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Aims: Osteoblastoma-like osteosarcoma is a rare variant of osteosarcoma (1% of all osteosarcomas), histologically similar to osteoblastoma. In the current World Health Organisation (WHO) classification, osteoblastoma-like osteosarcoma is classified within the group of conventional (high-grade) osteosarcomas. However, several published cases have been actually regarded as low-grade malignant tumours. As strict morphological criteria to distinguish between low- and high-grade lesions are not available, we reviewed our series of osteoblastoma-like osteosarcomas in the attempt to identify clinical and morphological features predictive of aggressiveness. Methods and results: We retrieved 15 cases of osteoblastoma-like osteosarcoma from the files of the Istituto Ortopedico Rizzoli. Patients received various treatments. Five patients developed metastasis and five patients developed local recurrences (all after incomplete surgery). Eleven patients were alive without disease, while four patients died of their disease. Statistical analysis revealed a statistically significant (P=0.048) lower disease-free survival in patients with areas of conventional (high-grade) osteosarcoma. Conclusions: With the important limitation of a small cohort of patients, the presence of areas of conventional (high-grade) osteosarcoma is the only parameter to predict the aggressiveness of osteoblastoma-like osteosarcoma.

Aims Giant cell tumor of soft tissue (GCT-ST) is a primary soft tissue neoplasm histologically similar to GCT of bone (GCT-B). Recently, it has been reported that >90% of GCT-B have a driver mutation in H3F3A gene. Since the relationship between GCT-ST and GCT-B is unclear, we compared a series of GCT-ST and GCT-B for the presence of H3F3A mutations and for several immunophenotypic markers. Methods and Results Eight cases of GCT-ST were retrieved from our institutional archives. Fifteen GCT-B served as controls. Direct sequencing for H3F3A mutations in coding regions between codons 1 and 42, including the hot spot codons (28, 35 and 37) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue. Tumors were studied immunohistochemically for the expression of CD14, CD33, RANKL, RANK, P63 and for the osteoblastic markers SATB2 and RUNX2. None of the 7 cases of GCT-ST that could be analyzed presented H3F3A mutations, whereas 14 GCT-Bs (93.3%) were mutated. All 8 cases of GCT-ST were positive for RANK and RUNX2, while RANKL and SATB2 were detected only in 2 cases (25%). CD14 was detected only in mononuclear elements, while multinucleated giant cells and part of the mononuclear population expressed CD33. Few mononuclear cells of GCT-ST expressed P63. In comparison, GCT-B showed higher expression of p63 (14/15 cases with >50% of positive mononuclear cells), RANKL and SATB2, while CD14, CD33, RANK and RUNX2 were similarly expressed. Conclusions Although similar in the histologic appearance, our results indicate that GCT-ST is immunophenotypically and genetically distinct from GCT-B. This article is protected by copyright. All rights reserved.

Aims Round-cell sarcomas lacking specific translocations represent a diagnostic challenge. The aim of this study was to describe seven cases of CIC-DUX4 fusion-positive sarcomas, including the first reported example arising primarily in bone. Methods and results Patients ranged in age from 15 years to 44 years (median: 33 years). Six cases arose from the soft tissues, and one from the iliac bone. Morphologically, all cases showed an undifferentiated round-cell population with greater atypia and pleomorphism than Ewing sarcoma. Immunohistochemically, all tumours showed focal and weak positivity for CD99, and five of seven showed nuclear and/or cytoplasmic positivity for Wilms tumour 1. Five patients had lung metastases at presentation. All patients received chemotherapy according to Ewing sarcoma protocols. All but one patient (the one with a bone tumour) died of disease after a mean of 14.5 months from the diagnosis (range: 8-20 months). Conclusions Our series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis, and with clinical, histological and genetic differences from Ewing sarcoma. The best therapeutic approach needs to be investigated.

Aims To evaluate the clinical impact of excision repair cross-complementation group 1 (ERCC1) expression in high-grade osteosarcoma (OS). Methods and results Immunohistochemistry was performed on biopsies from 99 OS patients enrolled in the ISG/OS-Oss training set or ISG/SSG1 validation set neoadjuvant chemotherapy protocols, based on the use of cisplatin, adriamycin, methotrexate, and ifosfamide. In the training set, ERCC1 positivity was found in eight of 31 (26%) patients, and was significantly associated with worse event-free survival (EFS) (P = 0.042) and overall survival (OVS) (P = 0.001). In the validation set, ERCC1 positivity was found in 22 of 68 (32%) patients, and its significant associations with poorer EFS (P = 0.028) and OVS (P = 0.022) were confirmed. Multivariate analyses performed on the whole patient series indicated that ERCC1 positivity was the only marker that was significantly associated with a higher risk of worse prognosis, in terms of both EFS and OVS (P = 0.013). Co-evaluation of ERCC1 and ABCB1 expression showed that patients who were positive for both markers had a significantly worse prognosis. Conclusions The ERCC1 level at diagnosis is predictive for the outcome of patients with non-metastatic, high-grade OS treated with neoadjuvant chemotherapy, and co-evaluation with ABCB1 can identify high-risk groups of OS patients who are refractory to standard regimens.

Balla P, Moskovszky L, Sapi Z, Forsyth R, Knowles H, Athanasou N A, Szendroi M, Kopper L, Rajnai H, Pinter F, Petak I, Benassi M S, Picci P, Conti A & Krenacs T (2011) Histopathology59, 376–389 Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone Aims: Epidermal growth factor receptor (EGFR) is implicated in bone remodelling. The aim was to determine whether EGFR protein expression contributes to the aggressiveness and recurrence potential of giant cell tumour of bone (GCTB), an osteolytic primary bone tumour that can exhibit markedly variable clinical behaviour. Methods and results: Immunohistochemical analysis on tissue microarrays (TMA) of 231 primary, 97 recurrent, 17 metastatic and 26 malignant GCTBs was performed using TMA analysis software and whole digital slides allowing validated scoring. EGFR expression was restricted to neoplastic stromal cells and was significantly more frequent in recurrent (71 of 92; 77%) than in non-recurrent GCTBs (86 of 162; 53%) (P = 0.002); and in clinicoradiologically aggressive (31 of 43; 72%) than latent (27 of 54; 50%) cases (P = 0.034). Detecting phosphotyrosine epitopes pY1068 and -pY1173 indicated active EGFR signalling, and finding EGFR ligands EGF and transforming growth factor-α restricted to cells of the monocytic lineage suggested paracrine EGFR activation in stromal cells. In functional studies EGF supported proliferation of GCTB stromal cells, and the addition of EGF and macrophage-colony stimulating factor promoted osteoclastogenesis. Conclusion: In GCTB, EGFR signalling in neoplastic stromal cells may contribute to disease progression through promoting stromal cell proliferation and osteoclastogenesis.

Pazzaglia L, Conti A, Chiechi A, Novello C, Magagnoli G, Astolfi A, Pession A, Krenacs T, Alberghini M, Picci P & Benassi M S (2010) Histopathology 57, 59–72 Differential gene expression in classic giant cell tumours of bone: Tenascin C as biological risk factor for local relapses and metastases Aims: To identify candidate prognostic biological markers useful in selecting high-risk patients with classic primary giant cell tumours (GCT). GCT specimens with different behaviour associated with an increased risk of local and/or distant relapses were studied. Methods and results: Screening mRNA microarray analysis followed by real-time polymerase chain reaction and immunohistochemistry on tissue microarray sections was used to validate the prognostic role of differentially expressed genes on a larger series by statistical analysis tests. Global gene expression profiling identified 109 differentially expressed genes according to prognosis. A correlation was found between mRNA levels and clinical outcome identifying Tenascin C (TNC) as the most significant prognostic biological marker. By means of backward Wald logistic regression, TNC overexpression defined an eightfold increased risk for metastasis and fourfold for local recurrence. At the protein level, TNC immunoreactivity resulted in a significant difference in the disease-free survival probability curves, providing a stratification for GCT patients, useful for predicting relapse. Conclusions: Our study provides important data for the selection of biomarkers with a significant clinical impact and suggests the importance of TNC expression in identifying GCT patients at a higher risk of relapse for closer follow-up and adjuvant medical therapy.

Aims Chondrosarcoma is primarily a tumour of adulthood and old age. Some studies indicate that survival is worse in paediatric than in adult chondrosarcomas. In view of the rarity of paediatric chondrosarcoma, few large studies are currently available. Methods and results We evaluated the clinical, radiological and pathological features of a single institution series of chondrosarcomas presenting in patients younger than 17 years between 1981 and 2014. Seventeen patients with central (10), peripheral (five) and periosteal (two) chondrosarcoma were retrieved. The patients received various treatments according to the dimension, stage and grading of the lesions. Only two tumours, treated with resection, recurred after the first diagnosis, at 11 and 108 months, respectively. All patients but one were alive without disease at the time of the last follow-up (median: 148 months). The one patient who died of disease 27 months after diagnosis had a grade 2 central chondrosarcoma of the metacarpal bone. He was affected by Maffucci syndrome and developed multiple bone and lung metastases. Conclusions Chondrosarcoma in children is rare but does exist, and is not limited to the head and neck region. Our findings do not support the current view that chondrosarcomas are more aggressive in children than in adults.

Epidermal growth factor receptor (EGFR) is implicated in bone remodelling. The aim was to determine whether EGFR protein expression contributes to the aggressiveness and recurrence potential of giant cell tumour of bone (GCTB), an osteolytic primary bone tumour that can exhibit markedly variable clinical behaviour.Immunohistochemical analysis on tissue microarrays (TMA) of 231 primary, 97 recurrent, 17 metastatic and 26 malignant GCTBs was performed using TMA analysis software and whole digital slides allowing validated scoring. EGFR expression was restricted to neoplastic stromal cells and was significantly more frequent in recurrent (71 of 92; 77%) than in non-recurrent GCTBs (86 of 162; 53%) (P = 0.002); and in clinicoradiologically aggressive (31 of 43; 72%) than latent (27 of 54; 50%) cases (P = 0.034). Detecting phosphotyrosine epitopes pY1068 and -pY1173 indicated active EGFR signalling, and finding EGFR ligands EGF and transforming growth factor-α restricted to cells of the monocytic lineage suggested paracrine EGFR activation in stromal cells. In functional studies EGF supported proliferation of GCTB stromal cells, and the addition of EGF and macrophage-colony stimulating factor promoted osteoclastogenesis.In GCTB, EGFR signalling in neoplastic stromal cells may contribute to disease progression through promoting stromal cell proliferation and osteoclastogenesis.

To identify candidate prognostic biological markers useful in selecting high-risk patients with classic primary giant cell tumours (GCT). GCT specimens with different behaviour associated with an increased risk of local and/or distant relapses were studied.Screening mRNA microarray analysis followed by real-time polymerase chain reaction and immunohistochemistry on tissue microarray sections was used to validate the prognostic role of differentially expressed genes on a larger series by statistical analysis tests. Global gene expression profiling identified 109 differentially expressed genes according to prognosis. A correlation was found between mRNA levels and clinical outcome identifying Tenascin C (TNC) as the most significant prognostic biological marker. By means of backward Wald logistic regression, TNC overexpression defined an eightfold increased risk for metastasis and fourfold for local recurrence. At the protein level, TNC immunoreactivity resulted in a significant difference in the disease-free survival probability curves, providing a stratification for GCT patients, useful for predicting relapse.Our study provides important data for the selection of biomarkers with a significant clinical impact and suggests the importance of TNC expression in identifying GCT patients at a higher risk of relapse for closer follow-up and adjuvant medical therapy.