Conventional Osteosarcoma Research Articles

Primary Giant Cell Rich Osteosarcoma of Maxilla: An Unusual Case Report

Giant cell rich osteosarcomas, histological variant of conventional osteosarcomas account for 3% of all cases of osteosarcomas and most of them are arise from the appendicular skeleton. Giant cell rich osteosarcomas have been rarely reported in the head and neck region. This is the first case report of giant cell rich variant of osteosarcoma in the maxilla. It is important to recognize this variant, as its prognosis is worse as compared to conventional osteosarcomas of the head and neck region. We here present a case of giant cell rich variant of osteosarcoma of the maxilla and along with its characteristic radiological and histopathological picture.

Impact of close surgical margin on local recurrence and survival in osteosarcoma

Whether neoadjuvant chemotherapy safely allows close margins in osteosarcoma patients is still unknown. This study investigates the impact of close margins on local recurrence (LR) and overall survival (OS) for osteosarcoma patients treated with neoadjuvant chemotherapy. We retrospectively reviewed 47 cases of conventional osteosarcoma who were treated at our institution. Patient and treatment factors such as age, gender, MSTS stage, tumour site, surgery type, pathological type, tumour size, surgical margin, tumour necrosis rate, chemotherapy regimens and cycles were recorded. A close margin was defined as tumour present less than 5 mm from the closest resection margin. The average followup was 87.6 months (range, 25-135 months). Twenty-five patients were alive, 22 patients had died, and eight had LR. Twenty-eight patients had wide margins, seven had positive margins and 12 had close margins. Positive margins had a greater risk of LR (57.1%) than wide margins and close margins. There was no difference in LR (8.3% vs 10.7%) between close margins and wide margins. Margin status was not correlated with OS. Compared with wide margins, close margins did not lead to increased local recurrence in our study group. Whether close margins, as defined in our study, are just as acceptable as wide margins in terms of patient outcomes for osteosarcoma patients with neoadjuvant chemotherapy needs to be further confirmed in the future.

Periosteal Osteosarcoma of the Mandible: Case Report and Review of the Literature

Osteosarcoma (OS) is the most common primary malignancy of bone, with a reported incidence of 1:100,000 per year.1 These tumors typically originate in the extremities and the pelvis, with only 2.7–6.6% of OSs were located in the jaws.2,3 Although conventional OS arises intramedullary, some OSs occur on the outer surface of bone, this is called surface or juxtacortical OS and exhibits distinct radiographic, histologic features and biological behavior that is obviously different from conventional OS. OSs arising on the surface of bone can be classified into three types according to the nature of the tumor: parosteal, periosteal, and high-grade surface OS.4 Parosteal OS is a low-grade OS, with an incidence of about 4% of all OSs. Periosteal OS is an intermediate-grade chondroblastic OS, accounting for less than 2% of all OSs. High-grade surface OS is the most rare subtype, accounting for less than 1%. Periosteal type tends to have a better prognosis than that of conventional OS or high-grade surface OS, but poorer than that of parosteal OS and it is capable of local recurrence and distant metastasis.5 Periosteal OS occurs extremely rarely in the jaws. To our knowledge, including this report, only ten cases have been reported. We report a case of periosteal OS located at the mental region of the mandible and review the literature with respect to clinical, radiological and histopathological criteria, we also discuss the differential diagnosis.

Development of Conventional Osteosarcoma after 13 Years Continuous Disease-free Survival of Periosteal Osteosarcoma

Periosteal osteosarcoma is a rare variant of osteosarcoma and has represented 1-2% of all osteosarcomas. Most local recurrences or progression to metastatic disease occurred within the first 3 years after presentation and lung metastasis is more common than bony metastasis. We describe a periosteal osteosarcoma of tibia patient who developed conventional osteosarcoma of proximal humerus after 13 years from the completion of treatment.

A clinico-morphological study of 95 cases of sarcomas with metastases to the lungs

Metastasis of soft tissue sarcoma most commonly occurs to the lungs. There are very few studies on histology of pulmonary metastatectomy and hardly any wherein the histology of the primary tumor has been compared with the metastasis. To review histologically all metastatic sarcomas to lung and compare with the primary where available. Ninety-five patients with pulmonary metastases from sarcoma were analyzed histologically for type of sarcoma, chemotherapy-related changes, and changes in adjacent lung. Various clinical parameters like laterality, multiplicity, and interval between primary and metastasis were also studied. Osteosarcoma constituted half of the metastatic sarcomas (48 cases, 50.5%) followed by synovial sarcoma (16 cases, 16.8%) and high grade spindle cell sarcoma-NOS (10 cases, 10.5%). The histology of primary and the metastases was similar in 60% of cases of osteosarcoma. Osteosarcoma is the commonest metastatic sarcoma to the lung. There is often a change to fibroblastic histology in patients of conventional osteosarcoma treated with chemotherapy.

Imaging Characteristics of Primary Osteosarcoma: Nonconventional Subtypes

Osteosarcoma (OS) is a common primary malignant tumor of bone that produces osteoid matrix. According to the World Health Organization, OS of bone is classified into eight subtypes with distinct biologic behaviors and clinical outcomes: conventional, telangiectatic, small cell, low-grade central, secondary, parosteal, periosteal, and high-grade surface. Imaging plays a crucial role in the diagnosis of each subtype of OS and ultimately in patients' survival because the diagnosis is based on a combination of histopathologic and imaging features. Conventional OS is the most common subtype of OS and is readily identified at radiography as an intramedullary mass with immature cloudlike bone formation in the metaphyses of long bones. The imaging features of less common subtypes of primary OS are variable and frequently overlap with those of multiple benign and malignant entities, creating substantial diagnostic challenges. For accurate diagnosis, it is important to be aware of radiographic and cross-sectional imaging features that allow differentiation of each nonconventional subtype of OS from its mimics.

Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma

Conventional osteosarcoma is characterized by rapid growth, high local aggressiveness, and metastasizing potential. Patients developing lung metastases experience poor prognosis despite extensive chemotherapy regimens and surgical interventions. Previously we identified a subgroup of osteosarcoma patients with loss of CDKN2A/p16 protein expression in the primary tumor biopsies which was significantly predictive of a very poor prognosis. Here we aimed to identify the underlying mechanism(s) of this protein loss in relation to osteosarcoma behavior. The CDKN2A locus was analyzed in osteosarcoma cases with total loss of CDKN2A/p16 expression and in cases with high protein expression using melting curve analysis-methylation assay (MCA-Meth), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and mutation analysis. All cases with complete CDKN2A/p16 protein loss showed homozygous deletions at the CDKN2A locus. In none of the cases hyper methylation of the promoter region was seen which was confirmed by sequencing this region. Taken together we show that large or smaller deletions of the CDKN2A locus are evident in patient samples and underlie the CDKN2A/p16 protein expression loss while promoter methylation does not appear to be a mechanism of this expression loss. Genomic loss of CDKN2A instead of promoter methylation might be a plausible explanation for the rapid proliferation and high aggressiveness of osteosarcoma by simultaneous impairment CDKN2A/p14(ARF) function.

Expression of heat shock proteins in osteosarcomas

Heat shock proteins (HSPs) protect cells against stress-associated injuries and are overexpressed in several malignant tumours. We investigated the potential roles of HSP27, HSP60, and HSP70 in conventional and low grade central osteosarcoma. Expressions of HSP27, HSP60, and HSP70 were analysed using immunohistochemistry on tissue sections from 52 cases of conventional osteosarcoma and 21 cases of low grade central osteosarcoma. We evaluated the expression of each protein and examined its relationship with clinicopathological parameters. We found significantly different expressions of HSP27 and HSP70 between conventional and low grade central osteosarcoma [34.6% versus 4.8% (p = 0.008), 88.5% versus 14.3% (p < 0.001)]. However, HSP60 was highly expressed in both kinds of osteosarcoma (92.3% versus 85.7%). In conventional osteosarcoma, a higher expression of HSP27 was significantly related to distant metastasis (p = 0.034) and histological subtype [osteoblastic versus non-osteoblastic (p = 0.041)]. The expressions of HSP60 and HSP70 were not significantly related to any tested clinicopathological parameter. HSP27 and HSP70 may be used as differential markers to distinguish conventional and low grade central osteosarcoma. HSP27 may be used as a possible prognostic marker in conventional osteosarcoma cases.

Progression of Aggressive Metastatic Carcinosarcoma After Treatment of Epithelioid Osteosarcoma

Osteosarcoma is the most common primary malignant osseous neoplasm, constituting approximately 35% of skeletal malignancies. The different subtypes of osteosarcoma are differentiated based on clinical, histologic, and radiographic data, as well as the variable amount of osteoid produced by malignant cells. The epithelioid osteosarcoma subtype accounts for only 5.7% of all osteosarcomas and portends an extremely poor prognosis. The 5-year survival rate for patients with epithelioid osteosarcoma treated with surgery (with or without chemotherapy) is 13.5%. This is in direct contrast to the >70% ten-year survival rate of conventional osteosarcoma treated with surgery and chemotherapy. This article presents a fatal case of epithelioid osteosarcoma in an 11-year-old girl with right knee pain of 6 months' duration. Biopsy demonstrated morphologic findings consistent with high-grade osteosarcoma with epithelioid features. The epithelioid component was positive for vimentin and CD99; however, fluorescent in situ hybridization for the (11;22) translocation was negative. In this case, the epithelioid cells failed to respond to conventional or subsequent experimental chemotherapy for osteosarcoma and eventual metastasized to the lymph nodes and lungs despite multiple ablative surgeries. This case report supports the concept of carcinosarcoma with malignant cells lines arising from 2 different cellular lineages or a common cellular precursor. The epithelial component was more aggressive than the cells of mesenchymal origin, highlighting the need for continued research and a more favorable outcome for this rare subset of osteosarcoma.

Expression of Carbonic Anhydrase IX Correlates with Histologic Grade and Metastasis in Osteosarcoma

Background : Carbonic anhydrase IX (CA9) is reportedly overexpressed in several types of carcinomas, but little is known about the expression pattern of CA9 in osteosarcoma. We aimed to assess the prevalence of CA9 expression and its prognostic implications in osteosarcoma patients. Methods : We compared immunohistochemical expression of CA9 between conventional, high-grade and low-grade, central osteosarcomas. Specimens were obtained before chemotherapy and stained with anti-human CA9 antibody. We also evaluated the histologic grade, presence of metastasis, and patient prognosis. Results : Among 38 samples of conventional high-grade osteosarcoma, 22 (57.9%) tumors displayed CA9 overexpression. Twenty-five cases of low-grade central osteosarcomas were all negative (p < 0.0001). CA9 expression was significantly associated with the presence of metastasis (p = 0.0010). The overall survival rate was significantly reduced with increased CA9 expression (p = 0.0012), higher histologic grade (p < 0.0001), and younger age (p = 0.0140). However, the overall survival rate was not significantly correlated with gender, tumor size, or American Joint Committee on Cancer stage. Conclusions : CA9 expression is a frequent and tumor-specific event in osteosarcoma. CA9 expression is associated with higher grade tumors, metastasis and poor prognosis for the osteosarcoma patients.

Inactive Wnt/β‐catenin pathway in conventional high‐grade osteosarcoma

Osteosarcoma is the most common malignant bone tumour, with a peak incidence in children and young adolescents, suggesting a role of rapid bone growth in its pathogenesis. The Wnt/beta-catenin pathway plays a crucial role in skeletal development and is indispensable for osteoblasts' lineage determination. Previous studies suggesting an oncogenic role for the Wnt/beta-catenin pathway in osteosarcoma were based on cytoplasmic staining of beta-catenin or the detection of one component of this pathway. However, those approaches are inappropriate to address whether the Wnt/beta-catenin pathway is functionally active. Therefore, in this study, we examined nuclear beta-catenin expression in 52 human osteosarcoma biopsies, 15 osteoblastomas (benign bone tumours), and four human osteosarcoma cell lines by immunohistochemistry. Furthermore, we modulated Wnt/beta-catenin pathway activity using a GIN (GSK3beta inhibitor) and evaluated its effect on cell growth and osteogenic differentiation. Absence of nuclear beta-catenin staining was found in 90% of the biopsies and all osteosarcoma cell lines, whereas strong nuclear beta-catenin staining was observed in all osteoblastomas. Wnt-luciferase activity was comparable to the negative control in all osteosarcoma cell lines. GIN stimulated the Wnt/beta-catenin pathway, as shown by translocation of beta-catenin into the nucleus and increased Wnt-luciferase activity as well as mRNA expression of AXIN2, a specific downstream target gene. Stimulation of the Wnt/beta-catenin pathway by GIN significantly reduced cell proliferation in the cell lines MG-63 and U-2-OS and enhanced differentiation in the cell lines HOS and SJSA-1, as shown by an increase in alkaline phosphatase (ALP) activity and mineralization. In contrast with the oncogenic role of the Wnt/beta-catenin pathway in osteosarcoma as previous studies suggested, here we demonstrate that this pathway is inactivated in osteosarcoma. Moreover, activation of the Wnt/beta-catenin pathway inhibits cell proliferation or promotes osteogenic differentiation in osteosarcoma cell lines. Our data suggest that loss of Wnt/beta-catenin pathway activity, which is required for osteoblast differentiation, may contribute to osteosarcoma development.

5079 Role of paclitaxel in neoadjuvant chemotherapy in stage IIA-IIIA breast cancer

Purpose: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO.Patients and Methods: Between 1983 and 1998, we treated 20 RIO patients, ages 4–36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times.Results: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7–22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group.Conclusion: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).

Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma

Treatment of high-grade osteosarcoma remains a challenge. The prognostic significance of the pre-treatment serum lactate dehydrogenase (LDH) level is currently controversial. We reviewed records from all patients diagnosed with conventional high-grade osteosarcoma at our institution over a 25-year period and analysed the prognostic significance of LDH in high-grade localised extremity osteosarcomas treated with chemotherapy. Between June 1977 and March 2003, 66 patients for whom follow-up was available were diagnosed with localised high-grade extremity osteosarcoma and treated with chemotherapy. The median age was 15 years, with only 3% older than 40 years, and the median follow-up was 100 months. The median progression-free survival (PFS) was 67 months and the median overall survival (OS) was 113 months. The absence of a response to chemotherapy was correlated with a trend toward lower PFS and OS. High serum pre-treatment LDH level was associated in multivariate analyses with a poorer prognosis for both PFS (HR=8.623, 95%CI: 1.71-43.37; p=0.009) and for OS (HR=9.38; 95%CI: 1.73-50.74; p=0.009). In this series, the pre-treatment serum LDH level had an independent prognostic value for both PFS and OS in patients with high-grade localised extremity osteosarcoma. This measurement should be included in a large prospective prognostic series.

Molecular characterization of the response to chemotherapy in conventional osteosarcomas: Predictive value of HSD17B10 and IFITM2

The therapy regimen of high-grade osteosarcoma includes chemotherapy followed by surgical resection and postoperative chemotherapy. The degree of necrosis following definitive surgery remains the only reliable prognostic factor and is used to guide the choice of postoperative chemotherapy. The aim of this study was to find molecular markers able to classify patients with an osteosarcoma as good or poor responders to chemotherapy before beginning treatment. Gene expression screening of 20 nonmetastatic high-grade osteosarcoma patients was performed using cDNA microarray. Expression of selected relevant genes was validated using QRT-PCR. Immunohistochemistry on tissue microarrays sections of 73 biopsies was performed to investigate protein expression. Fluorescent in situ hybridization was performed for RPL8 gene. We have found that HSD17B10 gene expression was up-regulated in poor responders and that immunohistochemistry expression of HSD17B10 on biopsy before treatment was correlated to response to chemotherapy. Other results include correlation of IFITM2, IFITM3, and RPL8 gene expression to chemotherapy response. A statistical correlation was found between polysomy 8 or gain of RPL8 and good response to chemotherapy. These data suggest that HSD17B10, RPL8, IFITM2, and IFITM3 genes are involved in the response to the chemotherapy and that HSD17B10 may be a therapeutic target. RPL8 and IFITM2 may be useful in the assessment at diagnosis and for stratifying patients taking part in randomized trials.

Femoral parosteal osteosarcoma 18 years after its discovery: A case report

Osteosarcomas are a heterogeneous group of tumors with diverse anatomical, clinical, and progressional characteristics. Parosteal osteosarcoma, or juxtacortical osteosarcoma, is a rare form of osteosarcoma that develops at the bone surface, but has a better prognosis than other conventional osteosarcomas. We report the observation of a 22-year-old female patient whose initial presentation was an enormous tumefaction of the knee that had been progressing for 10 years. The biopsy concluded in PO of the lower third of the femur. Staging was negative. The tumor had reached an enormous size and required amputation of the left lower extremity. A custom external prosthesis was manufactured to get her back to walking. Eight years after surgery, no local recurrence or metastasis has been detected. Parosteal osteosarcoma is a rare form of osteosarcoma with very slow progression (in spite of the particularly dramatic presentation in our observation), with an excellent prognosis and very rare metastasis.

LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization

Osteosarcomas are the most common primary malignant tumor of bone, and almost all conventional osteosarcomas are high-grade tumors with complex karyotypes. We have examined DNA copy number changes in 36 osteosarcoma tumors and 20 cell lines using microarray-based comparative genomic hybridization. The most frequent minimal recurrent regions of gain identified in the tumor samples were in 1q21.2-q21.3 (78% of the samples), 1q21.3-q22 (78%), and 8q22.1 (72%). Minimal recurrent regions in 10q22.1-q22.2 (81%), 6q16.1 (67%), 13q14.2 (67%), and 13q21.1 (67%) were most frequently lost. A small region in 3q13.31 (2.1 Mb) containing the gene limbic system-associated membrane protein (LSAMP) was frequently deleted (56%). LSAMP has previously been reported to be a candidate tumor suppressor gene in other cancer types. The deletion was validated using fluorescence in situ hybridization, and the expression level and promoter methylation status of LSAMP were investigated using quantitative real-time reverse transcription PCR and methylation-specific PCR, respectively. LSAMP showed low expression compared to two normal bone samples in 6/15 tumors and 5/9 cell lines with deletion of 3q13.31, and also in 5/14 tumors and 3/11 cell lines with normal copy number or gain. Partial or full methylation of the investigated CpG island was identified in 3/30 tumors and 7/20 cell lines. Statistical analyses revealed that loss of 11p15.4-p15.3 and low expression of LSAMP (both P = 0.011) were significantly associated with poor survival. Our results show that LSAMP is a novel candidate tumor suppressor gene in osteosarcomas.

A Bayesian nonparametric method for model evaluation: application to genetic studies

Statistical models applied to genetic studies commonly assume linear relationships (between disease and risk factors) and simple distributional forms (by relying on asymptotic methods) for inference. However, when the sample size is small, inference using traditional asymptotic models can be problematic. Moreover, the gene-disease relationship is not always linear. In this article, we present a new nonparametric Bayesian method for model assessment, and we demonstrate the advantages of this approach particularly when the sample size is small and/or the true model is non-linear. We evaluate our approach on simulated data and find that it performs substantially better than alternative models. We also apply our method to two real studies: diagnosis of conventional high-grade non-metastatic osteosarcoma, and survival in Burkitt's lymphoma.

Ezrin immunohistochemical expression in cartilaginous tumours: a useful tool for differential diagnosis between chondroblastic osteosarcoma and chondrosarcoma

Ezrin is a cytoskeleton linker protein that is actively involved in the metastatic process of cancer cells. We have recently reported that ezrin expression in conventional osteosarcoma was an independent prognostic factor for event-free survival and overall survival. In this work, ezrin expression was found in all histological subtypes. Especially cartilaginous areas in chondroblastic osteosarcomas were immunopositive for ezrin. We wanted to know if ezrin could be a useful diagnostic marker in bone pathology. We have searched for ezrin expression in 208 cartilaginous tumours by immunohistochemistry and in 16 chondroblastic osteosarcomas. All conventional chondrosarcomas, whatever their grade, were negative, while ten of 16 chondroblastic osteosarcomas were positive. In contrast, dedifferentiated (five of 14) and mesenchymal chondrosarcomas (five of ten) showed ezrin positivity. Some chondroblastomas and more rarely chondromyxoid fibromas also exhibited ezrin expression. These data suggest that ezrin is a useful immunohistochemical marker for differential diagnosis between chondroblastic osteosarcomas and conventional chondrosarcomas with a specificity of 100%. Ezrin expression in dedifferentiated and mesenchymal chondrosarcomas which are aggressive neoplasms resistant to conventional treatment means that ezrin could be a therapeutic target. Ezrin expression in chondroblastomas is more intriguing and requires further study to assess prognostic value.

Epithelioid osteosarcoma of the maxilla: report of an unusual case

Epithelioid osteosarcoma is a rare histological variant of a conventional osteosarcoma that contains epithelioid cells with a mesenchymal component. It has rarely been reported in the jawbones and we know of only two other cases, one each in the maxilla and the mandible. We describe a rare case of epithelioid osteosarcoma in a 4½-year-old boy, and its immunohistochemical evaluation using cytokeratin and epithelial membrane antigen.

Aggressive Osteoblastoma: A Case Report Involving a Unique Chromosomal Aberration

Osteoblastomas are rare bone-producing neoplasms that generally occur in the young and can be misdiagnosed as an osteosarcoma if correlation with clinical history, radiology, and histology is not carefully considered or if the several variants of osteoblastoma are not recognized. These variants lie on a morphologic spectrum between conventional osteoblastoma and osteosarcoma. Aggressive osteoblastoma is one such subtype. As the name implies, the histologic features of aggressive osteoblastoma may appear malignant, and its biologic behavior may separate it from conventional osteoblastoma. We report a case of aggressive osteoblastoma occurring in the femoral diaphysis of a 12-year-old girl; this osetoblastoma was dyssynchronous from the radiologic appearance and a diagnostic challenge. Cytogenetic evaluation of the neoplasm revealed a pseudodiploid clone with a balanced translocation involving chromosomes 4, 7, and 14. Using the premise that cytogenetics might be useful as a diagnostic tool for a more specific classification, we reviewed the literature in order to compare our findings with known chromosomal aberrations.