年龄与脊柱骨巨细胞瘤预后关系的研究进展

骨巨细胞瘤（GCT）是一种有局部侵袭性的良性骨肿瘤。女性较男性多见,并且好发于20～40岁的青壮年[1-3]。骨巨细胞瘤的生物学行为较特殊,术后易复发。目前临床实践中常从肿瘤影像或病理等方面来分析其生物学行为,并对其预后进行判断。而以往骨巨细胞瘤的研究报道,不同年龄段患者术后复发率存在差异[4-5],提示年龄可能是影响骨巨细胞瘤生物学行为及预后的因素。但由于以往的研究多为全身骨骼骨巨细胞瘤的病例,并未明确反映出年龄与脊柱骨巨细胞瘤复发之间的关系。     

碱性成纤维细胞生长因子及受体在骨巨细胞瘤中的表达其及与预后的关系

目的：探讨碱性成纤维细胞生长因子（basic fibroblast growth factor，bFGF）及受体Bek在骨巨细胞瘤的表达情况，探索骨巨细胞瘤的生物学行为规律与预后影响因素。方法：采用免疫组化方法、Mias-2000图像分析技术检测了147例骨巨细胞瘤（复发组56例，未复发组91例）石蜡标本中Bek/bFGF的表达情况，用流式细胞术分析其DNA含量与S期细胞百分数（S-phase fraction，SPF），结合肿瘤直径、浸润情况、手术方式、复发情况等相关临床病理资料，采用多元回归分析方法综合分析骨巨细胞瘤的预后影响因素。结果：bFGF、Bek在骨巨细胞瘤主要瘤细胞成分中广泛表达，阳性信号主要定位于瘤细胞胞浆；复发组瘤组织中bFGF、Bek均呈强阳性表达的异形性较大的单核、双核及三核基质细胞与4-8个核的多核巨细胞明显增多，而未复发组瘤组织中bFGF、Bek阴性或弱阳性表达的体积大核多（多达几十个）的多核巨细胞数目较多；复发组bFGF、Bek表达信号较未复发组明显增强，两组间bFGF、Bek表达的灰度值与阳性面积差异均有显意义。复发组平均DNA指数（DNA Index，DI）为1.24，SPF为18.3％；未复发组平均DI值为1.05，SPF为11.7％；两组间DI值、SPF差异均有显意义。在13个相关研究因素中，有7个因素与骨巨细胞瘤的预后显相关，按影响强度由大到小依次为：手术方式、Bek灰度值、DNA含量、bFGF灰度值、SPF、Bek阳性面积和bFGF阳性面积。结论：bFGF及其受体Bek在骨巨细胞瘤中有广泛表达，其表达水平与骨巨细胞瘤的复发、恶变与肺转移等生物学行为密切相关，可作为骨巨细胞瘤生物学行为与预后判断的参考指标；手术方式、瘤细胞Bek/bFGF表达强度、DNA含量、S期细胞百分数与骨巨细胞瘤预后有关，其中手术方式与预后关系最为密切。     

CD147和Survivin在骨巨细胞瘤中的表达及其临床意义

目的 探讨骨巨细胞瘤中CD147和Survivin的表达与其临床及生物学行为的关系.方法 回顾分析我院骨病科2000年1月至2009年3月接受局部刮除手术治疗的34例骨巨细胞瘤患者的临床特点及变化;运用免疫组织化学S-P法,检测CD147和Survivin在34例骨巨细胞瘤中的表达,分析其与肿瘤临床病理资料及Jaffe分级、Campanacci＇s分级及预后的关系.结果 CD147和Survivin在34例骨巨细胞瘤中的阳性表达率分别为55.88﹪和58.82﹪,CD147和Survivin的阳性表达率与患者性别、年龄、发病部位、Jaffe分级及Campanicci＇s分级无相关性,与患者的预后呈正相关.CD147和Survivin在骨巨细胞瘤中的表达强度与预后之间均存在正相关性（r=0.489,P＜0.05;r=0.480,P＜0.05）.CD147和Survivin在骨巨细胞瘤中的表达具有相关性（r=0.503,P＜0.05）.CD147和Survivin在骨巨细胞瘤复发组的双阳性表达率（80﹪）明显高于无复发组的双阳性表达率（20.83﹪）,差异有显著性（P＜0.05）.结论 CD147和Survivin与骨巨细胞瘤恶性程度、发生及发展具有相关性,CD147和Survivin可作为评价骨巨细胞瘤恶性程度和判断预后的重要指标.     

骨巨细胞瘤组织中VEGF、NOS的表达及其与肿瘤血管形成的关系

目的 检测VEGF,iNOS和eNOS在骨巨细胞瘤组织中的表达及其与肿瘤血管形成的关系。方法 应用免疫组织化学的方法,检测49例骨巨细胞瘤微血管密度(MVD)和VEGF,iNOS和eNOS在肿瘤组织中的表达。结果 VEGF、iNOS和eNOS的阳性表达率分别为61.2％,57.1％和71.4％。骨巨细胞瘤组织Jaffe病理分级间MVD比较,Ⅲ级>Ⅰ级(P<0.01),Ⅲ级>Ⅱ级(P<0.01),而Ⅰ级与Ⅱ级之间差异无显著意义(P>0.05)。VEGF阳性骨巨细胞瘤组织中MVD为37.7±10.5/高倍视野,VEGF阴性的骨巨细胞瘤组织中MVD为24.5/高倍视野±6.8/高倍视野,两者差异有显著性(P<0.01);iNOS阳性骨巨细胞瘤组织中MVD为37.9/高倍视野±10.9/高倍视野,iNOS阴性骨巨细胞瘤组织中MVD为25.2/高倍视野±7.1/高倍视野,两者差异有显著性(P<0.01);eNOS阳性骨巨细胞瘤组织中MVD为35.4/高俯视野±11.7/高信视野,eNOS阴性骨巨细胞瘤组织中MVD为25.6/高倍视野±5.8/高抬视野,两备差异有显著性(P<0.01);VEGF与iNOS表达均阳性者21例,VEGF表达阴性,而iNOS阳性者7例,二者表达有相关性(P<0.05)。VEGF与eNOS表达均阳性者19例,VEGF表达阴性,而eNOS阳性者16例,二者表达无相关性(P>0.05)。结论MVD是评估骨巨细胞瘤生物学行为的重要指标,VEGF,iNOS与eNOS在骨巨细胞瘤中有促进肿瘤血管形成的作用     

骨巨细胞瘤组织中MMP-2、Ki-67的表达及其诊断价值

目的 探讨骨巨细胞瘤组织中基质金属蛋白酶-2(MMP-2)、Ki-67的表达及其诊断价值.方法 采用免疫组化S-P法检测100例骨巨细胞瘤和50例正常骨组织中MMP-2、Ki-67的表达,并分析两者与临床病理参数之间的关系.结果 骨巨细胞瘤组织中MMP-2、Ki-67的阳性率均高于正常骨组织,差异均有统计学意义(P均＜0.05).骨巨细胞瘤组织中MMP-2、Ki-67的表达均与患者的Jaffe分级、临床分期、是否复发有关(P＜0.05).骨巨细胞瘤组织中MMP-2、Ki-67的表达呈正相关(r =0.554,P＜0.05).结论 骨巨细胞瘤组织中存在高表达的MMP-2、Ki-67,两者的联合检测可用于骨巨细胞瘤的临床诊断、预后评估.     

手术治疗骨巨细胞瘤的临床观察

骨巨细胞瘤(GCT)多发于骨干骺端,组织来源尚不清楚.GCT生物学行为特殊,其局部侵袭性生长常导致局部复发[1].     

骨巨细胞瘤术后复发原因分析

 目的 分析骨巨细胞瘤特点与术后复发的相关性。方法 回顾性分析获得随访的451例骨巨细胞瘤患者发病部位、手术方式、Campanacci分级、病理性骨折、肺转移与骨巨细胞瘤复发率的相关性。结果 脊柱骨盆骨巨细胞瘤的复发率较膝关节周围（P<0.001）、桡骨远端（P=0.005）及其他部位（P<0.001）骨巨细胞瘤复发率高；Ⅲ级骨巨细胞瘤单纯刮除术后复发率高于扩大刮除术（P<0.001）以及瘤段或分块切除术（P=0.002），差异有统计学意义；行单纯刮除术的CampanacciⅠ级、Ⅱ级、Ⅲ级骨巨细胞瘤术后复发率比较差异有统计学意义（P=0.028），行扩大刮除及瘤段或分块切除术后的CampanacciⅡ级与Ⅲ级的骨巨细胞瘤复发率比较差异无统计学意义（P>0.05）；骨巨细胞瘤复发病例肺转移率高于无复发病例肺转移率，差异有统计学意义（P<0.001）；伴病理性骨折与无病理性骨折骨巨细胞瘤术后复发率比较差异无统计学意义（P>0.05）。结论 手术方式影响骨巨细胞瘤的肿瘤外科边界，与术后复发率密切相关；复发病例的肺转移率明显升高；为改善骨巨细胞瘤患者预后，临床上骨巨细胞瘤手术应考虑足够的外科边界。     

儿童骨巨细胞瘤五例报告

儿童骨巨细胞瘤五例报告深圳市布吉人民医院（深圳市５１８１１２）刘俊芳骨巨细胞瘤是成人的一种常见骨肿瘤，儿童少见。我们收集５例经手术及病理诊断的儿童骨巨细胞瘤，现报告如下。１临床资料１９８４～１９９６年，１３年间经手术病理诊断儿童骨巨细胞瘤５例，其中男...     

PCNA在骨巨细胞瘤的表达及与病理分级和复发的关系

应用免疫组织化学技术，对32便骨巨细胞瘤进行增殖细胞核抗元原（PCNA）的检测分析，探讨PCNA在骨巨细胞瘤的表达分布及与Jaffe病理分级和复发的关系。结果显示，PCNA的阳性反应只在骨巨细胞瘤波形蛋白阳性的单核基质细胞的胞核中出现，而多核巨细胞均无阳性表达；PCNA在骨巨细胞瘤中的增殖指数虽随Jaffe病理分级增高有呈递增趋势，但各级相互之间在交叉重叠现象；PCNA增殖指数低即低度增生的骨巨细胞瘤复发率低，PCNA增殖指数高即中度和重度增生者复发率明显增高。本文结果进一步支持单核基质细胞是骨巨细胞瘤的主要肿瘤细胞成份的观点，并提示PCNA的表达与Jaffe病理分级不完全一致，但PCNA是判断骨巨细胞瘤预后的一个重要参考指标。     

29例骨巨细胞瘤临床病理分析

骨巨细胞瘤（ＧｉａｎｔＣｅｌｌＴｕｍｏｒｏｆＢｏｎｅ,ＧＣＴ）是我国常见的骨肿瘤之一。自采用Ｊａｆｆｅ病理诊断和分级标准以来,文献报道日益增多。尽管应用电镜、组织培养、组织化学、免疫组化、细胞定量和组织图像分析研究ＧＣＴ已取得很大进展［１,３］,但目前许多作者对骨巨细胞瘤的起源,其形态学特征、分级标准与生物学特性之间的关系等问题,仍存在不同的看法。本文通过对２９例ＧＣＴ的病理诊断和临床资料分析,结合文献复习,对其临床病理特征和生物学特性进行分析。１资料和方法１．１临床资料本文２９例ＧＣＴ的资料,来自本院…     

RECK在骨巨细胞瘤中的表达及与MMP-2的关系

目的 检测RECK基因以及金属蛋白酶-2 (MMP-2)在骨巨细胞瘤(GCT)以及骨软骨瘤中的表达情况,以探讨RECK基因的表达与GCT的发生、生长以及生物学行为之间的相关性.方法 应用免疫组织化学SP方法检测30例GCT和10例骨软骨瘤肿瘤组织中RECK与MMP-2的表达,进而分析RECK、MMP-2在上述肿瘤组织中表达的阳性率及两者之间的相关性.结合临床资料,分析和比较RECK基因在不同外科学分期、影像学分级GCT肿瘤组织中表达的差异性,了解RECK基因的表达与GCT预后(复发率)之间有无关系.结果 RECK基因在GCT肿瘤组织中表达较对照组(骨软骨瘤)阳性率低(P＜0.05),并且在不同外科学分期和影像学分级的GCT肿瘤组织,表达的阳性率差异有统计学意义(P＜0.05).同时发现RECK基因与MMP-2蛋白的表达呈负相关性.RECK基因的表达与GCT患者的性别、年龄、发病部位等无显著相关性,与肿瘤的预后(术后复发率)有相关性,但Logistic回归分析显示,RECK及MMP-2均不是GCT预后的独立危险因素,而手术方式是GCT预后的独立危险因素.结论 GCT肿瘤组织中RECK基因低表达、MMP-2高表达.RECK基因可能在骨巨细胞瘤的发生、生长过程中起重要作用.本研究结果可以为GCT的预后判断及分子靶向药物的开发提供实验依据.     

骨囊肿、骨巨细胞瘤和骨肉瘤的计算机图象定量研究

目的:研究和解决骨巨细胞瘤的传统组织学分级与生物学行为不甚相符的问题.方法:利用自动图象分析仪对13例骨囊肿,51例骨巨细胞瘤(GCT)和15例骨肉瘤,共计79例标本进行了8项参数的形态定量研究.结果:在8项参数中,核X_6(核圆度)、X_7(核椭率)在不同肿瘤或分级的两两比较中全部无显著性差异;其余6项参数GCTⅠ、Ⅱ级均无显著性差异,而 GCTⅠ级与骨囊肿、Ⅲ级骨肉瘤各组间均有显著性差异,GCTⅡ级与骨囊肿、Ⅲ级骨肉瘤各组织间也有显著性差异.结论:经计算机图象定量研究,将8项参数经多元逐步判别分析,结果优选出有较多诊断价值的3项参数见、X_1、X_5、X_8,并依次建立判别函数方程(回归方程).     

Benign granular cell tumor of the breast: a misleading disease.

Granular cell tumor (GCT) is a relatively rare neoplasm, and almost always benign in its prognostic behavior. Location of this tumor in the breast presents serious problems for differential diagnosis, both from a clinical point of view and at gross pathological examination, because of its resemblance to carcinoma. Fine needle aspiration biopsy and intraoperative frozen section examination may not be of any further help. The histogenesis of these lesions has been widely debated in the past, but no universally accepted conclusion has been reached. Most GCTs appear to be derived from Schwann cells, but many different neoplastic and non-neoplastic lesions show granular cell changes. Therefore, GCT should not be considered as a single entity but as the result of a cytoplasmic change due to still unknown metabolic alterations that may occur in various cell types. No firm conclusions can be drawn regarding the suspected hormonal influence on the development of breast GCT. The authors describe three typical cases of breast GCT that occurred in patients of different ages, and discuss the most important questions concerning this lesion.     

Family history of cancer and malignant germ cell tumors in children: A report from the Children’s Oncology Group

Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children’s Oncology Group case–control study that included 274 GCT cases (195 female and 79 male) diagnosed <age 15 years and 418 controls frequency matched to cases on sex and age. Family history data were collected through telephone interviews with biological mothers and fathers and unconditional logistic regression was used to evaluate associations with GCT adjusting for potential confounders. A family history of cancer with onset <age 40 years was associated with a reduced risk of GCT among female cases (Odds Ratio (OR) = 0.50, 95% Confidence Interval (CI) 0.28–0.89) and an increased risk among male cases (OR = 2.56, 95% CI 1.02–6.44). Male cases were more likely to report family history of melanoma compared with male controls (OR = 4.65, 95% CI 1.40–15.4). There was an inverse association between family history of ovarian or uterine cancers and GCT in girls (OR = 0.46, 95% CI 0.22–0.96). These sex and cancer site specific associations should be confirmed in additional studies as they may provide clues to the etiology of pediatric GCT.     

Granular cell tumor: a clinicopathologic study of 110 patients

The clinicopathologic features of 118 granular cell tumors (GCT) encountered at two affiliated hospitals were reviewed. A total of 110 patients were affected over this 32-year period of study (71 men, 39 women), and in 5% GCT were multiple. Patients ranged in age from 16 to 58 years (average 32 years) and were symptomatic for an average duration of 11 months prior to diagnosis. There was a greater than expected frequency of GCT among black patients (29%). Although tongue was the single most common anatomic site involved, relatively more GCT (44%) occurred in skin or subcutaneous tissue. Less common locations were breast parenchyma (10 cases), rectal mucosa and anus (6), vulva (4), esophagus and larynx (2 cases each). The correct preoperative diagnosis of this protean tumor was made in only three patients. GCT were surgically treated with the average diameter of resected tumor being 1.2 cm (range 0.2--3.5 cm). Pseudoepitheliomatous hyperplasia was noted in 11 tumors and in one vulvar GCT there was overlying in situ squamous cell carcinoma. Tumors were incompletely excised in 24 of 56 patients having adequate followup; only five of these 24 patients experienced a local recurrence of tumor. Malignant behavior was not observed. Results of histochemical and ultrastructural study are briefly discussed. The precise histogenesis of GCT is uncertain but Schwann cell origin is favored in most cases.     

The value of cell proliferation and angiogenesis in the prognostic assessment of ovarian granulosa cell tumors.

OBJECTIVES: Most cases of granulosa cell tumors (GCT) of the ovary are characterized by a relatively good outcome. However, some tumors behave aggressively and some tend to recur many years after the initial diagnosis. Tumor growth depends on cell proliferation and angiogenesis. Thus, proliferative indices and microvessel density were studied to determine possible valuable methods to assess the GCT patient's outcome. METHODS and study design: Paraffin-embedded tissue blocks were available for 60 patients with primary GCT and were investigated by immunostaining with monoclonal antibodies against PCNA, Ki-67 and factor VIII-related antigen. The follow-up was available for 51 patients and ranged from 25 to 206 months. A clinical follow-up distribution of patients was made: 8 patients with recurrence (group I); 6 patients who lived with no evidence of recurrence for 100 months or more (group II), and 37 patients alive with no evidence of recurrence in the follow-up period of less than 100 months (group III). RESULTS: There was a statistical correlation between PCNA and Ki-67 proliferative indices. A significant increase (P <0.05) of mean PCNA and Ki-67 proliferative indices and mean tumor size was seen in patients of Group I compared to those of Group II. The mean PCNA proliferative index positively correlated with the mean Ki-67 proliferative index for Groups I and II. Mean microvessel density showed a positive correlation with mean PCNA and Ki-67 proliferative indices and with mean tumor size for Group I, whereas it was negatively correlated with PCNA proliferative index and tumor size for Group II. A positive correlation was found between mean mitotic count and both proliferative indices only for Group II. The following features were indicative of a relatively poor prognosis: GCT measuring >9 cm in diameter, PCNA >4.0%, Ki-67 >1.2%, and diffuse, insular and sarcomatoid histologic patterns. CONCLUSIONS: The findings support the importance of proliferative factors, tumor size and histologic patterns as possible prognostic indicators for estimating the biologic behavior of patients with GCT. Unfortunately, angiogenesis did not seem to be a useful determinant parameter of a possible aggressive behavior. However, a longer follow-up period with larger series may be required to assess the value of the parameters in prediction of patient survival.     

Silencing of the UCHL1 gene in giant cell tumors of bone

Giant cell tumors are heterogeneous tumors consisting of multinucleated giant cells, fibroblast‐like stromal cells and mononuclear histiocytes. The stromal cells have been identified as the neoplastic cell population, which promotes the recruitment of histiocytes and the formation of giant cells. Strong evidence exists that these cells develop from mesenchymal stem cells (MSCs) but little is known about the molecular mechanisms involved in GCT tumorigenesis. The aim of our study was the identification of cancer‐related genes differentially expressed in GCTs compared to MSCs in order to identify possible targets for aberrant promoter methylation, which may contribute to MSC transformation and GCT development. Gene expression of 440 cancer‐related genes was analyzed by DNA microarrays in GCT stromal cells and bone marrow‐derived MSCs (BMSCs) isolated from the same patient (n = 3) to avoid interindividual variations. Differential expression was identified for 14 genes, which could be confirmed by quantitative PCR in further 21 GCT and 10 BMSC samples. The most pronounced difference in gene expression was detected for UCHL1, an important regulator of the ubiquitin proteasome pathway. Methylation‐specific PCR and bisulfite sequencing revealed a strong methylation of the CpG island covering the UCHL1 promoter in GCT stromal cells, whereas methylation was completely absent in BMSCs. UCHL1 expression in stromal cells could be restored by the methylation inhibitor 5‐aza‐dC. These data demonstrate that the UCHL1 gene is inactivated in GCTs but not in MSCs, suggesting a possible role of UCHL1 in MSC transformation and GCT development.     

Identification of markers of possible prognostic value in 57 giant cell tumors of bone

Giant cell tumor of bone (GCT) is a neoplasm characterized by the presence of large numbers of multinucleated osteoclast-like giant cells, together with mononuclear spindle-shaped cells. Although GCT can be considered a benign lesion, it may exhibit a high biological aggressiveness, which is often associated with enhanced osteolytic properties and development of lung metastasis. By selecting different groups of GCT patients, including patients without evidence of relapse after a median follow-up of 114 months and patients who recurred with lung metastasis, this study focused on the analysis of the expression at clinical onset and in the metastasis of a series of markers involved either in bone resorption modulation or in the metastatic process. By using immunohistochemistry, we analyzed the expression of interleukin-6 (IL-6), a cytokine stimulating bone resorption that has been demonstrated to be released by GCT cells. The expression of factors of the urokinase-type plasminogen activation system, including the urokinase-type plasminogen activator (u-PA) and the plasminogen activator inhibitor type 1 (PAI-1), which have been described to be frequently implicated in the process of degradation of the extracellular matrix during the metastatic process, were also analyzed. Finally, since the action of plasminogen activators is facilitated by the presence of specific receptors on cell surfaces, the analysis included also the u-PA receptor (u-PAR). Our results showed that all these proteins were variably either expressed or overexpressed both in primary tumors and lung metastasis. However, both the level of expression and the incidence of overexpression were higher in primary GCT that relapsed and in lung metastasis compared to primary tumors from disease-free patients, suggesting a possible association of these proteins with a higher biologic aggressiveness of GCT cells. The parallel analysis of a group of primary tumors and of their respective lung metastasis demonstrated that the enhanced expression of one or more of these proteins may confer a selective advantage to GCT cells in terms of systemic invasiveness. Therefore, the evaluation of the expression levels of these proteins at the time of diagnosis may be taken into consideration for a classification of GCT into categories characterized by a different risk to relapse.     

Proteases and interleukin-6 gene analysis in 92 giant cell tumors of bone.

BACKGROUND: Giant cell tumor of bone (GCT) is a benign tumor with a significant tendency to recur locally and rarely to produce pulmonary metastases. It is characterized by the presence of multinucleated osteoclast-like giant cells together with mononuclear spindle-shaped cells. Few prognostic markers have been reported to predict the clinical outcome of GCT patients, so is very important to find the factor that can be implicated in its potential aggressiveness. PATIENTS AND METHODS: Different groups of GCT patients were selected for this study, including patients without evidence of disease and patients who recurred locally or with lung metastasis.The total of 92 tumor samples also included the specimens of the local recurrences and the lung metastases. By using immunohistochemistry and real-time quantitative polymerase chain reaction techniques, the genetic and proteic analyses were performed on the urokinase-type plasminogen activator (u-PA), its receptor (u-PAR) and its inhibitor (PAI-1), which have been described to be frequently implicated in the process of degradation of the extracellular matrix during the metastatic process. Interleukin-6 (IL-6), a cytokine released by GCT cells, which stimulates resorption of bone, was also analyzed. RESULTS: IL-6, u-PA, u-PAR and PAI 1 genes were found amplified, respectively, in 7%, 5%, 8% and 12% of total cases (92). In particular, the percentages of amplified genes were higher in the GCT cells that gave rise to metastases (12 cases) and in the samples of lung metastases (nine cases) compared with the disease-free group of patients (60 cases). CONCLUSIONS: These results suggest a possible association of these factors with a higher biological aggressiveness of GCT. Morever, it appears that increased expression of the IL-6, u-PA, u-PAR and PAI1 proteins might not depend on mutation of the corresponding genes.