Diagnostic guidelines for the histological particle algorithm in the periprosthetic neo-synovial tissue.

BACKGROUND: The identification of implant wear particles and non-implant related particles and the characterization of the inflammatory responses in the periprosthetic neo-synovial membrane, bone, and the synovial-like interface membrane (SLIM) play an important role for the evaluation of clinical outcome, correlation with radiological and implant retrieval studies, and understanding of the biological pathways contributing to implant failures in joint arthroplasty. The purpose of this study is to present a comprehensive histological particle algorithm (HPA) as a practical guide to particle identification at routine light microscopy examination. METHODS: The cases used for particle analysis were selected retrospectively from the archives of two institutions and were representative of the implant wear and non-implant related particle spectrum. All particle categories were described according to their size, shape, colour and properties observed at light microscopy, under polarized light, and after histochemical stains when necessary. A unified range of particle size, defined as a measure of length only, is proposed for the wear particles with five classes for polyethylene (PE) particles and four classes for conventional and corrosion metallic particles and ceramic particles. RESULTS: All implant wear and non-implant related particles were described and illustrated in detail by category. A particle scoring system for the periprosthetic tissue/SLIM is proposed as follows: 1) Wear particle identification at light microscopy with a two-step analysis at low (× 25, × 40, and × 100) and high magnification (× 200 and × 400); 2) Identification of the predominant wear particle type with size determination; 3) The presence of non-implant related endogenous and/or foreign particles. A guide for a comprehensive pathology report is also provided with sections for macroscopic and microscopic description, and diagnosis. CONCLUSIONS: The HPA should be considered a standard for the histological analysis of periprosthetic neo-synovial membrane, bone, and SLIM. It provides a basic, standardized tool for the identification of implant wear and non-implant related particles at routine light microscopy examination and aims at reducing intra-observer and inter-observer variability to provide a common platform for multicentric implant retrieval/radiological/histological studies and valuable data for the risk assessment of implant performance for regional and national implant registries and government agencies.

15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics.

The histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0-9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to≤4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of≥5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew's disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8-0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals).

[Fifteen years of the histopathological synovitis score : Review and further developments of a diagnostic score]. / 15 Jahre histopathologischer Synovialitis-Score : Rückblick und Weiterentwicklung eines diagnostischen Scores.

The histopathological synovitis score evaluates in a graded approach, as is largely usual for diagnostic histopathological scores, the immunological and inflammatory changes caused by synovitis. A synovitis score of between 1 and ≤ 4 is classified as low-grade (osteoarthritis-related synovitis, post-traumatic synovitis, meniscopathy-related synovitis and synovitis in hemochromatosis). Synovitis scores of between ≥ 5 and 9 are classified as high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme's arthritis, post-infection/reactive arthritis and peripheral arthritis in Bechterew disease); sensitivity is 61.7% and sensitivity 96.1%. According to receiver operating characteristic (ROC) analysis (AUC: 0.8-0.9), diagnostic value is good. National and international acceptance of the synovitis score has grown since the first publication in 2002 and a related follow-up publication in 2006. PubMed data analysis (as of 11.01.2017) yielded the following citation values according to "cited by PubMed Central articles" for two publications relating to the synovitis score: there were 29 cited-by-PubMed articles for DOI: 10.1078/0344-0338-5710261 , and 44 cited-in-PubMed articles for the second publication, DOI: 10.1111/j.1365-2559.2006.02508 . This makes a total of 73 PubMed citations over a period of 15 years, thereby evidencing the score's international acceptance. Immunohistochemical determination of a number of CD antigens relevant to inflammation has been proposed to further specify the synovitis score for the purposes of risk stratification of high-grade synovitis (e.g., risk of progression and sensitivity to biological agents).

CD15 focus score: Infection diagnosis and stratification into low-virulence and high-virulence microbial pathogens in periprosthetic joint infection.

INTRODUCTION: The aim of the work was to validate the CD15 focus score for the infection pathology of periprosthetic joint infection in a large group and to clarify whether a stratification into low-virulence and high-virulence microbial pathogens is possible by means of the CD15 focus score (quantification of CD15 positive granulocytes). METHODS: The histopathology of 275 synovial tissue samples taken intraoperatively during revision operations (n=127 hip, n=141 knee, n=2 shoulder, n=5 ankle) was evaluated according to the SLIM consensus classification (SLIM=synovial-like interface membrane). Neutrophilic granulocytes (NG) were quantified by the CD15 focus score on the basis of the principle of focal maximum infiltration (focus) with evaluation of one field of vision (about 0.3mm2). The quantification values were compared with the microbiological diagnoses taking into consideration the virulence groups of low-virulence and high-virulence microbial pathogens and mixed infection. RESULTS: The patients with positive microbiological findings (n=160) had significantly (p<0.001, Mann-Whitney U test) higher CD15 focus score values than patients with negative microbiological findings (n=115), the cut-off value being 39 cells per high power field (HPF). The CD15 focus score values of low-virulence microbial pathogens (n=94) were significantly lower (p<0.001, Mann-Whitney U test) than the values of high-virulence microbial pathogens (n=55), the cut-off value being 106 cells per HPF. Based on the microbiological diagnosis the sensitivity with respect to a microbial infection is 0.91, the specificity 0.92 (PPV=0.94; NPV=0.88; accuracy: 0.92; AUC=0.95). Based on the differentiation of the CD15 focus score values between low-virulence and high-virulence microbes the sensitivity is 0.70 and the specificity 0.77 (PPV=0.63; NPV=0.81; accuracy=0.74; AUC=0.74). CONCLUSION: As a result of the high sensitivity and specificity, the easy to use CD15 focus score is a diagnostically valid score for microbial periprosthetic infection. A differentiation between low-virulence and high-virulence microorganism of sufficiently high diagnostic quality is additionally possible as a result of the defined quantification of CD15 positive granulocytes (the CD15 focus score) histopathological diagnosis of microbial infections is possible, which on the one hand supports the microbiological diagnosis and on the other hand by the stratification into low-virulence and high-virulence microbial pathogens could represent an additional basis for a pathogen-specific antibiotic treatment in the event of unclear constellations of findings.

Revised histopathological consensus classification of joint implant related pathology.

This extended classification of joint implant related pathology is a practical histopathologic classification based on defined morphological criteria covering the complete spectrum of pathohistologic changes in periprosthetic tissues. These changes may occur as a consequence of endoprosthetic replacement of large joints and may lead to a reduction in the prosthesis survival rate. We describe the established consensus classification of the periprosthetic membrane, in which aseptic and septic prosthetic loosening can be subdivided into four histological types, as well as histopathological criteria for additional significant pathologies including endoprosthetic-associated arthrofibrosis, particle-induced immunological, inflammatory and toxic mechanisms (adverse reactions), and bone tissue pathologies. These characteristic tissue alterations and their relationships are summarized in the extended classification. Since particle heterogeneity in periprosthetic tissue is high and particle identification is a necessary part of diagnosis, the identification of different types of particles is described in the histopathological particle algorithm. The morphological qualities of prosthetic material particles and the demarcation between abrasion and non-abrasion endogenous particles are also summarized. This feasible classification which is based on low cost standard tissue processing and examination and on well-defined diagnostic criteria is a solid platform for the histological diagnosis of implant associated pathologies providing a stable and reproducible tool for the surgical pathologist. Since this classification is suitable for standardized histopathological diagnostics, it might also provide a useful data set for joint arthroplasty registers, particularly for registers based on so-called routine data.

Histopathological Osteomyelitis Evaluation Score (HOES) - an innovative approach to histopathological diagnostics and scoring of osteomyelitis.

BACKGROUND: Treatment and diagnosis of osteomyelitis are still a challenging problem for surgeons, microbiologists and histopathologists. A direct microbiological detection of bacteria in tissues is still gold standard, but it is not always successful for example in chronic osteomyelitis and/or when an antibiotic treatment has already been started or in cases of low virulent bacteria. The goal of this study was to define diagnostic criteria of osteomyelitis, the inflammatory regression of osteomyelitis ("osteomyelitis score") under specific therapy by the correlation of histopathological and microbiological and clinical standard tests. METHODS: In this retrospective analysis patients with medical history and clinically clear signs of bacterial infection and osteomyelitis underwent surgery between 01.01.2013 and 31.12.2012. Their formal consent was given. Tissue samples were taken during surgery according to defined criteria including surgical interventions. Histopathological diagnosis was carried out by conventional techniques based on defined criteria of bacterial infection in connective tissue, peri-implant membrane and bone. These results were carried out in tables by numbers representing the histopathological criteria of acute osteomyelitis (A1 to A3) as well as the chronic criteria (C1 and C2) in a semiquantitative way (scale 0 to 3). On the other hand a notational, graduated histopathological report was performed. Preoperative clinical diagnosis, perioperative macroscopic diagnosis, histopathological and microbiological findings were correlated. RESULTS: Histopathological samples of 52 surgical interventions based on the preoperative diagnosis "osteomyelitis" (AOM, ECOM or COM) were included. 37 times preoperatively signs of a chronic osteomyelitis (COM), 10 times preoperatively acute osteomyelitis (AOM) was diagnosed. Another 5 patients were preoperatively diagnosed as acute exacerbated osteomyelitis (ECOM). The correlation of the histopathological infection including the inflammatory activity and microbiological detection of bacteria was 57%. The correlation between preoperative diagnosis and histopathological findings was 68%. CONCLUSION: The relatively small 68% correlation between clinical preoperative and histopathological diagnosis and 57% correlation between preoperative clinical diagnosis and microbiological findings indicates: Clinical findings are not sufficient for the diagnosis "osteomyelitis".Clinical findings are not sufficient for the differentiation between AOM, ECOM and COM.Histopathological analysis is the critical factor for the diagnosis ("osteomyelitis") and differential diagnosis (AOM vs. COM).Histopathological analysis represents the basis for further treatment.HOES facilitates the classification of the histopathological findings.HOES is a sufficient tool for the treating physician in order to define the further treatment.

Histopathological, immunohistochemical criteria and confocal laser-scanning data of arthrofibrosis.

Arthrofibrosis (af) is defined as a fibrosing disease of the synovial membrane, after joint operations, with painful restricted range of motion. The aim of this paper was to describe the histopathological substrate of af, hitherto only defined by clinical criteria. Based on a group of 222 tissue samples, the characteristic changes to af were analyzed. The control group comprised 29 cases with neosynovialis of the indifferent type. Due to cytoplasmic SM-actin positivity and the absence of specific cytoplasmic reactivity in CD 68 representation, af fibroblasts were characterized as myofibroblasts. In confocal laser-scanning microscopy, ß-catenin-positive aggregates were detected in the cytoplasm. Over and above this, unequivocal colocalization of ß-catenin and the tight junction protein ZO-1 became manifest, particularly on the cell membrane and, partly, in the cytoplasm. A threshold value of 20 ß-catenin-positive cells/HPF was determined. This enables the histopathological diagnosis of an af to be made (sensitivity: 0.733, specificity: 0.867). Af is a fibrosing disease of the synovial membrane with variable grade of fibrotization (fibroblast cellularity). A threshold value of 20 ß-catenin-positive fibroblasts per HPF was defined, which enables the histopathological diagnosis of af.

[Revised consensus classification. Histopathological classification of diseases associated with joint endoprostheses]. / Erweiterte Konsensusklassifikation. Histopathologische Klassifikation von Gelenkendoprothesen-assoziierten Erkrankungen.

The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register).

[Synovialitis of the arthrofibrotic type: criteria of a new synovialitis type for the diagnosis of arthrofibrosis]. / Synovialitis vom arthrofibrotischen Typ: Kriterien eines neuen Synovialitis-Typus für die Diagnose der Arthrofibrose.

After rheumatologic conservative medical therapy has been exhausted in degenerative and inflammatory joint diseases, arthroplastic operations are an important option to restore quality of life. Endoprosthesis-associated arthrofibrosis is a severe fibrosing disease of the synovial membrane after endoprosthetic operations. Neither the morphological substrate nor histopathological criteria have been described. The aim was to describe the histopathological substrate of arthrofibrosis and to define histological and immunohistochemical criteria of arthrofibrosis on the basis of tissue samples derived from revision. In histopathological analyses arthrofibrosis revealed a synovialitis with varying fibrosis, without detectable ossification and without minimal wear particle reaction (so-called synovialitis of arthrofibrotic type, SAT). A 3-stage grading was determined based on the cellular density of the fibrous tissue (fibroblast cellularity). In 191 cases with SAT, grade 1 was found in 24.1 % (n = 46), grade 2 was found in 51.8 % (n = 99) and grade 3 was found in 24.1 % (n = 46). The control group consisted of 29 cases with synovialitis of indifferent type (type IV membrane). If SAT grades 2 and 3 are summed together, i.e. the distance between the fibroblasts was less than two cell lengths, the difference of the fibroblast cellularity compared with the type IV membrane was significant (p < 0.001). Above SAT grade 2 the diagnosis of arthrofibrosis could be made with a sensitivity 0.7592 and specificity 0.8276. The SM-alpha-actin cytoplasmic positivity of fibroblasts indicates a myofibroblast phenotype and the ß-catenin positivity suggests a resemblance to fibromatosis or a keloid-like process. In the quantitative evaluation of the ß-catenin positive fibroblasts, there was a significant difference (p < 0.001) between type IV membrane and SAT. A threshold value of 20 beta-catenin positive cells per microscopic high power field (HPF) was determined, which represents in conjunction with the clinical information a new histopathological diagnosis component (sensitivity 0.720, specificity 0.867).

[Infectious bone diseases]. / Infektiöse Knochenerkrankungen.

Bacterial infection of the bone is a severe disease with complications, potentially including long-term physical disability. The diagnosis and therapy of osteomyelitis include several elements: histopathology, microbiology, radiologic imagining, as well as antibiotic and surgical therapy. Histopathologists differentiate between acute osteomyelitis (infiltration of cancellous bone with neutrophil granulocytes); specific osteomyelitis (epithelioid-like granulomatous inflammation, tuberculosis, mycotic infections); primary/secondary chronic osteomyelitis (lymphocytic infiltration); and special forms of chronic osteomyelitis (varying histomorphology, Brodie abscess, SAPHO syndrome). Another important task in the histopathological diagnosis of inflammatory bone diseases is to differentiate osteomyelitis from malignant entities (sarcoma, lymphoma). Therefore, biopsy samples should be of sufficient size for safe diagnosis. Clinical information and imaging as well as interdisciplinary teamwork between radiologists, microbiologists, orthopedic surgeons and pathologists is mandatory to verify these diagnoses.

[Seed migration to the vertebral venous plexus after prostate brachytherapy]. / Seedmigration in den vertebralen Venenplexus nach Prostatabrachytherapie.

We report on seed migration to the vertebral venous plexus after low dose rate prostate brachytherapy with (125)I. A 74-year-old man with T1c N0 M0 adenocarcinoma of the prostate with a Gleason score of 6 (3+3) and prostate-specific antigen level of 14.94 ng/ml underwent interstitial prostate brachytherapy. Six weeks after treatment at the follow-up to determine aftercare a migrated seed was detected in the vertebral venous plexus and a second one in the right lung. No tissue damage around the migrated seeds was documented and the patient exhibited no clinical symptoms.

[Meniscal degeneration score and NITEGE expression : immunohistochemical detection of NITEGE in advanced meniscal degeneration]. / Meniskusdegenerationsscore und NITEGE-Expression : Immunhistochemischer NITEGE-Nachweis in der schwergradigen Meniskusdegeneration.

BACKGROUND: Meniscal degeneration (MD) is a structural change of fibrous cartilage that is common in orthopaedic diagnostics and relevant for health insurance matters. So far, there has been neither a standardised scoring system nor an immunohistochemical marker for MD. MATERIAL AND METHOD: In this retrospective trial, the meniscal tissue of 60 patients was assessed immunohistochemically for NITEGE (G1 fragment of the proteoglycan aggrecan) expression. NITEGE expression was correlated with defined grades of MD: little (grade 0/1), medium (grade 2), or severe (grade 3). RESULTS: Detection of extracellular NITEGE deposits in grade 2 or 3 MD had a positive predictive value and specificity of 100%, whereas no deposits were found in grade 0/1 MD. Sensitivity in advanced MD was 55%. Detection of extracellular NITEGE correlated positively with the grade of degeneration, as did patient age and the grade of degeneration. The patient age of those with grade 0/1 MD was significantly lower than for grade 3 (p<0.0001). CONCLUSION: The thoroughly defined degeneration score (grade 1 - grade 3 MD) is suitable to assess the severity of degeneration. Extracellular NITEGE deposits can be regarded as an immunohistochemical marker for advanced (grades 2 and 3) MD.

[The area of conflict between the surgeon's duty to inform about diagnosis, prognosis, operation, complications, time schedule, alternative methods and the patient's right of self-determination]. / Das Spannungsfeld zwischen der Aufklärungspflicht des Chirurgen über Diagnose, Prognose, Operation, Komplikationen, zeitlichen Ablauf, alternative Methoden und dem Selbstbestimmungsrecht des Patienten.

The surgeon's duty to inform patients determines the indication to a therapeutic and/ or diagnostic procedure. Despite ongoing information made available by the professional associations, the complaints against surgeons providing treatment are on the increase. Only careful health education information with records kept of the course of treatment adopted will safeguard the doctor in charge from patients' claims for damages. Case law demands that the doctor put the patient in a position to understand what is happening to him or her and for him or her to be able to make a decision freely. The patient's compliance after being provided with health education information makes the corpus delicti of bodily harm void. A special form is the matter of fact of "transfer negligence", when the doctor and/ or the hospital is aware, prior to execution of the treatment, that treatment is not possible lege artis. What continues to be applicable to health education information is that the more urgent the operation, the less information is indicated, so that in emergencies such operation can be completely done without. Apart from general risks, such as wound infection and/or the danger of thrombosis, information must also be provided about special risks and the course of any follow-up treatment. Legal practice shows that simply handing over forms is not sufficient. The patient may forgo treatment. Aborting an operation for purposes of providing health information is balancing between the patient's interests in immediate execution of the indicated measure, on the one hand, and the right of self-determination on the other. Should the operation be able to be aborted without any serious consequences for the patient, then it is to be thus done.What does principally apply in civil litigation is the rule of the burden of proof.

[Histopathological degeneration score of fibrous cartilage. Low- and high-grade meniscal degeneration]. / Histopathologischer Degenerations-Score des Faserknorpels. Low-grade- und High-grade-Meniskusdegeneration.

Although histopathology of meniscal degeneration plays an important role, no criteria to assess severity of the degeneration are available to date. Our aim was to create a histopathological scoring system for meniscal degeneration with good interobserver variability, taking matrix degradation and cellularity in meniscal tissue into consideration. Degeneration is classified as follows: grade 1 (low), grade 2 (intermediate), grade 3 (high). The pattern of NITEGE deposits (G1 fragment of aggrecan) was assessed immunohistochemically (n=38) and compared with the grades of degeneration. In 48% of the patients with grade 2 or 3 degeneration extracellular NITEGE deposits (specificity 100%) were found, whereas grade 1 patients showed no deposits. Extracellular NITEGE deposits correlated positively with the grade of degeneration. In all, 30 cases (10 per grade) were assessed by three pathologists (A, B, C). Grading conformity was 70% for grade 1, 66% for grade 2 and 100% for grade 3. Cohen's Kappa coefficient was 0.6--0.7 between pairs of observers. Combining grade 1 and 2 to low-grade degeneration, compared to a grade-3 high-grade degeneration achieved Kappa coefficients of between 0.93 and 1.0. This reproducible degeneration score for fibrous cartilage could form the basis for the standardized assessment of meniscal degeneration.

[Is bioptic assurance reasonable in patients with Sjögren's syndrome? From focus score to diagnosing vasculitides]. / Ist eine bioptische Sicherung beim Sjögren-Syndrom sinnvoll? Vom Focus-Score zur Vaskulitisdiagnostik.

Sjögren's syndrome is an autoimmune disease which targets the salivary and lacrimal glands in particular, causing sicca syndrome. Extraglandular manifestations are often seen. Chronic sialadenitis of the parotid gland is the most common symptom to be assessed for differential diagnosis. Common HE and Giemsa slices are histopathologically examined and graduated for lymphocyte infiltration (focus): grade 0: absent, grade 1: slight, grade 2: moderate non-focal infiltration, grade 3: 1 focus (> or =50 lymphocytes) per 4 mm2, grade 4: >1 focus. Grade 3 infiltrates correspond to a focus score of 1, which is one of four disease-classifying criteria acknowledged for diagnosis. Bioptic examination is also performed to rule out different (non-) immunologic sialadenitises, such as the necrotizing or epithelioid-like form (in sarcoidosis), and the extranodal marginal-zone lymphoma. Extraglandular manifestations of Sjögren's syndrome can also be safely diagnosed by histopathological examination. Emphases lie on vasculitides and myositides. Bioptic work-up, therefore, is not only reasonable but also an essential tool for diagnostics in Sjögren's syndrome.

Tumor regression by means of magnetic drug targeting.

The expression 'magnetic drug targeting' is understood as meaning the targeted administration of a drug, for example, a cytostatic, with the intention of optimizing the local therapeutic effect. A magnetic field strength of 0.6 T is applied externally to the body. Iron oxides are administered intravasally into a vein. Cytostatics are bonded to the iron oxides. This form of administration, also known as sluicing, is particularly suitable for cytostatics, since the intention is to achieve a high concentration of the cytostatic at the target site (site of the tumor), but to minimize the harmful effect in the rest of the tissue. A reduction in tumor volume under the magnetic field and in the liver of 45-90% has been detected by MRI.

Colocalization of C4d deposits/CD68+ macrophages in rheumatoid nodule and granuloma annulare: immunohistochemical evidence of a complement-mediated mechanism in fibrinoid necrosis.

Rheumatoid nodule (RN) represents a palisading granuloma with central fibrinoid necrosis, which is not only a classical manifestation of rheumatoid arthritis (RA) and part of the American College of Rheumatology (ACR)-criteria, but also is its diagnostic hallmark. The pathogenesis of RN is still not fully understood. At present, only data on serum analyses indicating a complement-mediated pathogenesis in the development of RA are available. Equivalent examinations for RN have not yet been performed. Granuloma annulare (GA) represents another type of palisading granuloma. A special subtype of GA, subcutaneous GA (SGA), is an important differential diagnosis to RN. Therefore, our aim was to examine RN and SGA regarding the complement deposition (C4d) by immunohistochemical means. All RN and GA were stained by hematoxylin/eosin and different special stains. In addition, all specimens were stained immunohistochemically with antibodies against CD68. Five GA and five RN were analyzed immunohistochemically with antibodies against C4d and CD68, and evaluated using single- and doublestaining immunohistochemistry. All RN and GA displayed depositions of C4d within their central necroses and between the surrounding palisading macrophages. Most importantly, C4d/CD68 double staining was visible in the palisading macrophages next to the necroses, while macrophages in the periphery were negative for C4d but positive for CD68. The main difference between RN and GA was a quantitative phenomenon with less positively reacting macrophages in a more incomplete palisade in GA. The positive reactions of all central necroses to C4d and colocalization of CD68 and C4d suggest that a complement-mediated mechanism may be operative in the formation of fibrinoid necrosis. This mechanism may be involved in any form of "fibrinoid necrosis", since no different patterns of C4d/CD68 expression could be observed in GA. This may explain why RG/GA are not distinguishable morphologically.

[Diagnostic spectrum of synovitis]. / Das differenzialdiagnostische Spektrum der Synovialitis.

This review will suggest an algorithm for standardised histopathological diagnosis of synovial biopsies and synovectomy specimens. In principal, changes of the synovial membrane can be inflammatory or non-inflammatory. To the latter group belong some benign tumors, such as tenosynovial giant cell tumor, lipoma or synovial chondromatosis. Rare non-inflammatory changes are the group of storage diseases. Inflammatory synovial diseases can be differentiated into crystal-induced arthropathy, such as gout and pseudogout, granulomatous diseases, such as tuberculosis, sarcoidosis and foreign body reactions and into the large group of non-granulomatous synovitis. This last group is by far the most common and often causes difficulties in assigning the histopathological findings to a definite diagnosis. Therefore, the synovitis score should be applied in these cases as a diagnostic means, leading to the diagnosis of low-grade synovitis (which is associated with degenerative and posttraumatic arthropathies) or high-grade synovitis (associated with rheumatic diseases), the sensitivity and specificity being 60.5% and 95.5%, respectively. In detritus synovitis the synovitis score is not applicable.

Gene expression in endoprosthesis loosening: chitinase activity for early diagnosis?

The aim of the study was to identify markers for the early diagnosis of endoprosthesis loosening, for the differentiation between wear particle-induced and septic loosening and to gather new insights into the pathogenesis of endoprosthesis loosening. Gene expression profiles were generated from five periprosthetic membranes of wear particle-induced and five of infectious (septic) type using Affymetrix HG U133A oligonucleotide microarrays. The results of selected differentially expressed genes were validated by RT-PCR (n = 30). The enzyme activity and the genotype of chitinase-1 were assessed in serum samples from 313 consecutive patients hospitalized for endoprosthesis loosening (n = 54) or for other reasons, serving as control subjects (n = 259). Eight hundred twenty-four genes were differentially expressed with a fold change greater than 2 (data sets on http://www.ncbi.nlm.nih.gov/geo/ GSE 7103). Among these were chitinase 1, CD52, calpain 3, apolipoprotein, CD18, lysyl oxidase, cathepsin D, E-cadherin, VE-cadherin, nidogen, angiopoietin 1, and thrombospondin 2. Their differential expression levels were validated by RT-PCR. The chitinase activity was significantly higher in the blood from patients with wear particle-induced prosthesis loosening (p = 0.001). However, chitinase activity as a marker for early diagnosis has a specificity of 83% and a sensitivity of 52%, due to a high variability both in the disease and in the control group.

[Synovitis score: value of histopathological diagnostics in unclear arthritis. Case reports from rheumatological pathological practice]. / Synovialitis-Score: Wertigkeit histopathologischer Diagnostik bei unklaren Arthritiden. Fallberichte aus der rheumatologisch-pathologischen Praxis.

Histopathological assessment of synovial biopsies has an established value. The value for inflammatory joint diseases without standardized rating mechanisms was, however, unknown until recently. The exemplary use of the synovitis score in four cases all including recurrent bruises of the knee joint portrays its value for diagnosis and therapy. Usage of the score includes assessing the enlargement of the lining layer, cellular density of synovial stroma and leucocyte infiltration by giving each a score of 0-3 points and adding them. Presence of high-grade synovitis (>or=4 points) in all cases displayed the reason for the joint bruises within a primarily inflammatory, rheumatoid circle. In this report we show the broad variety of uses for the synovitis score dealing with cases of Lyme arthritis, rheumatoid arthritis, seronegative monarthritis and HLA-B27-positive peripheral arthritis.