去分化软骨肉瘤的诊断及治疗进展*

去分化软骨肉瘤（DDCS）约占所有软骨肉瘤的10% ,预后极差,5 年生存率不到10% 。好发于股骨、肱骨和骨盆。DDCS是软骨肉瘤中的一个独特类型。典型的特点是分化良好的软骨样成分和高度恶性的间充质细胞来源的肉瘤成分并存、毗邻。DDCS的诊断非常复杂,需要详细的影像学和病理学检查及准确的活检。DDCS去分化成分可以是骨肉瘤、恶性纤维组织细胞瘤,甚至是任何级别的未分化肉瘤成分。约1/3 的X 光片,1/3 的MR,一多半的CT扫描,DDCS表现为典型的“双态”征。最近利用微阵列- 比较基因组杂交技术,发现反复发生的5q14.2~q21.3,6q16~q25.3,9p24.2~q12和9p21.3。染色体缺失更多见于高度恶性的软骨肉瘤（3 级和DDCS）,该差异具有统计学意义。9 号染色体的缺失是DDCS最常见的染色体缺失。早期研究发现DDCS的去分化成分有p53和p53杂合性的丢失现象,进一步研究发现同时伴随Rb基因杂合性的丢失。DDCS的两种成分可出现p16INK 4,FHIT和E-cadherin（上皮型钙黏附蛋白）甲基化的异常。手术切除包括合适足够的外科切缘或根治性的切除,是目前DDCS最主要的治疗手段。化疗效果目前仍然不确定。最近针对软骨肉瘤（包括DDCS）发现了一些新的药物靶标,有些已经进入临床Ⅱ期试验阶段,其中包括Apomab、Perifosine （哌立福新）、Dasatinib（达沙替尼）和多烯紫杉醇联合吉西他滨的联合化疗。同时几个Ⅰ期药物临床试验报告针对DDCS新的有效药物,如组蛋白去乙酰酶抑制剂和血管内皮生长因子反义寡合甘酸。DDCS患者预后极差,预后主要由DDCS中的去分化成分决定。因此,早期诊断、早手术对改善患者的预后非常关键。      

基因芯片筛选软骨肉瘤去分化相关基因初步探讨

目的：探讨用基因芯片技术区分普通型软骨肉瘤与去分化软骨肉瘤组织中基因的差异表达。方法：对病理证实的普通型软骨肉瘤及去分化软骨肉瘤组织,提取细胞mRNA,用寡核苷酸芯片,与正常关节软骨组织杂交后获得荧光信号,计算机软件分析荧光信号结果,并对数据进行归一化处理,分析组间显著变化的基因,然后对其进行聚类和主成份分析,筛选出差异表达的基因。结果：在所检测的人普通型软骨肉瘤与去分化软骨肉瘤组织中,31个基因有表达异常,其中高表达14条,低表达17条。结论：去分化软骨肉瘤与普通型软骨肉瘤间基因表达差异是明显的,这些差异基因主要分布于涉及TGT信号途径、Wnt信号途径、IHH/PThRP轴以及凋亡机制等多方面,且有些基因的作用目前尚不清楚。     

胸腔内去分化软骨肉瘤1例

去分化软骨肉瘤(dedifferentiated chondrosarcoma,DDCS)是一种较为罕见的原发性骨恶性肿瘤.去分化软骨肉瘤发病部位以股骨、胫骨最为多见,其次是骨盆,指(趾)骨少见,发生在肋骨者较少见报道.现报道杭州师范大学附属医院2010年7月收治的1例胸腔内肋骨起源的去分化软骨肉瘤的诊治经过,以提高临床医生对该病的认识.     

Runx2 在去分化软骨肉瘤细胞系中的表达及其意义

 目的　检测Runx2基因在去分化软骨肉瘤中与普通软骨肉瘤中的表达差异,进一步明确Runx2在去分化软骨肉瘤发生发展中的意义。方法　培养去分化软骨肉瘤细胞系NDCS-1及普通软骨肉瘤细胞系SW1353,提取细胞mRNA及总蛋白,RT-PCR、Western blotting及细胞免疫学检测Runx2在细胞系中的表达,之后对病理证实的去分化软骨肉瘤进行免疫组织化学染色,检测其在组织中的表达。结果　RT-PCR和Western blotting结果显示与普通软骨肉瘤细胞系SW1353相比,Runx2在去分化软骨肉瘤细胞系NDCS-1中高表达;免疫组织化学结果显示与普通软骨肉瘤成分相比,Runx2 在组织中的高度恶性成分中高表达。结论　Runx2在去分化软骨肉瘤中的高表达参与了去分化软骨肉瘤的发生和发展。     

Sox9 在人普通型与去分化型软骨肉瘤差异表达*

目的:探讨Sox9 在人普通软骨肉瘤,去分化软骨肉瘤和正常软骨中的表达。方法:取12例2003年1 月至2007年1 月在北京大学人民医院经病理切片确诊为软骨肉瘤（普通软骨肉瘤6 例,去分化软骨肉瘤6 例）及正常软骨组织（6 例）的新鲜冰冻标本,利用基因芯片的方法分析后,将Sox9 作为候选基因,而后利用Real-time PCR,Western blot和免疫组化的方法比较其在人普通软骨肉瘤,去分化软骨肉瘤和正常软骨组织中的差异表达。结果:基因芯片结果显示:与正常软骨组织相比,Sox9 在普通软骨肉瘤中上调约1.6 倍,在去分化软骨肉瘤中,其表达水平为正常软骨组织表达水平的0.082 倍;Real-time PCR检测结果显示:Sox9mRNA 在普通软骨肉瘤和去分化软骨肉瘤中表达水平分别为1.68± 0.119 和0.088 ± 0.017;Western blot分析表明Sox9 蛋白在人普通软骨肉瘤的表达量明显高于正常软骨组织,在去分化软骨肉瘤中的表达量显著低于正常软骨组织。免疫组化实验结果表明与正常软骨组织相比,6 例普通软骨肉瘤均有Sox9 表达,细胞染色呈较强的阳性,而去分化软骨肉瘤未发现较强阳性细胞出现,只有可疑的阳性细胞散在出现。结论:Sox9 在普通软骨肉瘤中的表达水平明显高于正常软骨组织,在去分化软骨肉瘤中的表达水平显著低于正常软骨组织。Sox9 在去分化软骨肉瘤中低水平表达与去分化软骨肉瘤疾病进展快,预后差呈正向相关。      

腹膜后去分化脂肪肉瘤的CT和MRI表现

目的：探讨腹膜后去分化脂肪肉瘤（dedifferentiated liposarcoma,DDL）的CT及MRI表现,旨在提高对腹膜后DDL的认识和术前诊断的准确率。方法：回顾性分析2012年1月至2022年6月天津医科大学肿瘤医院经病理证实的25例腹膜后DDL患者的临床及影像学特征。结果：25例患者中单发19例、多发6例,10例呈类圆（椭圆）形、15例呈不规则形,患者中病变多数边界不清,15例侵犯周围组织器官。25例患者中15例可见增粗扭曲血管影、7例可见钙化或骨化、仅3例可见囊变坏死。CT或MRI增强扫描呈“慢进慢出”的向心性、渐进性持续强化特点。根据其CT和MRI表现分为两型：Ⅰ型（软组织肿块型）肿瘤为软组织成分肿块,内不见脂肪成分（14例）;Ⅱ型（含脂型）肿瘤内同时见软组织成分及脂肪成分,两者大多界限清楚,较少呈镶嵌状,异常脂肪区域内可见索条状纤维间隔,其中以瘤内脂肪成分<50%为Ⅱa型（10例）,瘤内脂肪成分≥50%为Ⅱb型（1例）。结论：结合影像学分型,综合分析腹膜后DDL的CT和MRI影像学特点,对其术前定性诊断有重要价值。     

α-双炔失碳酯对 Swarm大鼠软骨肉瘤的分化诱导作用

目的：研究α -双炔失碳酯（ alpha-anordrin,α -anordrin）对 Swarm大鼠软骨肉瘤（ swarm rat chondrosarcoma,SRCS）生长的影响及其作用机制。方法：观察α -anordrin和全反式维甲酸（ all-trans retinoic acid, ATRA）对 SRCS在大鼠体内生长的影响;用 MTT法研究药物对细胞增殖的影响;用 von Kossa 法显示钙盐在组织中的沉积;用免疫组织化学法研究 S-100蛋白的表达水平;用硝基苯酚磷酸酯显色法检测碱性磷酸酯酶活性;用 Fura-2/AM荧光法测定细胞内自由钙离子浓度。结果：α -anordrin对 SRCS在大鼠体内生长有剂量依赖性的抑制作用,在 16 mg· kg-1时的抑制率为 41.2％ (P<0.05), ATRA在 10 mg· kg－ 1剂量下抑制率为 70.6％ (P< 0.01)。同时,经α-anordrin和 ATRA治疗后, SRCS中出现明显钙盐沉积; S-100蛋白表达水平升高。α-anordrin对 SRCS细胞体外生长的抑制作用明显弱于 ATRA,作用 48 h后对 SRCS细胞生长的 IC50分别为 161.7 μ mol/L和 1.47 μ mol/L。α-anordrin和 ATRA在体外可使 SRCS细胞中碱性磷酸酯酶活性和自由钙离子浓度显著性升高。结论：α-anordrin对 SRCS的生长有明显的抑制作用,这种抑制作用可能与其能够诱导 SRCS向成骨化方向分化有关。     

LDN-193189对人去分化软骨肉瘤细胞系NDCS-1 的抑制作用研究*

目的：检测骨形成蛋白（BMP ）受体抑制剂LDN-193189对人去分化软骨肉瘤（DDCS）细胞系NDCS- 1 的抑制作用,探讨LDN-193189对去分化软骨肉瘤的抑癌机制。方法：以5 nmol/L 的LDN-193189作用于NDCS- 1 细胞,MTT 、平板克隆法检测LDN-193189对NDCS- 1 细胞的增殖抑制作用,Transwell 法、划痕实验检测LDN193189对NDCS- 1 细胞的侵袭抑制作用,Westernblot检测BMPR 2、p-Smad1/ 5 及RUNX 2 的蛋白表达抑制情况。结果：药物处理后NDCS- 1 细胞增殖、侵袭被明显抑制;药物处理后NDCS- 1 细胞的BMPR 2、p-Smad1/ 5 及RUNX 2 蛋白表达下降。结论：LDN-193189通过抑制BMPR 2-p-Smad 1/ 5-RUNX2 信号传导通路能有效抑制去分化软骨肉瘤细胞系NDCS- 1 的增殖侵袭能力。     

腹膜后巨大去分化脂肪肉瘤一例报告

患者男性63岁,以腹部肿块闷痛不适1年余于2003年6月18日入院.查体:腹部较膨胀.可触及巨大肿块.上界于剑突及肋弓下.下界达耻骨上方,两侧达腋前线.以左侧腹为主,肿块质地比较柔软,部分隆起呈大结节状且质地比较硬,无明显边界,表面欠光滑,活动度差,无压痛.     

软骨肉瘤化疗耐药机制

软骨肉瘤在国内虽然不是高发疾病,但是软骨肉瘤发病后所造成的后果却足以引起我们的重视。手术治疗的局限性,对放化疗的不敏感,导致病人预后不良。若能克服软骨肉瘤的耐药性,使化学治疗能高效率杀灭肿瘤的同时抑制其侵袭转移的能力,病人的预后会有飞跃性的提高。找到软骨肉瘤的耐药机制是克服软骨肉瘤耐药性及改善预后的关键,因此本文就国内外对软骨肉瘤耐药机制的研究做如下综述。     

Poorly differentiated ("dedifferentiated") chondrosarcoma

Out of 162 chondrosarcomas studied, 9 were found to be of "dedifferentiated" type. Histological examination established two patterns of the tumor: well-differentiated chondrosarcoma and spindle-shaped sarcoma cells. The survival time was 1.0-2.5 years.     

p53 expression in dedifferentiated chondrosarcoma

Background. p53 acts as a tumor suppressor gene because of to its negative control of the cell cycle and its central role in programmed cell death. It frequently is mutated, as observed in a variety of human neoplasms. The mutations inhibit tumor-suppressor activities of p53, which may gain a new function of tumor promotion. In this study, p53 was investigated in various components of dedifferentiated chondrosarcoma and correlated with their proliferative activities. Methods. Immunohistochemical assays for p53, Ki-67, and proliferating cell nuclear antigen (PCNA) were used in a series of eight dedifferentiated chondrosarcomas of bone. The cartilaginous component was low grade (Grade I-II) in five cases. It was predominantly low grade with foci of a high grade (Grade III) chondrosarcoma in the remaining three cases. The noncartilaginous (de-differentiated) high grade component consisted of malignant fibrous histiocytoma in five cases and osteosarcoma in three. Results. Regardless of the histological type, diffuse strong nuclear staining for p53 occurred in the high grade noncartilaginous component of all eight of the tumors. The low grade cartilaginous component of six cases was negative for p53, with focal weak staining in the two remaining cases. The high grade cartilaginous component showed strong positive staining for this protein in all three cases. Ki-67 and PCNA expression were similar to that of p53. Conclusions. The percentage of p53 positive staining roughly was parallel to the proliferating fraction of cells in various components of dedifferentiated chondrosarcoma. Moreover, p53 overexpression was consistently present in the high grade noncartilaginous (dedifferentiated) component of the tumor and was accompanied by increased proliferative activity. Cancer 1995; 76:223-7.     

A common cytogenetic abnormality and DNA content alterations in dedifferentiated chondrosarcoma

Dedifferentiated chondrosarcoma is an uncommon and aggressive variant of chondrosarcoma. The authors report the flow cytometric characteristics and cytogenetic findings in culture of two cases of dedifferentiated chondrosarcoma. The first case was DNA diploid by flow cytometry but had cytogenetic abnormalities consisting of breaks in the short arms of both chromosomes 1, resulting in deletion in one homolog and recombination in the other. In addition, cells from this tumor showed a balanced translocation between chromosomes 4 and 5, deletion of chromosome 9, and monosomy for chromosome 10. The second case was DNA aneuploid and more complex cytogenetically but had, in common with the first case, rearrangement and translocation at the same band on chromosome 1. These cytogenetic changes are compared with abnormalities previously reported for chondrosarcoma. Possible relationships between the nonrandom chromosomal abnormalities and subclassification among chondrosarcomas are discussed.     

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone

ABSTRACT: BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. METHODS: We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. RESULTS: We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5-8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. CONCLUSIONS: Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies.     

Chondrosarcoma with additional mesenchymal component (dedifferentiated chondrosarcoma). II. An immunohistochemical and electron microscopic study

Light microscopic, immunocytochemical and ultrastructural studies were performed on chondrosarcomas which contained a second, noncartilagenous mesenchymal component. Attention was focused on the nonchondroid portion of each tumor in an attempt to elucidate the histogenesis of this mixed variant of chondrosarcoma. The immunoreactivity of 20 tumors was studied using antisera for S-100 protein, alpha-1-antitrypsin, alpha-1-antichymotrypsin, smooth muscle myosin, desmin, and myoglobin. Cells of the nonchondroid portion stained for alpha-1-antichymotrypsin in 12 of 20 cases, and these were predominantly tumors that had been classified as fibrosarcoma or malignant fibrous histiocytoma by conventional light microscopic study. Staining for S-100 protein was consistently negative, whereas the chondrosarcoma component stained in 14 cases. Six tumors stained for desmin, and four of the six were positive for myoglobin and two for smooth muscle myosin; in four, a rhabdomyosarcomatous component was identified in the hematoxylin and eosin-stained sections. Electron microscopic study was performed on ten tumors and there was a good correlation between the immunohistochemical and ultrastructural findings. Three of the ten were pure rhabdomyosarcomas while the others displayed a range of ultrastructural appearances that can be seen in fibrosarcomas and malignant fibrous histiocytomas. The findings from this study support the view that the tumors are formed by the synchronous differentiation of two separate clones of cells.     

Chondrosarcoma with additional mesenchymal component (dedifferentiated chondrosarcoma). I. A clinicopathologic study of 26 cases

During a 37-year period, 26 patients were seen who had chondrosarcoma with additional mesenchymal components ("dedifferentiated low-grade chondrosarcoma"). Sixteen were men and 10 were women aged 30 to 85 years (median, 61 years). The tumors' chondroid areas were of borderline or low-grade malignancy. The additional mesenchymal component was histologically classified as malignant fibrous histiocytoma (16), rhabdomyosarcoma (4), low-grade fibrosarcoma (3), osteosarcoma (2), and undifferentiated sarcoma (1). Preferred locations were pelvis (10) and femur (8). Symptoms had been present for 1 year or less in most cases. Pain was the most common symptom. In 15 of 26, major amputation was the primary treatment. Twelve patients received chemotherapy, usually after developing metastatic disease, but only one achieved a partial response. Median disease-free interval after diagnosis was 4 months, median survival was 6 months, and 19 patients died within 1 year. Of 4 who survived longer than 18 months, 3 presented with a low-grade fibrosarcoma. Survival and development of metastasis appeared unrelated to cell type, initial treatment, or chemotherapy, except when the tumor's initial nonchondroid component was low-grade fibrosarcoma.     

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi‐institutional study

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease‐specific survival (DSS) and disease‐free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5‐year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5‐year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high‐grade chondrosarcoma, particularly for those with DDCS.