[Morphological characteristics of osteopetrosis]. / Morphologische Veränderungen des Knochengewebes bei Osteopetrose.

Osteopetrosis is a rare inherited bone disorder characterized by increased bone density owing to failure in bone resorption by the osteoclasts. The disease is genetically and histologically heterogeneous with a wide spectrum of microscopic findings. The histology varies from cases with a total absence of osteoclasts to bone biopsies characterized by high numbers of enlarged multinucleated osteoclasts on a background of sclerotic cancellous bone with or without additional defect of mineralization of the bone matrix. Here we present typical cases of human osteopetrosis on the basis of bone biopsies with four distinct genotypes (mutations of TNFRSF11A, TCIRG1, CNCL7, KINDLIN-3 genes) and discuss genotype-phenotype relationships. Analyzing human bone biopsies of rare skeletal disorders might improve our understanding of bone metabolism with possible implications for the clinical management of other bone diseases.

Calcium gluconate supplementation is effective to balance calcium homeostasis in patients with gastrectomy.

UNLABELLED: We demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice. INTRODUCTION: Gastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification. METHODS: Undecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b-/-) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism. RESULTS: Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p < 0.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6 months (p < 0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria. CONCLUSION: Gastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.

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.

[Detritic synovitis and rare skeletal diseases]. / Detritussynovialitis und seltene Skeletterkrankungen.

Detritic synovitis represents a common finding in routine orthopedic pathology. Microscopically, the synovium displays cartilaginous and bony fragments in the synoviocyte layer or within the subsynovial soft tissues associated with resorptive changes. In the vast majority of cases, detritic synovitis is associated with conditions leading to the destruction of articular cartilage and subchondral bone, such as severe osteoarthritis, collapsed avascular necrosis, diabetes mellitus, Charcot arthropathy or non-union fractures. The objective of this article is to review the literature regarding the microscopic findings in ochronosis, rapidly destructive hip disease and apatite crystal depositions that can enable a confident diagnosis or a limited differential diagnosis of detritic synovitis.

Altered lacunar and vascular porosity in osteogenesis imperfecta mouse bone as revealed by synchrotron tomography contributes to bone fragility.

Osteogenesis imperfecta (brittle bone disease) is caused by mutations in the collagen genes and results in skeletal fragility. Changes in bone porosity at the tissue level indicate changes in bone metabolism and alter bone mechanical integrity. We investigated the cortical bone tissue porosity of a mouse model of the disease, oim, in comparison to a wild type (WT-C57BL/6), and examined the influence of canal architecture on bone mechanical performance. High-resolution 3D representations of the posterior tibial and the lateral humeral mid-diaphysis of the bones were acquired for both mouse groups using synchrotron radiation-based computed tomography at a nominal resolution of 700nm. Volumetric morphometric indices were determined for cortical bone, canal network and osteocyte lacunae. The influence of canal porosity architecture on bone mechanics was investigated using microarchitectural finite element (µFE) models of the cortical bone. Bright-field microscopy of stained sections was used to determine if canals were vascular. Although total cortical porosity was comparable between oim and WT bone, oim bone had more numerous and more branched canals (p<0.001), and more osteocyte lacunae per unit volume compared to WT (p<0.001). Lacunae in oim were more spherical in shape compared to the ellipsoidal WT lacunae (p<0.001). Histology revealed blood vessels in all WT and oim canals. µFE models of cortical bone revealed that small and branched canals, typical of oim bone, increase the risk of bone failure. These results portray a state of compromised bone quality in oim bone at the tissue level, which contributes to its deficient mechanical properties.

[Dupuytren's contracture associated with silicone wear reaction in late failure of lunate bone spacer prosthesis]. / Silikonabriebassoziierte Dupuytren-Kontraktur bei Spätversagen einer Lunatumspacerprothese.

The pathophysiological mechanisms of palmar fibromatosis (Dupuytren's contracture) are still not yet fully understood. In the vast majority of cases, however, reactive changes and reparative processes of tendon tissue can easily be ruled out by clinical and histopathological investigations. This article presents the case of a 62-year-old male patient suffering from palmar fibromatosis associated with a failed silicon spacer of the lunate bone 30 years after index surgery. Although silicon wear particles were observed in distal locations, proximal tendon tissues showed changes consistent with a degenerative palmar fibromatosis in the absence of a pathological wear reaction. The findings are discussed in the light of the current literature on Dupuytren's contracture.

[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).

Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis.

UNLABELLED: Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations. INTRODUCTION: It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated. METHODS: We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation. RESULTS: We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis. CONCLUSION: Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement.

[Intramuscular myxoma of the lower leg]. / Intramuskuläres Myxom des Unterschenkels.

The intramuscular myxoma is a rare benign soft tissue tumor characterized by bland spindle-shaped and stellate cells embedded in hypovascular myxoid stroma. We report the isolated case of a 44-year-old female patient with an intramuscular myxoma in the anterior tibial muscle and report the clinical and radiographic findings. We performed an analysis of the GNAS gene mutation status with a positive finding. In difficult cases, recurrent tumors or small biopsies detection of a GNAS mutation can be useful to confirm the diagnosis of an intramuscular myxoma.

Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development.

Premature fusion of cranial sutures is a common problem with an incidence of 3-5 per 10,000 live births. Despite progress in understanding molecular/genetic factors affecting suture function, the complex process of premature fusion is still poorly understood. In the present study, corresponding excised segments of nine patent and nine prematurely fused sagittal sutures from infants (age range 3-7 months) with a special emphasis on their hierarchical structural configuration were compared. Cell, tissue and architecture characteristics were analysed by transmitted and polarised light microscopy, 2D-histomorphometry, backscattered electron microscopy and energy-dispersive-x-ray analyses. Apart from wider sutural gaps, patent sutures showed histologically increased new bone formation compared to reduced new bone formation and osseous edges with a more mature structure in the fused portions of the sutures. This pattern was accompanied by a lower osteocyte lacunar density and a higher number of evenly mineralised osteons, reflecting pronounced lamellar bone characteristics along the prematurely fused sutures. In contrast, increases in osteocyte lacunar number and size accompanied by mineralisation heterogeneity and randomly oriented collagen fibres predominantly signified woven bone characteristics in patent, still growing suture segments. The already established woven-to-lamellar bone transition provides evidence of advanced bone development in synostotic sutures. Since structural and compositional features of prematurely fused sutures did not show signs of pathological/defective ossification processes, this supports the theory of a normal ossification process in suture synostosis - just locally commencing too early. These histomorphological findings may provide the basis for a better understanding of the pathomechanism of craniosynostosis, and for future strategies to predict suture fusion and to determine surgical intervention.

[Crystal arthropathies]. / Kristallarthropathien.

Crystal arthropathies represent a heterogenic group of skeletal diseases associated with the deposition of mineralised material within joints and periarticular soft tissues. Gout is the most common and pathogenetically best understood crystal arthropathy, followed by basic calcium phosphate and calcium pyrophosphate dihydrate deposition diseases, and, in very rare cases, calcium oxalate crystal arthropathy. These crystals are responsible for different rheumatic syndromes, including acute or chronic synovial inflammation, and also contribute to cartilage degeneration. This review gives an overview of the pathological and clinical changes of these arthropathies.

Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis.

UNLABELLED: Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix. INTRODUCTION: Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia. METHODS: Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy. RESULTS: Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia. CONCLUSIONS: Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.

[Subtrochanteric renal cell carcinoma metastasis: implantation of a femoral head preserving prosthesis]. / Subtrochantäre Nierenzellkarzinommetastase: Hüftkopferhaltender Femurteilersatz.

A 60-year-old man presented to our institution with a singular subtrochanteric renal cell carcinoma metastasis of the right femur. Tumor resection and implantation of a cemented femoral head preserving prosthesis was considered as the best treatment option to obtain a good hip joint function. After successful surgery (R0 resection) the patient was immediately mobilized with full weight-bearing. One year postoperatively the patient presented with good joint function and absolute mobility. X-ray examinations revealed a good position of the implanted prosthesis without signs of tumor recurrence or femoral head necrosis. Implantation of a femoral head preserving prosthesis is a good option for the treatment of subtrochanteric/diaphyseal tumors of the femur.

Effects of strontium ranelate administration on bisphosphonate-altered hydroxyapatite: Matrix incorporation of strontium is accompanied by changes in mineralization and microstructure.

Strontium ranelate (SR) is one therapeutic option for reducing risk of fracture in osteoporosis. The effects of SR treatment on hydroxyapatite (HA) previously altered by bisphosphonate (BP) administration remain to be established. Patients who have received long-term BP treatment and present with persistent high fracture risk are of particular interest. Paired iliac crest biopsies from 15 patients post-BP therapy were subjected to a baseline biopsy and a follow-up biopsy after treatment with 2g SR day⁻¹ after either 6 months (n=5) or 12 months (n=10). Dual energy X-ray absorptiometry scans, serum parameters and biochemical markers were obtained. Quantitative backscattered electron imaging and energy-dispersive X-ray analyses combined with micro-X-ray fluorescence determinations were performed to observe any mineralization changes. Static 2-D histomorphometry was carried out to evaluate cellular and structural indices. After 6 months of SR treatment, increases in osteoid surface and strontium content were observed, but no other indices showed significant change. After 12 months of SR treatment, there was a significant increase in bone volume and trabecular thickness, and further increases in strontium content and backscattered signal intensity. These structural changes were accompanied by increased numbers of osteoblasts and increased osteoid surface and volume. Additionally, low bone resorption, as measured by beta-cross-laps, and a low number of osteoclasts were observed. SR treatment led to increased strontium content within the BP-HA nanocomposites and to increased osteoid indices and bone volume, which is indicative of newly formed bone, while osteoclasts were still suppressed. These data points suggest that SR might be considered as a therapeutic option for patients following long-term BP treatment.

Hypercementosis and odontogenic epithelial hyperplasia associated with a tooth root remnant mimicking a neoplasm. A case report.

Hypercementosis presents as painless, single or multiple non-neoplastic cementum formation beyond the physiological limits of the tooth. It often occurs in the apical area of the involved tooth following infection, chemical or mechanical trauma. We report on radiographic and histopathological findings in a single case of late intraosseous hypercementosis and odontogenic epithelial hyperplasia associated with a minute apical tooth root remnant years after its extraction, mimicking a tumour.

[Osteoid osteoma. X-ray-controlled resection and histologic verification using a minimally invasive diamond bone-cutting system]. / Osteoidosteom. Minimal-invasive, bildwandlergesteuerte Resektion und histopathologische Diagnosesicherung mittels Diamanthohlfräsen.

BACKGROUND: In recent years, osteoid osteomas have been treated more frequently by means of percutaneous procedures. The main disadvantage in patients with suspected osteoid osteoma is the lack of histological verification. Our study presents the results that we obtained using a minimally invasive diamond bone-cutting system allowing histologic verification. MATERIALS AND METHODS: Six patients (age 10-20 years) with osteoid osteoma in the lower extremities were subjected to resection of the nidus using a minimally invasive water-cooled diamond bone-cutting system. All specimens were histologically processed and diagnosed. RESULTS: In all patients the nidus was resected successfully, and the diagnosis was histologically confirmed. The mean operating time was 22.8 min. All patients were allowed full weight-bearing immediately, and hospitalization was a maximum of 2 days. All patients were free of pain and relapse-free during the entire 2-year postoperative follow-up. CONCLUSION: In selected localizations with a clearly visible nidus, the minimally invasive diamond bone-cutting system presented here offers an alternative to the established surgical and percutaneous procedures for treating osteoid osteomas. This procedure combines the advantages of a minimally invasive technique with the option of histological verification of the diagnosis and correct nidus ablation.

[Osteoarthritis--histopathologic diagnosis: typing, grading, and staging]. / Osteoarthrose--histopathologische Begutachtung: Typing, Grading und Staging.

Osteoarthritis is one of the most common diseases in modern western societies, particularly in the elderly, but it is occurring more and more often in the younger and middle-aged population, especially after traumatic injuries. The classification and grading of changes during cartilage degeneration is difficult due to the notoriously high heterogeneity of the disease process and is only partly clinically relevant. Overall, the process of joint destruction can always be evaluated for the pathogenesis (typing), its extent (staging), and the degree of the most extensive focal damage (grading). However, in the clinical routine, description and reporting of the basic findings might be best restricted to specimens obtained from endoprosthetic surgery. Only the identification of previously unknown underlying conditions such as rheumatoid disease, gout, or extensive osteonecrosis is of particular clinical interest.

[Crystal arthropathies]. / Kristallarthropathien.

Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystals are the most common types of pathologic crystals, followed by monosodium urate crystals and, in rare cases, calcium oxalate crystals. These crystals have been associated with a variety of quite different rheumatic syndromes. They are responsible for acute synovial inflammation and also contribute to cartilage degradation and bone lesions within the joint. Although understanding of the molecular mechanisms involved in generating the pathologic effects of these crystals has increased, the role of BCP crystals in particular remains poorly understood. The clinical implication of articular deposits of calcium-containing crystals in osteoarthritis is unknown. This review provides an overview of the clinical and pathological changes of these four different types of crystals.

[Synovial chondromatosis]. / Synoviale Chondromatose.

Primary articular synovial chondromatosis is a benign, self-limiting neoplastic process in which hyaline cartilage nodules form in the synovial tissue. The disease most frequently affects the knee in men, followed by the elbow. The basic feature of this disease is a metaplastic maturation of the mesenchymal cells in the synovial membrane of a joint into cartilage. These cells mature into chondroblasts and form small nodules of cartilage in the synovial membrane. These nodules subsequently enlarge and detach to lie within the joint space. They become free within the joint as multiple small cartilaginous loose bodies nourished by the synovial fluid. The chondrocytes in the loose bodies continue to multiply, and the loose bodies grow in diameter. Calcification appears in the central zone of the loose bodies, and in some cases, enchondral ossification takes place. The operative therapy depends on the stage of the disease: synovectomy with removal of chondral fragments if active intrasynovial disease is present, and removal of the multiple chondral bodies alone in cases of late inactive disease with no synovial abnormalities. Malignant transformation is unusual and can be difficult to distinguish from benign disease.

HER-2/neu analysis in breast cancer bone metastases.

BACKGROUND: HER-2 is the target for antibody-based treatment of breast cancer (trastuzumab), which is highly successful in both advanced disease and the adjuvant setting. HER-2 can be analysed by fluorescence in situ hybridisation (FISH) for gene amplification or immunohistochemistry (IHC) for protein overexpression. AIM: As both methods are known to be influenced by previous tissue processing, to analyse the applicability of both FISH and IHC to decalcified bone metastases of breast cancer. METHODS: A tissue microarray (TMA) was constructed from 149 breast cancer bone metastases. Consecutive TMA sections were analysed by FISH (PathVysion) and IHC (HercepTest). RESULTS: FISH analysis was interpretable in 113 (85.0%) cases. Amplification was seen in 14 (12.4%) interpretable metastases. HER-2 positivity on IHC analysis was 3+ in 9.8% of cases and 2+ in 11.3%. A comparison of the two techniques revealed high concordance. Of the 14 cases of amplification, 10 (71%) showed 3+ IHC staining, two (14%) showed 2+, one (7%) showed 1+, and one (7%) showed 0+. Three of the four amplified cases that did not show 3+ IHC staining had an equivocal FISH result, with a HER-2/centromere 17 ratio of 1.8-2.2. Of the 13 cases that showed IHC 3+ staining, amplification was present in 10 (77%). CONCLUSIONS: HER-2 FISH analysis has an excellent success rate in highly standardised EDTA-decalcified bone metastases, suggesting that this method is easily applicable to decalcified tissues. The high concordance between IHC and FISH suggests that HER-2 IHC may be equally applicable to EDTA-treated tissues as to the usual formalin-fixed tissues.