Francesca Maggiani

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.

BACKGROUND: Tissue necrosis and a macrophage and perivascular lymphocytic infiltrate are commonly seen in periprosthetic tissues around metal-on-metal hip resurfacing implants, including pseudotumors associated with these implants. The purpose of the present study was to correlate pathological changes in periprosthetic tissues with clinical findings and the amount of implant-derived metal wear. METHODS: We analyzed morphological changes in the periprosthetic soft tissues around fifty-six failed metal-on-metal hip resurfacing implants. The most common reason for failure was the presence of a symptomatic pseudotumor (n = 45). The extent of necrosis and the nature of the inflammatory cell infiltrate, including aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL), was evaluated semiquantitatively. Bearing surface wear was determined for all patients. Prostheses were considered to be highly worn if the total linear wear rate was ≥4 μm/yr. RESULTS: Substantial necrosis and a heavy macrophage infiltrate were noted in most periprosthetic tissues, including all pseudotumors, many of which contained a prominent ALVAL infiltrate. Most pseudotumors (80%) were associated with highly worn prostheses. It was noted that the extent of necrosis and macrophage infiltration correlated with the volume of generated metal wear. Although increased wear volume moderately correlated with a high ALVAL response, all pseudotumors associated with low wear had a strong ALVAL response. CONCLUSIONS: The majority of pseudotumors are associated with increased implant wear. This increased wear is associated with soft-tissue necrosis and a heavy nonspecific foreign-body macrophage response coupled with a variable adaptive or specific immune response (ALVAL). A minority of pseudotumors are associated with low wear and a prominent immune response. These findings confirm that minimizing wear from metal-on-metal hip resurfacing arthroplasty prostheses would lead to a reduction in the incidence of pseudotumor. However, a small number of pseudotumors are still likely to occur, which may be due to an exacerbated adaptive immune response.

To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75% of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours.