasculitis, the lower extremities constitute common sites with clinical symptoms of palpable purpura, nodules, and ulcers. In histopathology of cutaneous vasculitis, it is of utmost importance to correctly identify the vessel types involved and to discriminate between vasculitic vessel damage, unspecific reactive vessel changes, vascular occlusive diseases, noninflammatory purpura, or perivascular infiltrates due to other inflammatory skin diseases. Small-vessel vasculitis is the most frequent type of cutaneous vasculitis; during florid phases, a dermal leukocytoclastic vasculitis is found regardless of etiology. Additional extravascular changes may give etiological clues, however, a correlation with the clinical picture, radiology, and serology is essential. The biopsy type and technique need to be adjusted to the suspected diagnosis and site of the vessels involved. Polyarteritis nodosa and nodular vasculitis can be diagnosed only in biopsies with sufficient subcutaneous tissue. Especially in cutaneous ulcers, a lateral rim of vital skin and subcutaneous tissue is indispensable for a correct diagnosis. Large-vessel vasculitis is not found in skin biopsies of the lower extremities.

[Pathogenesis of large vessel vasculitides]. / Pathogenese der Großgefäßvaskulitiden.

Large vessel vasculitides comprise two distinct entities, giant cell arteritis (GCA) and Takayasu arteritis (TAK). GCA is the most common vasculitis in central Europe, becoming manifested at an age over 50 years. In contrast, the much rarer TAK affects almost exclusively young adults and mostly women. Both vasculitides are granulomatous arteritides affecting mainly the aorta and its major arterial branches. GCA and TAK are associated with different major histocompatibility complex genes. Infections possibly play a role in the initiation of large vessel vasculitides. Activation of dendritic cells in the adventitia induces chemokine and cytokine-mediated recruitment and maturation of T­helper (Th)1 and Th17 cells and macrophages producing cytokines, growth factors and matrix metalloproteinases. In GCA, CD4+ T­helper cells and macrophages are predominantly found in the inflammatory infiltrate. In TAK, the infiltrate also contains cytotoxic CD8+ T­cells and γδ T­cells. This could indicate different antigenic triggers in GCA and TAK. Inflammatory infiltration with T­cells and macrophages and activation of myofibroblasts and smooth muscular cells induce vascular remodeling with intimal hyperplasia and destruction of the media. Remodeling is histologically characterized by progressive arterial wall fibrosis, vascular stenosis and obstruction. In summary, GCA and TAK represent two different entities with a distinct human leukocyte antigen (HLA) and potentially etiopathogenetic background. Clinically, inflammation-related general symptoms and signs of ischemia are encountered, accompanied by increased levels of serological markers of inflammation.

[Granulomatous reaction pattern of the skin : Interstitial granulomatous dermatitis - lymphoma - vasculitis]. / Granulomatöses Reaktionsmuster in der Haut : Interstitielle Dermatitis ­ Lymphome ­ Vaskulitis.

A particular diagnostic situation in the classification of a granulomatous dermatitis results when no circumscribed granulomas but instead a diffuse interstitial histiocytic inflammatory infiltrate, a granulomatous vasculitis or a neoplastic lymphocytic infiltrate is found. Interstitial granulomatous dermatitis was originally described in patients with arthritis. Later, it was recognized that there are also associations with other usually immunological diseases. Differentiating between interstitial granulomatous dermatitis and the interstitial form of granuloma annulare, early morphea and variants of borreliosis or scleromyxedema as well as interstitial granulomatous drug reaction can be very difficult. In long-standing cutaneous granulomatous infiltrates, T­cell lymphoma should be excluded. Occasionally only a small number of atypical lymphocytes can be found. The detection of a monoclonal T­cell expansion is then particularly helpful. Only recently, a CD8-positive granulomatous cutaneous T­cell lymphoma was described which occurred in patients with immunodeficiencies. A granulomatous vasculitis in the skin is extremely rare. According to the Chapel Hill classification from 2012, systemic granulomatous vasculitis is equated with giant cell arteritis. Extracutaneous large arteries are involved. On rare occasions, involvement of the temporal artery can result in skin necrosis. More commonly granulomatous infiltrates in combination with vasculitis can be observed, whereby various infectious diseases, sarcoidosis and nodular vasculitis should be considered. Granulomatosis with polyangiitis (formerly Wegener's granulomatosis), presents in the skin as leukocytoclastic vasculitis. Here granulomas are extremely rare.

[Non-infectious granulomatous inflammation: Focus on the lungs and skin]. / Nichtinfektiöse granulomatöse Entzündungen: Schwerpunkt Lunge und Haut.

Whereas a granulomatous reaction represents a physiologically useful immune defense mechanism against many infections, in autoimmune diseases granuloma formation and the concomitant inflammatory mechanisms may provoke a potentially organ-threatening reaction. Morphologically, several defined sub-types of granuloma have long been known, e.g. foreign body granuloma, tuberculous granuloma,sarcoid, pseudosarcoid, rheumatoid and rheumatic fever granulomas. However, in practice, assigning granulomas to a certain etiology from a biopsy or resection specimen can be a challenging diagnostic process. This article gives a practically oriented overview of the clinically most relevant non-infectious granulomatous diseases. The etiology, epidemiology, clinical correlation and morphology of granulomatous diseases are discussed, focussing on the lungs and skin.

[Vasculitis: New nomenclature of the Chapel Hill consensus conference 2012]. / Vaskulitis: Neue Nomenklatur der Chapel-Hill-Konsensuskonferenz 2012.

Within the last years, many advances have been made in the understanding of the etiopathology of vasculitis as well as of different disease courses. The revised 2012 Chapel Hill consensus conference (CHCC) nomenclature reflects current knowledge on the etiopathology in addition to the descriptive principles of vessel size and types of inflammation. The anti-neutrophil cytoplasmic antibody (ANCA)-associated forms of vasculitis have been separated as a group, as opposed to immune complex small vessel vasculitis. When consensus was achieved eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's granulomatosis) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes and summarizes the results of important new articles on the clinical picture and morphology of vasculitis.

[Polyarteritis nodosa: differential diagnostics and therapy]. / Polyarteriitis nodosa: Differenzialdiagnostik und Therapie.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium size arteries that may affect various organs. The clinical appearance is very variable. The most common manifestations are of the skin, the peripheral nervous system presenting as mononeuritis multiplex and the mesenteric and renal blood vessels due to the development of stenoses and small aneurysms. Of the cases one third are estimated to be associated with hepatitis B virus (HBV). The therapy depends on the pathogenesis of the disease: primary PAN is treated with immunosuppressants, whereas patients with HBV-related PAN should receive antiviral therapy and plasmapheresis. Differentiating PAN from other forms of vasculitis can be difficult and requires complex differential diagnostics.

[Vasculitis. New nomenclature of the Chapel Hill consensus conference 2012]. / Vaskulitis. Neue Nomenklatur der Chapel-Hill-Konsensuskonferenz 2012.

In recent years, many advances have been made in our understanding of vasculitis etiopathology as well as of different disease courses. The revised Chapel Hill Consensus Conference (CHCC) 2012 nomenclature reflects current knowledge about etiopathology, in addition to the descriptive principles of vessel size and type of inflammation. Anti-neutrophil cyptoplasmic antibody (ANCA)-associated vasculitides have been classified as a separate group, as opposed to immune complex small vessel vasculitis. In cases where consensus was achieved, eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes, focussing on those types that are relevant to the histopathologist, and summarizes the results of important new articles on morphology and clinical picture of vasculitis.

[Accreditation in pathology and neuropathology : Paths and pitfalls]. / Akkreditierung in der Pathologie und Neuropathologie : Wege und Pitfalls.

There are many good reasons for accreditation in pathology or neuropathology as per DIN EN ISO/IEC 17020, regardless of the size and range of services of the facility. Only accreditation - in contrast to certification - also confirms professional competence. This article describes how to establish a quality management system that conforms to standards as effectively as possible and how to maintain it, involve staff, and avoid common pitfalls. Adequate resources and active management support are essential. In this way, not only can accreditation succeed, but the facility itself and its employees can benefit from quality management in their daily work.

[Histopathology of systemic vasculitis]. / Histopathologie systemischer Vaskulitiden.

Inflammatory diseases of blood vessels can occur in any part of the vascular system with a variety of clinical and histopathological manifestations. Possible etiologies include primary systemic vasculitis, secondary vasculitis or isolated single organ vasculitis. Key criteria of morphological vasculitis work-up are vessel size, type of inflammation (granulomatous, necrotizing and/or leukocytoclastic) as well as presence or absence of immune complexes and extravascular inflammatory changes. Together with the typical organ involvement and serological data, these criteria constitute the basis of vasculitis classification. A histopathologically confirmed biopsy is the gold standard for a diagnosis of vasculitis, although a definite diagnosis can frequently not be made solely on histopathological grounds. Differential diagnostic overlaps and possible ways of discrimination are presented. In many cases, however, histopathology can only provide a definite diagnosis in combination with clinical and serological data. A conclusive morphological diagnosis depends on the right time of biopsy and selection of appropriate biopsy material.

[Histomorphology of interstitial lung disease and pulmonary vasculitis]. / Histomorphologie interstitieller Lungengerüstveränderungen und pulmonaler Vaskulitiden.

Rheumatic diseases or collagen vascular diseases represent a heterogeneous group of immunologically mediated inflammatory disorders. The respiratory system is often affected,the causes being manifold: infection, medication toxicity and specific manifestations of immunological processes due to the underlying disease. The lung can be involved in all its components. Due to their extremely broad differential diagnosis, pulmonary vasculitic syndromes still constitute a major challenge for the pathologist. Pulmonary involvement is frequent in primary systemic vasculitis (PSV) associated with anti-neutrophil-cytoplasmic antibodies (ANCA); other PSV only rarely affect the lungs. Histomorphologically, small vessel vasculitis with neutrophil alveolitis and diffuse alveolar hemorrhage, as well as extravascular intraparenchymal or peribronchial granulomas, can point to PSV. A single biopsy is often insufficient to identify all diagnostic criteria. Therefore, the selection of suitable biopsy material and correlation with clinical, serological and radiological parameters is indispensable. Almost all forms of interstitial lung disease may be present in collagen vascular disease; however, several parallel morphological types, rather than one in isolation, are frequently found.

[Vasculitis: histopathology and differential diagnosis]. / Vaskulitis: Histopathologie und Differenzialdiagnose.

A histopathologically confirmed biopsy is the gold standard for the diagnosis of vasculitis. Possible etiologies include primary systemic vasculitis, secondary vasculitis or isolated single organ vasculitis, although on histopathological grounds alone a clear differentiation is frequently not possible. The key criteria of morphological vasculitis work-up include vessel size, type of inflammation (granulomatous, necrotizing and/or leukocytoclastic) as well as the presence or absence of immune complexes and extravascular inflammatory changes. Together with the typical organ involvement and serological data, these criteria constitute the basis of vasculitis classification. Differential diagnostic overlaps and possible discrimination methods are presented. In the same way that the clinical approach of vasculitis patients is an interdisciplinary one, histopathology can only provide a definite diagnosis in combination with clinical and serological data. A conclusive morphological diagnosis depends on the right time of biopsy and the selection of appropriate biopsy material.

Single cell analysis of B lymphocytes from Wegener's granulomatosis: B cell receptors display affinity maturation within the granulomatous lesions.

Increased amounts of anti-neutrophil cytoplasm antibody (ANCA) directed against proteinase 3 (PR3) are a diagnostic and pathogenic hallmark of full-blown Wegener's granulomatosis (WG). Aggregates of B lymphocytes proximal to PR3+ cells as well as plasma cells have been described as substantial components of Wegener's granuloma and could participate in forming tertiary lymphoid structures, which might promote autoantibody formation. Our aim was a molecular analysis of single B cells in order to develop a methodological approach that allows examination of potential ANCA formation in the tissue. Single B cells from cryo-conserved endonasal biopsies of three WG patients were isolated, using laser-assisted microdissection. Subsequently, their immunoglobulin variable heavy (VH) and light (Vkappa, Vlambda) chain genes were analysed by single cell polymerase chain reaction and direct sequencing. Sixteen immunoglobulin VH-Vkappa or VH-Vlambda chain gene couples were characterized. Twelve of these immunoglobulin gene couples resembled memory B cells. Two offsprings of one B cell were detected, indicating clonal expansion. VH genes representing 39 single B cells of WG tissues displayed significantly more mutations when compared with VH genes from peripheral blood of a healthy donor. The findings confirm and extend our previous results, arguing for an initial selection and affinity maturation of B cells within Wegener's granuloma. Further, the methodology provides the initial basis for the recombinant generation of antibodies derived from tissue cells.

Unclassified vasculitis with acral ischemic lesions: "forme fruste" or idiopathic vasculitis?

BACKGROUND AND OBJECTIVES: While acral ischemia and necrosis represent a common problem in connective tissue diseases and other disorders, acral ischemic lesions are also occasionally encountered in primary and secondary systemic vasculitides. Here we report on the course of 4 patients with acral ischemic lesions as a hallmark of unclassified vasculitis. We compare these cases with 4 additional cases of acral ischemia complicating classified vasculitis. OBJECTIVES: To report on our experience with cases of unclassified vasculitis and acral ischemic lesions during the past 5 years and review the literature on vasculitis and acral ischemic lesions. METHODS: The case history of one of the patients with unclassified vasculitis and acral ischemic lesions is reported in detail. The Medical history of another 3 patients presenting with vasculitic acral ischemic lesions and unclassified vasculitis during the past 5 years in our department (Lübeck/Bad Bramstedt) is summarized and compared to the course of patients with acral ischemic lesions complicating classified vasculitides. A PubMed database review of reports on acral ischemic lesions and vasculitis from 1985 to August 2006 was performed using the following combination of keywords: "Vasculitis" [MeSH] AND ("Necrosis" [MeSH] OR "Ischemia" [MeSH] OR "Infarction" [MeSH]) AND ("Extremities" [MeSH] OR "Fingers [MeSH] OR "Toes" [MeSH] OR "limb"), yielding 1328 entries. This search was subsequently limited to "Humans, All Adult (19+ years)", yielding 904 entries. Only three (0.7%) of these entries described one (one paper) or more (n=28) patients (two papers) with idiopathic vasculitis characterized by digit necrosis in the absence of systemic manifestations (except in some cases for arthralgia) or laboratory parameters pointing to a diagnosis of an established type of vasculitis. RESULTS: A 37-year-old female presented with acral ischemic lesions of the left forefoot, fingers and toes, and Raynaud's phenomenon. Angiography showed multiple stenoses of ulnar and digital arteries, anterior and posterior tibialis arteries, and occlusions of radial artery and occlusion of the plantar artery in the absence of large vessel abnormalities. Histological analysis of an amputation disclosed giant cell arteritis of small vessels. The patient achieved remission with immunosuppressive treatment (cyclophosphamide and prednisolone). Three other patients with acral ischemic lesions and unclassified vasculitis also lacking other manifestations and defining laboratory and technical features during initial presentation and follow-up of 4 month to 5 years are presented. Necrotizing and leukocytoclastic vasculitis were present in two other patients, respectively. In contrast, acral ischemic lesions could be attributed to rheumatoid vasculitis and essential cryoglobulinemic vasculitis in two other cases each based on the patient's history and laboratory findings at the time of presentation of acral ischemic lesions. CONCLUSIONS: While acral ischemic lesions could represent initial or isolated (forme fruste) manifestations of a defined vasculitis, acral ischemic lesions may rarely be encountered as the predominant manifestation of an as yet unclassified vasculitis. the histological findings seem to differ. Our report includes a peculiar case of giant cell arteritis of small arteries not classifiable as giant cell arteritis of large arteries or Takayasu disease.

[Hypereosinophilic syndrome and Churg-Strauss syndrome: is it clinically relevant to differentiate these syndromes?]. / Hypereosinophiles Syndrom und Churg-Strauss-Syndrom. Ist die Differenzierung der Syndrome klinisch relevant?

Churg-Strauss syndrome and the hypereosinophilic syndrome share many clinical features, particularly in the early disease stages. Beside blood and tissue eosinophilia, peripheral neuropathies, cutaneous manifestations, eosinophilic alveolitis and gastroenteritis are frequently found. In contrast to the hypereosinophilic syndrome, Churg-Strauss syndrome is defined by the presence of systemic vasculitis. However, frequently symptoms related to eosinophilia are (mis)interpreted as indirect signs of vasculitis. New treatment modalities and diagnostic methods render the early differentiation between Churg-Strauss syndrome and the hypereosinophilic syndrome increasingly clinically important. Patients with hypereosinophilic syndrome should be tested for the presence of the FIP1L1-PDGRFA-mutatition in order to identify patients that could benefit from a treatment with a tyrosine kinase inhibitor such as Imatinib. At present, immunosuppression is still the treatment of first choice for Churg-Strauss syndrome. Novel treatment modalities for both diseases include immunomodulation with interferon alpha and biologics such as antibodies against interleukin 5.

Immune phenomena in localized and generalized Wegener's granulomatosis.

Wegener's granulomatosis (WG) is characterized by granulomatous inflammation and systemic vasculitis with a predilection for the lungs and kidneys. In most patients WG begins with a localized organ involvement of the upper respiratory tract that progresses to systemic disease (generalized WG) (1). Because of the life-threatening nature of systemic vasculitis, much effort has concentrated on elucidating the pathogenesis of the vasculitis. However, based upon a renewed interest in (innate) immune defenses against microbes, a better understanding of the chronic granulomatous inflammation may contribute to a more precise insight into the early genesis of WG. Thus, this review focuses on summarizing and discussing data for a potential pattern of disease, i.e. from localized to generalized WG with a special emphasis on granulomatous lesions of the upper respiratory tract and their alterations during the disease course.

Severe CNS manifestations as the clinical hallmark in generalized Wegener's granulomatosis consistently negative for antineutrophil cytoplasmic antibodies (ANCA). A report of 3 cases and a review of the literature.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 are highly specific for Wegener's granulomatosis (WG); their sensitivity for active generalized WG is nearly 100%. There are patients, however, who fulfill both the ACR 1990 criteria and the CHC 1992 definition for WG but who remain ANCA negative. The authors report 3 young patients with biopsy-proven active generalized WG who were consistently negative for ANCA over observation times ranging from 58 to 114 months. METHODS: ANCA titers were determined serially every 3 months. ANCA-negativity was defined by the absence of any fluorescence pattern on IFT plus the absence of any specific ELISA reactions. This included negative results for the antibody classes IgG, IgM and IgA. The sera of all patients were also tested in a capture PR3-ANCA ELISA. At 1- to 6-month intervals each patient underwent a standardized set of interdisciplinary examinations. RESULTS: Although CNS involvement in large WG cohorts is about 10%, severe CNS manifestations were the clinical hallmark in all 3 patients. One patient suffered from both intraspinal and intracerebral disease with fatal outcome; the other 2 had meningeal manifestations that responded favorably to immunosuppressive therapy. CONCLUSION: Severe CNS manifestations could represent a clinical hallmark of patients with generalized Wegener's granulomatosis who are consistently negative for antineutrophil cytoplasmic antibodies (ANCA).