The aim was to investigate the value of quantitative histological analysis in the diagnosis of fracture-related infection (FRI). The clinical features, microbiology culture results and histological analysis in 156 surgically treated non-unions were used to stratify the likelihood of associated infection. There were 64 confirmed infected non-unions (≥1 confirmatory criteria; pus, sinus and bacterial growth in ≥2 samples), 66 aseptic non-unions (no confirmatory criteria) and 26 possibly infected (pathogen identified from a single specimen and no confirmatory criteria). The histological inflammatory response was assessed by average neutrophil polymorphs (NPs) counts per high power field (HPF) and compared to the established diagnosis.Aim
Patients and Methods
Pathological assessment of periprosthetic tissues is important, not only for diagnosis, but also for understanding the pathobiology of implant failure. The host response to wear particle deposition in periprosthetic tissues is characterised by cell and tissue injury, and a reparative and inflammatory response in which there is an innate and adaptive immune response to the material components of implant wear. Physical and chemical characteristics of implant wear influence the nature of the response in periprosthetic tissues and account for the development of particular complications that lead to implant failure, such as osteolysis which leads to aseptic loosening, and soft-tissue necrosis/inflammation, which can result in pseudotumour formation. The innate response involves phagocytosis of implant-derived wear particles by macrophages; this is determined by pattern recognition receptors and results in expression of cytokines, chemokines and growth factors promoting inflammation and osteoclastogenesis; phagocytosed particles can also be cytotoxic and cause cell and tissue necrosis. The adaptive immune response to wear debris is characterised by the presence of lymphoid cells and most likely occurs as a result of a cell-mediated hypersensitivity reaction to cell and tissue components altered by interaction with the material components of particulate wear, particularly metal ions released from cobalt-chrome wear particles. Cite this article: Professor N. A. Athanasou. The pathobiology and pathology of aseptic implant failure.
Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour of bone which contains numerous osteoclast-like giant cells. GCTB is a locally aggressive tumour which can cause extensive bone destruction that can be difficult to control surgically, up to 35% of cases recurring after simple curettage. Bisphosphonates are anti-resorptive agents that have proved effective in the treatment of a number of osteolytic conditions. In keeping with its known effect on osteoclasts, we found that the aminobisphosphonate zoledronate abolished in vitro lacunar resorption in cultures of osteoclasts isolated from GCTB. The effect of zoledronate and other bisphosphonates on 15 cases of recurrent primary GCTB, four of which had metastasised to the lung, was assessed clinically. Most recurrent tumours did not exhibit progressive enlargement and, in some cases, both primary and metastatic GCTBs showed a degree of radiological improvement following treatment However, tumours did not diminish in size and, in some cases, no apparent treatment effect was noted. Our findings provide in vitro evidence for the use of bisphosphonates to inhibit the progressive osteolysis associated with GCTB. In vivo, these agents produced a degree of clinical and radiological improvement in some cases. This study reports results from three European centres where bisphosphonates are being used to treat recurrent GCTB and highlights the fact that these centres are all employing different clinical indications and different regimes of bisphosphonate treatment. Bisphosphonates have significant side effects and indications for treatment and standardisation of drug type and dosage regimes (and measurement of agreed outcome measures to determine treatment efficacy) should be established before these agents are included as part of a treatment protocol to control GCTB tumour growth and osteolysis.
Giant cell tumour of bone (GCTB) is a primary tumour of bone characterised by a proliferation of mononuclear stromal cells and infiltrating macrophages and osteoclast-like giant cells. GCTB has a variable and unpredictable course and can produce metastatic lesions, mostly in the lungs, in up to 3% of cases. Whether these represent tumour implants rather than true neoplastic secondaries is uncertain. In this study, we analysed morphological and immunophenotypic features of primary GCTBs which metastasised to the lung as well as the metastatic lesions themselves in order to determine if these would provide a clue as to the mechanism of lung metastasis in GCTB. 17 cases of primary GCTB which metastasised to the lung and the lung metastases in these cases were obtained from IOR, Bologna. Morphologically, primary tumours showed variable features, often containing both giant cell-rich and mononuclear stromal cell-rich areas. Mononuclear cells showed frequent mitotic activity and a degree of nuclear pleomorphism; none of the tumours showed cytological features of malignancy. The tumours were highly vascular and frequently contained dilated thin-walled blood vessels and large areas of haemorrhage. GCTB lung metastases were generally small and contained osteoclast-like giant cells and mononuclear stromal cells which showed typical mitotic activity; cytologically, the metastatic tumours were relatively bland and showed little nuclear pleomorphism. Expression of HLA-DR (an allele of which has been associated with a more aggressive GCTB phenotype) and smooth muscle actin (SMA) was noted in stromal cells in primary and secondary GCTBs; frequently, the same pattern of SMA expression was seen in both primary and secondary lesions. Osteoclasts were vitronectin receptor+, CD14-HLA-DR- in both primary and secondary GCTBs. Our findings indicate that mononuclear stromal cells in lung metastases of GCTB often recapitulate the immunophenotype of the primary tumours from which they derive. Taken with the morphological finding that many primary GCTBs are highly vascular and contain areas of haemorrhage, it is possible that the lung “secondaries” of GCTB more likely represent tumour implants than true neoplastic metastases.
Cellular mechanisms that account for tumour osteolysis associated with Ewing’s sarcoma are uncertain. Osteoclasts are marrow-derived multinucleated cells that effect tumour osteolysis. Osteoclasts are known to form from macrophages by both receptor activator for nuclear factor κB ligand (RANKL)-dependent and RANKL-independent mechanisms. In this study our aim has been to determine whether tumour-associated macrophages (TAMs) isolated from Ewing’s sarcoma are capable of differentiating into osteoclasts and to characterise the cellular and humoral mechanisms whereby this occurs. TAMs were isolated from two Ewing’s sarcomas and cultured on both coverslips and dentine slices for up to 21 days with soluble RANKL and human macrophage colony stimulating factor (M-CSF). Osteoclast formation from TAMs (CD14+) was evidenced by the formation of tartrate–resistant acid phosphatase and vitronectin receptor-positive multinucleated cells which were capable of carrying out lacunar resorption. This osteoclast formation and resorption was inhibited by the addition of the bisphosphonate, zoledronate. Osteoclast formation was also seen when Ewing’s sarcoma-derived TAMs were cultured with TNF α in the presence of M-CSF. We also found that TC71 Ewing’s sarcoma cells were capable of independently stimulating osteoclast formation through the release of a soluble factor. These results indicate that TAMs in Ewing’s sarcoma are capable of osteoclast differentiation by both RANKL-dependent and RANKL-independent mechanisms and that Ewing’s sarcoma cells produce an osteoclastogenic factor. The role bisphosphonates may play in inhibiting osteoclast formation and osteolysis in Ewing’s sarcoma merits further investigation.
It has a characteristic radiographic appearance with marked periostitis in the involved bone mimicking osteosarcoma and associated focal abnormality in juxtaposed skeletal sites. With the help of two previously reported cases from the literature of aggressive bone forming tumours in children who presented with marked anorexia and cachexia diagnosed as osteomyelitis and osteosarcoma and treated by ablative surgery this tumour was correctly diagnosed with planned subtotal scapulectomy and reconstruction enabling a good functional result. The systemic symptoms fully resolved following surgery with return of appetite and weight gain.
