Osteosarcoma: A Multifactorial Clinical and Histopathological Study with Special Regard to Therapy and Survival

A multifactorial analysis was performed on all 153 unequivocal cases of genuine osteosarcoma recorded in the Swedish Cancer Registry for the years 1958 through 1968. Cases of so-called parosteal osteosarcoma, soft-tissue osteosarcoma and osteosarcoma secondary to Paget's disease of bone were not included. The osteosarcomas were subclassifiecl as follows: osteoblastic (69 per cent), chondroblastic (19 per cent) and fibroblastic (12 per cent). The overall 5-year survival rate was 22 per cent; 55 per cent for those who had undergone amputation above the joint proximal to the involved skeletal part, 22 per cent for those amputated on the involved skeletal part, 11 per cent for those treated with local extirpation of the tumor, and 1 per cent in cases in which the lesion was not radically removed. Tumors of the femur, humerus and scapula were as malignant as axial tumors. The former carried a 5-year survival rate of 13 per cent, regardless of whether the patients had been treated with exarticulation or amputation on the involved skeletal part. Patients with axial tumors showed a 5-year survival rate of 15 per cent. These survival data suggest that proximal amputation alone might suffice for lesions situated distally to the knee and elbow joints, while tumors in the humerus and femur should be treated with amputation combined with multicytostatic treatment or immunotherapy and axial tumors with local resection and multicytostatic or immunologic treatment.     

Pathology of osteosarcoma.

Osteosarcoma of bone is a tumor composed of malignant cells that produce osteoid. Some tumors show predominant chondroid or fibromatoid ground substance. All, however, are highly malignant and about 80 per cent produce death with metastases. The roentgenogram affords important evidence for the correct diagnosis of many of them. Differential diagnosis should include consideration of those sarcomas with many benign giant cells and the group of "telangiectatic" osteosarcomas that may contain only small diagnostic areas. Malignant fibrous histiocytoma is now considered as a possible diagnosis for some malignant bone tumors, but the exact criteria for the diagnosis of this condition are still somewhat obscure. Newer modalities of adjunctive treatment, such as resection of pulmonary metastases, chemotherapy, and immunotherapy, give promise of improving the prognosis for osteosarcoma.     

BMI-1基因在骨肉瘤中的表达及其临床意义

背景：目前,骨肉瘤发病机制的研究已逐步深入。BMI-1基因作为近年来肿瘤致癌基因研究中的热门分子,在恶性肿瘤方面的研究证据较为丰富,但针对其在骨肿瘤方面的研究相对较少。目的：探讨BMI-1基因在骨肿瘤中的表达及其临床相关性研究。方法：采用免疫组化染色检测80例骨肿瘤组织及20例非肿瘤骨组织中BMI-1蛋白的表达,骨肿瘤包括骨肉瘤30例（分为EnnekingⅠ、Ⅱ、Ⅲ期）、骨软骨瘤20例、软骨肉瘤20例、尤因肉瘤10例。并对30例骨肉瘤的主要临床资料进行比较,用卡方检验进行统计学处理。结果：BMI-1基因在骨肉瘤、软骨肉瘤及尤因肉瘤中均有较高的阳性表达率,相比较无统计学差异;而在骨软骨瘤和非肿瘤骨组织中阳性表达率明显较低,且存在统计学差异（P=0.000）;良、恶性骨肿瘤之间的阳性表达率亦存在统计学差异（P=0.000）。骨肉瘤EnnekingⅠ、Ⅱ、Ⅲ期之间两两比较BMI-1蛋白的阳性表达率无统计学差异;不同年龄、性别、肿瘤发生部位及术后是否有转移中BMI-1蛋白的阳性表达率均无统计学差异,但年龄越小,BMI-1蛋白的阳性表达率越高以及有转移骨肉瘤患者的BMI-1蛋白阳性表达率升高。结论：BMI-1基因可能为骨肉瘤的分子靶点之一,并具有作为判断骨肉瘤进展及患者预后参考指标的潜力。揭示其作用于骨肉瘤的分子机理,将有助于骨肉瘤发病机制的探索。     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

Osteosarcomas arising on the surfaces of long bones

Malignant bone-forming tumors that arise from the surfaces of long bones are far less common than those that arise from within bone. These surface osteosarcomas are clinically and radiographically similar, yet histologically they are quite distinct. In reviewing the literature, we classified the tumors according to three subgroups: parosteal (juxtacortical) osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. We also studied the clinical, radiographic, and histological findings in eighty patients who had been treated for an osteosarcoma over a forty-four-year period. Adequate follow-up data existed for forty-eight of the eighty patients. The duration of follow-up ranged from two to fifteen years after the initial operation (amputation or resection). Patients who had a parosteal osteosarcoma had the best prognosis; those who had a periosteal osteosarcoma, the next best; and those who had a high-grade surface osteosarcoma, the poorest. Because of these widely varying prognoses, the lesions require different treatment.     

Osteosarcoma of bone and its important recognizable varieties.

Osteosarcoma of bone is a recognizable entity if the histopathologist designates tumors as such when their malignatn cells produce osteoid substance even if only in small foci. Such definition distinguishes this lesion from other sarcomas that arise in bone, especially chondrosarcoma and fibrosarcoma. There is a general tendency to consider that osteosarcomas represent a stereotyped form of disease for which new modalities of treatment can be applied and assessed. The question of whether a given osseous lesion is actually malignant and not a benign neoplasm or even a reactive non-neoplastic condition simulating a malignant tumor may be difficult for the histopathologist. Pathologists without considerable experience in the diagnosis of bone tumors find this question especially vexing. The establishment of a valid diagnosis of osteosarcoma introduces the additional problem that the 11 varieties considered in this paper may pose significant recognizable variations in the clinical capability of the disease. It is apparent that the physician must recognize the known clinicopathologic and prognostic factors of these subtypes in his assessment of the overall problem.     

Prion proteins (PRNP and PRND) are over-expressed in osteosarcoma

Although osteosarcoma is the most common bone malignancy, the molecular and cellular mechanisms influencing its pathogenesis have remained elusive. Prion proteins (PRNP and PRND), known mostly for its involvement in neurodegenerative spongiform encephalopathies, have been recently demonstrated to be involved in resistance to apoptosis, tumorigenesis, proliferation, and metastasis. The main aim of research was to study whether prion proteins were over-expressed in human osteosarcoma, and if prion proteins could have a role also in osteosarcomas. We evaluated differential gene expression between 22 cases of osteosarcoma and 40 cases of normal bone specimens through cDNA microarray analysis spanning a substantial fraction of the human genome. PRNP and PRND are significantly over-expressed in osteosarcoma. PRNP and PRND appear involved with some important genes related to tumorigenesis and apoptosis. PRNP is linked to PTK2, RBBP9, and TGFB1 while PRND is linked to TNFSF10, BCL2A1, NFKB2, and TP53RK. Increased expression on Affymetrix arrays of prion proteins seems to be associated with the development of osteosarcoma. Prions seem to induce a negative regulation of apoptosis, thus promoting osteosarcoma development and progression. Osteosarcoma is a very aggressive tumor and even after modern chemotherapy and excision of tumors efforts are needed to improve clinical outcome. Since Prion proteins seem to be related to osteosarcoma development, their inhibition could represent a new approach to the molecular treatment of osteosarcoma.     

Hypoxia‐related microRNA‐210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma

Osteoblastoma is a benign bone tumor that can often be difficult to distinguish from malignant osteosarcoma. Because misdiagnosis can result in unfavorable clinical outcomes, we have investigated microRNAs as potential diagnostic biomarkers for distinguishing between these two tumor types. Next generation RNA sequencing was used as an expression screen to evaluate >2,000 microRNAs present in tissue derived from rare formalin fixed paraffin embedded (FFPE) archival tumor specimens. MicroRNAs displaying the greatest ability to discriminate between these two tumors were validated on an independent tumor set, using qPCR assays. Initial screening by RNA‐seq identified four microRNA biomarker candidates. Expression of three miRNAs (miR‐451a, miR‐144‐3p, miR‐486‐5p) was higher in osteoblastoma, while the miR‐210 was elevated in osteosarcoma. Validation of these microRNAs on an independent data set of 22 tumor specimens by qPCR revealed that miR‐210 is the most discriminating marker. This microRNA displays low levels of expression across all of the osteoblastoma specimens and robust expression in the majority of the osteosarcoma specimens. Application of these biomarkers to a clinical test case showed that these microRNA biomarkers permit re‐classification of a misdiagnosed FFPE tumor sample from osteoblastoma to osteosarcoma. Our findings establish that the hypoxia‐related miR‐210 is a discriminatory marker that distinguishes between osteoblastoma and osteosarcoma. This discovery provides a complementary molecular approach to support pathological classification of two diagnostically challenging musculoskeletal tumors. Because miR‐210 is linked to the cellular hypoxia response, its detection may be linked to well‐established pro‐angiogenic and metastatic roles of hypoxia in osteosarcomas and other tumor cell types. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1137–1146, 2017.

     

Periosteal osteosarcoma with secondary bone marrow involvement: a case report

Periosteal osteosarcoma is an exceedingly rare type of chondroblastic osteosarcoma, showing a rather good prognosis, and secondary bone marrow involvement is unusual. However, there have been some reports describing periosteal sarcoma involving medullary bone. We encountered a patient, a 38-year-old man, who had a bone surface tumor in the left tibia. An X-ray showed an erosive cortical mass extraosseous portion, located in the diaphysis of the tibia. Other images revealed a thin cortex, periosteal reactions, coarse mineralization in the extraosseous portion, and bone marrow involvement. Grossly, surgical materials showed that the tumor mainly existed at the periosteal portion, only a part of the cortex was destroyed, and there was medullary involvement throughout. Histological examinations showed a predominantly chondroid component with malignant osteoid formation. On the basis of the histological macroscopic and microscopic findings, we made the diagnosis of periosteal osteosarcoma with secondary bone marrow involvement.     

Surface osteosarcomas: Diagnosis,treatment and outcome

Surface osteosarcomas are a rare form of osteosarcomas accounting for around 3-6% of all osteosarcomas. Three major groups of surface osteosarcomas are parosteal, periosteal and the high grade surface osteosarcomas. Of these, the parosteal osteosarcoma is the most common. Parosteal and periosteal osteosarcomas are distinct clinical entities and it is important to identify the clinicoradiological differences between the two types. Surface osteosarcomas occur at a later age as compared to conventional osteosarcomas. The classical site is the lower end of the femur followed by the upper end of the tibia and upper end of humerus, in that order. The periosteal variant affects the tibia more commonly than the parosteal variety. Neo-adjuvant chemotherapy is the standard of care for high grade surface osteosarcomas. Parosteal osteosarcomas, being low grade lesions, can be treated by upfront wide excision without adjuvant systemic therapy. Controversy prevails over the need for chemotherapy in periosteal osteosarcomas, which are intermediate grade lesions.     

Osteosarcoma. A multifactorial clinical and histopathological study with special regard to therapy and survival.

A multifactorial analysis was performed on all 153 unequivocal cases of genuine osteosarcoma recorded in the Swedish Cancer Registry for the years 1958 through 1968. Cases of so-called parosteal osteosarcoma, soft-tissue osteosarcoma and osteosarcoma secondary to Paget's disease of bone were not included. The osteosarcomas were subclassified as follows: osteoblastic (69 per cent), chondroblastic (19 per cent) and fibroblastic (12 per cent). The overall 5-year survival rate was 22 per cent; 55 per cent for those who had undergone amputation above the joint proximal to the involved skeletal part, 22 per cent for those amputated on the involved skeletal part, 11 per cent for those treated with local extirpation of the tumor, and 1 per cent in cases in which the lesion was not radically removed. Tumors of the femur, humerus and scapula were as malignant as axial tumors. The former carried a 5-year survival rate of 13 per cent, regardless of whether the patients had been treated with exarticulation or amputation on the involved skeletal part. Patients with axial tumors showed a 5-year survival rate of 15 per cent. These survival data suggest that proximal amputation alone might suffice for lesions situated distally to the knee and elbow joints, while tumors in the humerus and femur should be treated with amputation combined with multicytostatic treatment or immunotherapy and axial tumors with local resection and multicytostatic or immunologic treatment.     

Nucleolar organizer regions in bone tumors

Silver-stained nucleolar proteins (AgNORs) were counted in a variety of bone tumors. In osteosarcomas, the number of AgNORs was also quantified before and after chemotherapy. Malignant bone tumor cells possessed more than five small AgNORs (5.85 +/- 1.39). Nuclei of benign bone tumor cells had less than three (2.61 +/- 0.51). A significant difference in the number of AgNORs between osteosarcomas before chemotherapy (6.10 +/- 1.22) and after chemotherapy (4.20 +/- 1.07) was observed. (p less than 0.001). The number of AgNORs in osteosarcoma patients with better prognoses was smaller than that of osteosarcoma patients showing poor prognoses, but without significant difference. The results of the present study indicate that the AgNOR count might help in determining malignancy, evaluating the effect of chemotherapy, and deciding the prognosis.     

Classification,imaging, biopsy and staging of osteosarcoma

Osteosarcoma is the most common primary osseous malignancy excluding malignant neoplasms of marrow origin (myeloma, lymphoma and leukemia) and accounts for approximately 20% of bone cancers. It predominantly affects patients younger than 20 years and mainly occurs in the long bones of the extremities, the most common being the metaphyseal area around the knee. These are classified as primary (central or surface) and secondary osteosarcomas arising in preexisting conditions. The conventional plain radiograph is the best for probable diagnosis as it describes features like sun burst appearance, Codman''s triangle, new bone formation in soft tissues along with permeative pattern of destruction of the bone and other characteristics for specific subtypes of osteosarcomas. X-ray chest can detect metastasis in the lungs, but computerized tomography (CT) scan of the thorax is more helpful. Magnetic resonance imaging (MRI) of the lesion delineates its extent into the soft tissues, the medullary canal, the joint, skip lesions and the proximity of the tumor to the neurovascular structures. Tc99 bone scan detects the osseous metastases. Positron Emission Tomography (PET) is used for metastatic workup and/or local recurrence after resection. The role of biochemical markers like alkaline phosphatase and lactate dehydrogenase is pertinent for prognosis and treatment response. The biopsy confirms the diagnosis and reveals the grade of the tumor. Enneking system for staging malignant musculoskeletal tumors and American Joint Committee on Cancer (AJCC) staging systems are most commonly used for extremity sarcomas.     

An individual patient data meta‐analysis on the effect of chemotherapy on survival in patients with craniofacial osteosarcoma

Chemotherapy improves the survival of patients with long bone osteosarcomas. However, the benefits of chemotherapy in the treatment of craniofacial osteosarcoma (CFOS) are still controversial. We searched PubMed and EMBASE from February 1997 to December 2016 to identify studies on CFOS. The individual patient data of these studies were pooled into a meta‐analysis. Univariate and multivariate survival analyses were performed. Thirteen studies with a total of 184 patients met our inclusion criteria. Positive resection margin was a poor prognostic factor for CFOS in the univariate and multivariate survival analyses. Chemotherapy improved overall survival (OS) and disease‐specific survival (DSS) in patients with CFOS who had tumors in the maxilla, positive resection margins, or high‐grade tumors. Patients with local tumor recurrence had better OS and DSS when treated with chemotherapy. Chemotherapy improves survival in patients with CFOS with adverse factors, such as tumors with positive margins, high‐grade tumors, and recurrent tumors.     

MET oncogene aberrant expression in canine osteosarcoma.

The objective of this study was to investigate the role of the MET oncogene in canine osteosarcoma. Seven large-breed dogs affected by spontaneous skeletal osteosarcoma underwent en bloc tumor excision. Total RNA was extracted from frozen tumor samples and assessed for expression of the MET oncogene by Northern blot analysis. Five of seven biopsy samples expressed high levels of the MET oncogene; its expression in the primary tumors was comparable with that previously identified in primary osteosarcomas in humans. A lung metastasis from one of the dogs expressed MET at a higher level than did its primary tumor. Spontaneously arising osteosarcoma in dogs clinically and pathologically mimics the corresponding disease in humans. We previously demonstrated that the MET oncogene was aberrantly expressed in a high percentage of human osteosarcomas. The results of the current study also provide a molecular parallel between the tumors in dogs and humans. This in vivo model may be helpful in evaluating new strategies for therapy against osteosarcoma.     

Parosteal osteosarcoma of the distal ulna. A rare tumour at a rare location: a case report

We report a case of a histologically well differentiated, grade I, parosteal osteosarcoma of the distal ulna. The tumour's radiological and histological features are described, and the patient's course after wide en-bloc resection is detailed. Parosteal osteosarcoma is a rare low-grade malignant neoplasm. It belongs to the group of the osteosarcomas originating from the surface of the bone, representing a distinct tumour entity within this group, with defined histological and radiological features. We describe the radiological and histological characteristics of parosteal osteosarcoma and, based upon these features, present its classification. The differential diagnosis, including parosteal osteoma, myositis ossificans and osteochondroma, is also discussed. Finally, therapy and prognosis are outlined in accordance with the current literature. Wide en-bloc resection represents the mainstay of therapy offering an excellent prognosis with a 5-year survival rate of more than 90%. Incomplete resection, on the other hand, increases the risk of recurrence and dedifferentiation of the tumour. Dedifferentiation induces tumour spread and is associated with a poor prognosis equivalent to conventional osteosarcoma.     

Drug-induced apoptosis in osteosarcoma cell lines is mediated by caspase activation independent of CD95-receptor/ligand interaction.

Osteosarcoma is one of the most common primary malignant tumors of bone. Treatment of this tumor with systemic chemotherapy dramatically improves the prognosis, although the molecular mechanisms involved in the drug action are poorly understood. In chemosensitive leukaemic T cells and certain solid tumors, cytotoxic drugs mediate the induction of apoptosis by activation of the CD95/APO-1/Fas system. Triggering of the corresponding signaling pathway may involve CD95-receptor/ligand interaction, activation of caspases, or alterations in mitochondrial function. The purpose of our study was to determine if similar mechanisms are involved in the chemosensitivity of osteosarcomas. We found that cytotoxic drugs induce characteristic biochemical and morphological alterations related to apoptosis in osteosarcoma cell lines, including activation of caspases and disturbance of mitochondrial function. However, drug treatment did not result in activation of CD95-receptor or CD95-ligand mRNA. In addition, drug-induced apoptosis was blocked by caspase inhibitors but not by inhibition of CD95-ligand action, indicating a CD95-receptor/ligand-independent mechanism in osteosarcoma cell lines.