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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. 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. 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. 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 IX‑A with histopathological infection eradication and type IX‑B with histopathological infection persistence.

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, Muc‑4, 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, TTF‑1, TGB, PSA, androgen receptor, GATA, CD56, chromogranin, CDX‑2, 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.

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, Muc‑4, 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, TTF‑1, TGB, PSA, androgen receptor, GATA, CD56, chromogranin, CDX‑2, 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.In dieser Übersichtarbeit wird die Differenzialdiagnostik von malignen und benignen Gelenktumoren sowie Pseudotumoren der Gelenke und des periimplantären Gewebes dargestellt. Diese sehr heterogene Gruppe von Erkrankungen stellt seltene, aber wichtige Differenzialdiagnosen in der Rheumatologie und in der orthopädischen Rheumatologie dar. Als gewebliche Ursprungssorte liegen die Synovialis, das periartikuläre fibröse Gewebe, das periartikuläre ossäre sowie das periimplantäre Gewebe vor. Pseudotumoren sind als eine eigenständige allerdings heterogene Entität anzusehen. Dieses Bild zeigt sich im Wesentlichen durch umschriebene, somit tumorartige Depositionen von Kristallen, kalkartigen Ablagerungen, vaskulären Malformationen, Ektasien der Synovialis und des Gelenkkapselgewebes, Pseudozysten, aber auch durch fokale destruktive (z. B. fremdmaterialinduzierte) Entzündungen, fokale fibrinoide Nekrosen (im Sinne eines Rheumaknotens) und durch eine High-grade-Synovialitis. Methodisch basiert diese Diagnostik auf konventionellen Standardfärbungen, auf immunhistochemischen Analysen von formalinfixierten und in Paraffin eingebetteten Materialien und auch auf molekularen Diagnoseverfahren. Letztere können insbesondere bei Diagnosen von benignen und malignen Gelenktumoren weisend sein. Rheumapathologisch gelten für die Typisierung von Gelenktumoren folgende Marker: S100, SM-Actin, CD68, CD34, STAT6, Clusterin, Muc‑4, beta-Catenin und MDM2-FISH. Für die Typisierung von periartikulären Karzinommetastasen sind die Marker AE1/AE3, CK8, p63, TTF‑1, TGB, PSA, Androgenrezeptor, GATA, CD56, Chromogranin, CDX‑2, SAT-B2, SALL4, Östrogenrezeptor, Progesteronrezeptor, CD45LCA, CD30, CD79a und S100 wegweisend. Nekrosen, ausgeprägte entzündliche Infiltrationen und reparative entzündliche Veränderungen können die rheumapathologische Einordnung erschweren. Eine Korrelation mit klinischen, mikrobiologischen und radiologischen Daten im Sinne einer interdisziplinären, synergistischen Diagnostik kann daher erforderlich sein.

Bei der aseptischen Knochennekrose handelt es sich um einen Gewebstod und somit um eine Nekrose des Lamellenknochengewebes. Die Bezeichnung aseptisch bezieht sich auf die kausale Pathogenese: Es handelt sich daher nicht um eine infektios, septisch induzierte Knochennekrose wie bei der infektiosen akuten Osteomyelitis. Formalpathogenetisch konnen zwei divergente Pathogeneseprinzipien vorliegen: (1) eine Minderdurchblutung des Lammellenknochens im Sinne einer ischamischen Nekrose oder (2) eine direkte toxische Schadigung von Osteozyten und Osteoblasten mit der Folge von Apoptosen oder Knochennekrose. Die Ursachen der Minderdurchblutung sind vielfaltig und umfassen: vaskulare Malformationen, Koagulopathien, Hamoglobinopathien, maligne hamatologische Erkrankungen, Luftembolien, Dekompressionserkrankungen, Makro- und Mikrotraumata und Vaskulitiden. Die Ursachen fur die direkte Osteozyten‑, Osteoblasten-toxische Schadigung beinhalten im Wesentlichen den Alkoholabusus, medikamentose Therapien (z. B. Chemotherapeutika, Kortison) und Storungen des Lipidmetabolismus. In aktuellen molekularen und zellularen Pathogenesemodellen wird von einer „Dysbalance“ der katabolen und anabolen ossaren Stoffwechselprozessen in Osteozyten und Osteoblasten ausgegangen. Fur die molekulare Pathogenese spielen das RANKL-RANK-System, das ROS-System und die PPAR-Gamma-Signaltransduktion eine wesentliche Rolle. Die histopathologische Differenzialdiagnose einer aseptischen Huftkopfnekrose ist umfassend, beinhaltet alle fokalen ossaren Veranderungen, in welchen Knochennekrosen im unterschiedlichen Ausmas auftreten konnen: infektiose Osteomyelitis, chronische immunologisch bedingte Osteomyelitiden, Pseudarthrose, infizierte Pseudarthrose, Frakturen, Luxation, Epiphysenschaden sowie maligne metastatische intraossare Erkrankungen und nichtmetastatische intraossare malignen Erkrankungen.

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.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.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.

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).

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 (β‑catenin); allergic/immunologic/toxic adverse reactions (CD20, CD3, CD4, CD8, CD117 and for T‑cell characterization T‑bet, GATA-3, and FOXP3).