[Histopathological diagnostics of arthrofibrosis]. / Histopathologische Diagnostik der Arthrofibrose.

Joint surgery is one of the most important and successful disciplines in surgery; nevertheless, complications still occur, especially in total knee arthroplasty and surgery of the anterior cruciate ligament. A significant disease in this context is arthrofibrosis. This review article presents the cellular and molecular pathogenetic concept of arthrofibrosis, the spectrum of histopathological diagnostics and differential diagnostics and a classification into joint endoprosthesis-associated and non-joint endoprosthesis-associated arthrofibrosis is proposed. The basis of the histopathological diagnostics is the standardized tissue removal with subsequent fixation in formalin. In the case of joint implant failure and the problem of endoprosthesis-associated arthrofibrosis, the histopathological diagnostics can be carried out according to the consensus classification of synovia-like interface membrane (SLIM). Arthrofibrosis is characterized by fibrosis, a high fibroblast cellularity with immunohistochemical detection of cytoplasmic beta catenin expression. The presence of endoprosthesis-associated arthrofibrosis is probable above a threshold of 20 beta catenin positive fibroblasts per high-power field (HPF). The diagnosis of a non-endoprosthesis-associated arthrofibrosis can be classified according to the joint pathology algorithm. Diffuse non-endoprosthesis-associated arthrofibrosis is characterized by generalized proliferation of connective tissue in the whole joint and localized circumscribed arthrofibrosis is characterized by a nodose cyclops-like fibrosis. The clarification of the cause of arthrofibrosis is based on an interdisciplinary cooperation. In addition to the histopathological diagnostics, this includes clinical, surgical, biomechanical, arthroscopic, microbiological, laboratory parameter and radiological findings.

Diagnostic value of the CD 15 focus score in two-stage revision arthroplasty of periprosthetic joint infections : High specificity in diagnosing infect eradication.

INTRODUCTION: The purpose of this study is to use the CD15 focus score (FS) to determine the sensitivity and specificity of bacterial infection persistence in spacer-based two-stage revision arthroplasty. METHODS: The analysis comprises 112 cases that were subjected to revision due to the presence of infection upon replacement of a joint endoprosthesis. The histopathological data were collected in accordance with the synovial-like interface membrane (SLIM) classification and the CD15-FS and correlated with the microbiological data (MD). The quantifying evaluation of the CD15-FS was performed without knowledge regarding the microbiological data (MD). Correlation with the MD was performed after a 14-day cultivation period. RESULTS: With a single evaluation (1 focus, field area: 1.2 mm2) with a score value of 42, the CD15-FS showed a sensitivity for the eradication of infections of 0.64 and a specificity of 0.79 (PPV = 0.5; NPV = 0.87). With tenfold evaluation (10 foci, field area: 12 mm2) with a score value of 220, the sensitivity for the eradication was 0.68, the specificity 0.91 (PPV = 0.7; NPV = 0.89). No statistically significant correlation between the score values and the different infectious species could be detected. Based on the MD in 112 cases the rate of infection eradication was 75%. Polymethylmethacrylate-particles (PMMA) were detected in the perispacertissue in 64 cases (58%). No significant correlation could be established between microbiological pathogen detection and the presence of PMMA. CONCLUSION: In all cases (n = 112), periimplant synovial tissue (SLIM) with variable fibroblastic cellularity, capillary proliferation, leukocytic infiltration, fibrin deposition, new formation of woven bone and detection of PMMA particles was observed. These cases were classified as type IX perispacer synovialis/SLIM: type IX­A with histopathological infection eradication and type IX­B with histopathological infection persistence.

[Joint tumors: rare but important differential diagnoses of malignant and benign tumors as well as pseudotumors in rheumatology]. / Gelenktumoren: Seltene, aber wichtige Differenzialdiagnosen von malignen und benignen Tumoren sowie Pseudotumoren in der Rheumatologie.

This review article elucidates the differential diagnostics of malignant and benign joint tumors, pseudotumors of the joints and the peri-implant tissue, which are rare but important entities in rheumatology and orthopedic rheumatology. The tissue of origin includes the synovium, peri-implant tissue, peri-articular fibrous tissue and peri-articular osseous tissue. Pseudotumors can be viewed as independent but heterogeneous entities. These are essentially manifested as tumor-like depositions of crystals, calcareous deposits, vascular malformations, ectasia of the synovia and joint capsule tissue and pseudocysts. Other causes for pseudotumors are focal destructive inflammation (e.g. induced by foreign bodies), high grade synovitis and focal fibrinoid necrosis (i.e. rheumatoid nodules). Methodologically, these diagnostics are based on conventional standard staining methods, immunohistochemical analyses of formalin-fixed and paraffin-embedded materials and on molecular diagnostic procedures. The latter are of great importance in cases of benign and malignant joint tumors. The most important immunohistochemical markers with respect to joint tumors are S100, SM-actin, CD68, CD34, STAT6, clusterin, Muc­4, beta-catenin and MDM2-FISH. The following markers are recommended for the differential diagnostics and typing of periarticular tumor metastases in the pathology of rheumatic diseases: AE1/AE3, CK8, p63, TTF­1, TGB, PSA, androgen receptor, GATA, CD56, chromogranin, CDX­2, SAT-B2, SALL4, estrogen and progesterone receptors, CD45LCA, CD30, CD79a and S100. Necrosis, inflammatory infiltrations and reparative inflammatory changes may complicate the histopathological classification. Therefore, a correlation with clinical, microbiological and radiological data in the sense of interdisciplinary synergistic diagnostics may be required.

[Pathophysiology of aseptic femoral head necrosis: Pathogenesis and histopathological differential diagnosis]. / Pathophysiologie der aseptischen Hüftkopfnekrose: Pathogenese und histopathologische Differenzialdiagnostik.

BACKGROUND: Aseptic osteonecrosis is characterized by a complete death of the tissue (necrosis), more specifically, an ischemic necrosis of the lamellar bone tissue. The denotation aseptic refers to causal pathogenesis; therefore, it is not a matter of an infectious, septic-induced bone necrosis as in the case of acute infectious osteomyelitis. Formal pathogenesis leads to either (1) a hypoperfusion of the lamellar bone in the sense of an ischemic necrosis or (2) to directly induced damage of osteocytes and osteoblasts, which causes aseptic osteonecrosis. CAUSE: The causes of hypoperfusion/ischemia are manifold and entail vascular malformations, coagulopathies, haemoglobinopathies, thrombotic embolisms, myeloproliferative illnesses, air embolisms, decompression-caused illnesses, macro as well as micro traumata and, finally, vasculitis with necrosis, which complete the vascular-induced spectrum. Direct toxic damage to the osteocytes and osteoblasts is primarily caused by alcohol abuse, medical drug therapies (i. e. chemotherapeutic substances or cortisone) and disorders of the lipid embolism. Contemporary molecular and cellular models of pathogenesis assume a so-called dysbalance of the catabolic and anabolic osseous metabolism in osteocytes and osteoblasts. The RANKL-RANK system, the ROS system and PPAR-gamma signal transduction are involved in the molecular pathogenesis. DIFFERENTIAL DIAGNOSIS: The most relevant histopathologic differential diagnosis entails the complete spectrum of focal osseous changes among which osteonecrosis can occur to a diverse extent: infectious osteomyelitis, chronic immunologic induced osteomyelitis, pseudoarthrosis, infected pseudoarthrosis, bone fractures and malignant metastatic intraosseous diseases and non-metastatic intraosseous malignant diseases.

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.

[Histopathological diagnostic work-up of joint endoprosthesis-associated pathologies]. / Histopathologische Diagnostik von Gelenkendoprothesen-assoziierten Erkrankungen.

Increasing classes of joint implants and the combination of materials results in increased and wear-associated pathologies. According to the revised consensus classification, the following types can be recognized at conventional histological examination: Type I, particle-induced type; Type II, infection type; Type III, combination type; Type IV, indifferent type; Type V arthrofibrotic type; Type VI, allergic/immunological/toxic adverse reactions and Type VII, bone pathologies. Wear particles are histopathologically characterized according to the Krenn particle algorithm which focuses on a descriptive identification of wear particles and the differentiation of other nonwear-related particles. Type VII is considered histologically when there is evidence of a perivascular/interstitial lymphocytic CD20- and CD3-positive infiltrate, presence of mast cells and eosinophils, and tissue necrosis/infarction associated with implant wear material. Since wear particle-induced toxicity cannot be differentiated with certainty from hypersensitivity/allergic reaction on histological examination, immunological-allergological and clinical data should be used as supplementary criteria for the differential diagnosis. Tissue sampling should be performed from periprosthetic soft tissue with location mapping and when feasible also from bone tissue. Additional information regarding the type of implant and clinical, radiological, immunological, and microbiology data should be available to the pathologist. Further immunohistochemical studies are recommended in the following settings: infection (CD15, CD20, CD68); prosthesis-associated arthrofibrosis (ß­catenin); allergic/immunologic/toxic adverse reactions (CD20, CD3, CD4, CD8, CD117 and for T­cell characterization T­bet, GATA-3, and FOXP3).