Advances in the diagnosis and management of sarcomas.

Cytogenetic alterations that characterize different histologic subtypes of soft tissue sarcomas have been identified. In a few situations, more precise chromosomal mapping has allowed identification of certain genes that may be involved in the development or tumor progression of sarcomas. Careful family histories must be elicited in sarcoma patients. While "cancer families" are rarely identified when screening close relatives of sarcoma patients, the discovery of the currently known tumor suppressor gene syndromes associated with germ line retinoblastoma gene and p53 gene defects were made possible by their association with sarcomas. Optimal management of primary sarcomas includes function-sparing complete resection and radiotherapy. Innovative radiotherapy, utilizing radiation sensitizers or brachytherapy, may increase local control in patients with unresectable tumors. New drugs are needed. Epirubicin and other anthracycline analogues do have significant activity; however, no other novel drugs have documented efficacy. Dose intensity is being explored with sarcoma trials providing the "vehicle" to evaluate new cytokines. Several mechanisms of doxorubicin resistance have been identified in cell lines and fresh tumors, including alterations in glutathione peroxidase activity and MDR-1 gene expression. These observations need to be taken to the clinic.     

Prognostically important chromosomal aberrations in soft tissue sarcomas: a report of the Chromosomes and Morphology (CHAMP) Study Group

Cytogenetic analysis has not only provided important information on the pathogenesis of soft tissue tumors but, by disclosing distinct chromosomal rearrangements in different histopathological entities, has also come to serve as a valuable diagnostic tool. Little is known as yet about the potential prognostic impact of cytogenetic features detected in these tumors. A total of 239 benign and 221 malignant soft tissue tumors with clonal chromosome aberrations were subdivided according to general karyotypic features, such as degree of complexity and ploidy level, and rearrangements of specific chromosomal regions. The cytogenetic variables were analyzed regarding clinical outcome, using time to metastasis as the end point. Selected variables were then compared with established clinicopathological predictors of metastasis development. When the entire material was considered, 167 of 268 investigated cytogenetic variables were associated with clinical outcome. Focusing on the subset of 151 patients with high-grade sarcoma, 17 variables were identified that, besides grade and size, were associated with increased risk of metastasis development. A final Cox regression analysis identified five independent cytogenetic predictors of adverse outcome; breakpoints in chromosome regions 1p1, 1q4, 14q1, and 17q2, and gain of regions 6p1/p2. An increasing effect on metastatic risk was seen with increasing involvement of the selected cytogenetic variables, even when different histopathological types were studied separately. We conclude that cytogenetic data provide independent prognostic information in soft tissue sarcomas. Furthermore, our results point to specific areas of the genome harboring genes that may influence the metastatic potential of sarcoma cells.     

Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas

Previous studies have shown that the prognosis of patients who have tumours with high microvessel density (MVD) is worse than that of patients who have a lower density in a variety of cancers. In this study, we investigated the clinical relevance of neovascularity assessed by MVD and the concentration of vascular endothelial growth factor (VEGF) in the tumour tissue of patients with soft tissue sarcoma in comparison with major clinicohistologic parameters by univariate and multivariate analysis. In 115 patients with soft tissue sarcoma, MVD was measured by counting vessels stained with factor VIII antibody. The concentration of VEGF in the tumour tissue was determined by enzyme-linked immunosorbent assay. These parameters were then compared with disease outcome. The concentration of VEGF in the tumour tissue, but not MVD, was found to be correlated with disease outcome in patients with soft tissue, sarcoma. VEGF concentration in the tumour tissue showed a relationship with the clinical stage and histologic grade of the tumour. There was no significant difference in the levels of tissue VEGF concentration and MVD among soft tissue sarcomas classified according to histologic type. The level of tissue VEGF concentration in patients who had subsequent local recurrence and metastasis were significantly higher than the respective values in patients who did not have such disease outcome. No significant correlation existed between MVD and the concentration of VEGF in the tumour tissue. Univariate analysis showed that a high tissue VEGF concentration was associated with poor overall survival of the patient and a greater probability that local recurrence and metastasis had occurred. Multivariate analysis revealed that the tissue concentration of VEGF is an independent prognostic factor for the disease outcome of patients with soft tissue sarcoma. VEGF concentration in the tumour tissue, but not MVD, is an additional prognostic parameter for disease outcome in patients with soft tissue sarcoma, regardless of histologic type.     

Chemotherapy of advanced bone and soft tissue sarcoma

The primary site of metastasis of bone and soft tissue sarcoma is the lung. Control of these sarcomas depends upon the prevention and treatment of their pulmonary metastasis. The introduction of a chemotherapy consisting mainly of Adriamycin and high-dose methotrexate dramatically improved the prognosis of osteosarcoma. However the effectiveness of chemotherapy has not yet been duplicated in soft tissue sarcomas except some childhood sarcomas. We analyzed the clinical data for pulmonary metastasis of osteosarcomas and soft tissue sarcomas. Based on these analyses, we tried to clarify the nature of pulmonary metastasis of these sarcomas and to evaluate its response to treatment, that this would yield clues to future treatment of these sarcomas.     

Sarcomas of soft tissue and bone

Sarcomas arise primarily from mesenchymal structures at any site in the body, even within visceral stroma and neurovascular bundles. Sarcomas have been associated with prior radiation therapy, toxic exposures, and genetic conditions and soft tissue sarcomas have been distinguished from bone sarcomas. For localized soft tissue sarcoma, tumor grade is the most important prognostic variable. Low-grade tumors are generally cured by wide surgical excision, but there is a significant rate of both local recurrence and development of distant metastasis in high-grade lesions. The treatment of soft tissue sarcoma histologic subtypes is generally similar grade-for-grade, with the exception of rhabomyosarcoma, Kaposi's sarcoma, and mesothelioma. Tumor location strongly influences resectability. Radiation therapy has been used successfully in conjunction with conservative surgery to improve local control rates for soft tissue sarcomas, particularly in extremity lesions. Currently, adjuvant chemotherapy remains unproven for most adult soft tissue sarcomas, but is established in the treatment of rhabdomyosarcomas, osteosarcomas, and Ewing's sarcomas.     

nm23蛋白在软组织肉瘤中的表达及意义

目的探讨nm23蛋白在软组织肉瘤中的表达及与软组织肉瘤分级的关系。方法应用FNCLCC（法国癌症中心联盟）分级系统对108例软组织肉瘤进行组织病理学分级并应用免疫组织化学技术Evision二步法检测nm23蛋白在这些肿瘤中的表达情况。结果108例软组织肉瘤中1级、2级、3级分别为23例、28例和57例;免疫组织化学染色结果显示,在1级、2级、3级中nm23蛋白的阳性表达率分别为26．1％、32．1％、61．4％,经卡方检验P〈0．05,差异有显著性。结论nm23蛋白表达与软组织肉瘤组织学分级相关并且分级越高阳性表达率越高,因此nm23在软组织肉瘤中可能扮演着促进肿瘤浸润与转移的作用。     

New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas

Nonrhabdomyosarcoma soft tissue sarcomas form a group of rare tumors with a different biology and clinical behavior. The recently established European Pediatric Soft Tissue Sarcoma Study Group is organizing a new study devoted specifically to these tumors that were formerly treated according to the principles derived from experience with rhabdomyosarcoma, which is a clearly distinct entity. The new study includes two prospective trials, one for synovial sarcoma and the other for adult-type nonrhabdomyosarcoma soft tissue sarcomas. While surgery remains the mainstay of treatment, the role of adjuvant therapy is not yet clear and our understanding of the biology and natural history of nonrhabdomyosarcoma soft tissue sarcomas is still incomplete. This review presents the latest data on nonrhabdomyosarcoma soft tissue sarcoma treatment and outcome, and the rationale behind a risk-adapted treatment program that investigates the role of full-dose ifosfamide-doxorubicin chemotherapy in improving the response rate of patients with unresectable disease, the chances of avoiding adjuvant chemotherapy in low-risk synovial sarcomas, and the possible role of chemotherapy in high-risk adult-type soft tissue sarcomas.     

Matrix metalloproteinase expression in high grade soft tissue sarcomas

Soft tissue sarcomas comprise a heterogeneous group of mesenchymal tumors with varying biological behavior ranging from indolent tumors with no or minimal metastatic risk to aggressive and frequently metastasizing tumors. Among the more common aggressive adult soft tissue sarcomas are malignant fibrous histiocytoma, synovial sarcoma and liposarcoma. Matrix metalloproteinases are enzymes which perform a homeostatic role in mesenchymal tissue and function in both tumorigenesis and metastasis. The objectives of this study are to determine the presence and relative quantity of matrix metalloproteinases (MMPs) -1, -2, -8, -9, and -13; extracellular matrix metalloproteinase inducer (EMMPRIN); and tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2 in high grade soft tissue sarcoma tumor specimens using real-time PCR. The second objective is to determine if a relationship exists between quantity of EMMPRIN, MMPs, and TIMPs expressed in tumor tissue and disease-free survival. One hundred and forty patients diagnosed with high grade soft tissue sarcomas between 1995-2003 were identified. Tissue blocks and histologic slides were acquired for 41 specimens. Tumor specimens included 29 malignant fibrous histiocytomas, 3 liposarcomas and 11 synovial sarcomas. RNA was extracted and RT-PCR was performed in triplicate. No significant differences were found between the three types of high grade soft tissue sarcomas studied and the expression of MMPs. Interestingly, no relationship was found between high or low levels of MMPs when compared with disease-free survival. Our data support other research which finds variable correlation between MMP expression in soft tissue sarcomas and disease-free survival. We assert that the difference in correlation between MMP expression in carcinomas and sarcomas and disease-free survival is based on the vast phenotypic and genotypic difference between the cells of origin.     

β-连环蛋白在软组织肿瘤中的研究进展

β-连环蛋白(β-catenin)作为一种胞浆蛋白及转录蛋白在肿瘤的发生发展中起双重作用。近年来,β-catenin及其相关Wnt/β-catenin信号通路在肿瘤中的异常调节受到越来越多的关注。软组织肉瘤好发于四肢及躯干,在中青年人群中发病率较高,其分类复杂,进展期恶性程度较高,亟待靶向药物缓解病程进展。本文就β-catenin在软组织肉瘤中的表达模式及其在增殖、转移、凋亡、分化、自我更新方面的相关作用机制进行全面概括,以期改善患者的临床预后,为软组织肿瘤的靶向治疗带来新希望。     

New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas

Nonrhabdomyosarcoma soft tissue sarcomas form a group of rare tumors with a different biology and clinical behavior. The recently established European Pediatric Soft Tissue Sarcoma Study Group is organizing a new study devoted specifically to these tumors that were formerly treated according to the principles derived from experience with rhabdomyosarcoma, which is a clearly distinct entity. The new study includes two prospective trials, one for synovial sarcoma and the other for adult-type nonrhabdomyosarcoma soft tissue sarcomas. While surgery remains the mainstay of treatment, the role of adjuvant therapy is not yet clear and our understanding of the biology and natural history of nonrhabdomyosarcoma soft tissue sarcomas is still incomplete. This review presents the latest data on nonrhabdomyosarcoma soft tissue sarcoma treatment and outcome, and the rationale behind a risk-adapted treatment program that investigates the role of full-dose ifosfamide–doxorubicin chemotherapy in improving the response rate of patients with unresectable disease, the chances of avoiding adjuvant chemotherapy in low-risk synovial sarcomas, and the possible role of chemotherapy in high-risk adult-type soft tissue sarcomas.     

Preclinical experimental therapeutic approaches in soft tissue sarcoma.

Soft tissue sarcomas are relatively rare tumors that are generally treated with a multimodality approach including surgery, chemotherapy, and radiation therapy. Despite this aggressive tri-modality therapy, greater than 50% of soft tissue tumors will recur and result in diffuse metastatic spread of disease and ultimately death of the patient. It is this clinical scenario that drives the development of preclinical experimental studies designed to explore alternative treatments or enhance the effectiveness of existing therapies. Rapid developments in the field of molecular biology have led to the understanding of basic cellular processes governed by oncogenes and tumor suppressor genes. These cellular genes are sometimes overexpressed, mutated or even deleted from tumor cells. Cytogenetic analysis has led to the discovery of sarcoma fusion genes which encode for oncoproteins peculiar to specific subtypes of soft tissue sarcomas. These fusion genes have proved to be helpful in terms of diagnostic dilemmas and are now being used as targets in treatment strategies aimed at suppression of the cellular expression and action of these oncoproteins. Tumor suppressor genes such as p53 and the retinoblastoma tumor suppressor play important roles in growth inhibition and cell cycle progression. These tumor suppressors are often mutated or deleted in soft tissue sarcomas. Using gene therapy strategies, p53 can be reintroduced into sarcoma cells and has been shown to result in a dramatic decrease in cell survival. It also appears that p53 may sensitize these tumor cells to radiation and chemotherapy agents. Strategies which can drive tumor cells into programmed cell death pathways are also showing promise as novel treatment approaches to soft tissue sarcomas. This review will highlight some of the current research exploring novel treatment strategies aimed at molecular targets. Further development of these and other preclinical experimental programs are important in improving the outcome for patients with these rare soft tissue tumors.     

Retrospective analysis of metastatic sarcoma patients

Numerous studies have reported the survival of metastatic sarcoma patients who have undergone either a lung metastasectomy or chemotherapy. However, little is known with regards to the clinical course of patients with bone or soft tissue sarcomas who have succumbed to disease. This study aimed to analyze the metastatic patterns of sarcoma patients and to describe the clinical course after the detection of distant metastasis. We reviewed the clinical records of 255 patients with a diagnosis of sarcoma who were referred to our institution, and found 63 patients who succumbed due to metastasis. We examined the clinical features of the initially detected distant metastases, the subsequent clinical course up to the time of patient death and the survival time of patients who died of lung metastasis. Of the 63 patients who died of distant metastasis, 52 (83%) developed lung metastasis as the first metastatic site, while 22 (35%) developed extra-pulmonary metastasis. The majority (77%; 49 of 63 patients) died of primary metastasis. While all 18 bone sarcoma patients died of lung metastasis, 11 of the 45 soft tissue sarcoma patients died of extra-pulmonary metastasis. Six patients died of brain metastasis. The survival of the patients with lung metastasis was only approximately 6 months following the cessation of treatment, regardless of the type of treatment used. These results indicate that planned follow-up and treatment of sarcomas require a precise knowledge of tumor clinical behavior, particularly of the preponderant activity.     

Cyclooxygenase-2 expression is not associated with clinical outcome in synovial sarcoma

Several studies have identified cyclooxygenase-2 (COX-2) expression in a variety of sarcomas, including rhabdomyosarcoma, osteosarcoma and chondrosarcoma. Although overexpression of COX-2 has been associated with poor prognosis and decreased survival in chondrosarcoma and osteosarcoma, no relationship between COX-2 expression and patient outcome has been demonstrated in rhabdomyosarcoma or adult soft tissue sarcomas. Little is known concerning the expression of COX-2 in synovial sarcoma. Therefore, the aim of this study was to examine the expression of COX-2 in synovial sarcoma and if shown, to identify any association with tumor stage and oncologic outcome. Paraffin-embedded specimens from 27 patients with synovial sarcoma who were treated with surgical resection or biopsy were obtained. Specimens were evaluated for the degree of COX-2 expression after immunohistochemical staining. Specimens were assigned an immunoreactivity score (IS) based on the percent positivity of the specimen. A retrospective chart analysis was performed to determine the clinical stage at presentation, incidence of local recurrence, presence of metastatic disease and overall survival. Statistical analysis was then performed to determine whether there was a significant relationship between IS and stage at presentation or patient outcomes. COX-2 expression was detected in 18 of 27 (66.67%) of the pathological specimens. There was a statistically significant relationship between COX-2 expression and patient clinical stage at presentation; however, we were unable to identify a significant relationship between IS and patient survival. We also found no significant relationship between IS and development of metastases or local recurrence. COX-2 was expressed to some degree in 67% of the tumor specimens. There was a significant relationship between IS and patient stage at presentation, but no significant relationship between COX-2 expression and clinical outcome could be identified. The fact that these tumors do express COX-2, however, suggests the potential for an additional target for more effective therapy.     

Surgical considerations for management of distal extremity soft tissue sarcomas

PURPOSE OF REVIEW: This review focuses on the surgical management of soft tissue sarcomas of the hands and the feet. With recent advances in limb salvage surgery and radiotherapy delivery, local control of soft tissue sarcoma in the extremity has become optimized, and the associated functional results of this treatment have taken on extreme importance. Techniques to limit the amount of normal tissue resected and to reconstruct the resulting defects are critical to the final functional result. RECENT FINDINGS: Several features of soft tissue sarcoma unique to the hand and foot have been reported. Certain histologic subtypes of soft tissue sarcoma have been noted to arise preferentially in the hand and the foot, such as epithelioid sarcoma, clear cell sarcoma, and synovial sarcoma. Patients with hand and foot sarcomas have been described as having improved overall survival, but this is likely a result of the smaller size of tumors arising in these locations. Reconstruction of bone defects using various techniques, vascular reconstruction, tendon transfers, and soft tissue reconstruction using regional flaps in the hand and free flaps in the foot have resulted in good functional outcomes. Amputation and early prosthetic fitting still have a role in management of some soft tissue sarcomas, most frequently in the foot. SUMMARY: Limb salvage remains the standard of care for extremity soft tissue sarcomas. Given the fact that patients have good oncologic and functional outcomes with limb salvage in tumors in the hand and foot, surgical oncologists should have this goal for each patient.     

Prognostic significance of macrophage infiltration in leiomyosarcomas.

PURPOSE: Macrophages are migratory cells that are frequently recruited to the site of tumors. Their presence is associated with poor clinical outcome in a variety of epithelial malignancies. The aim of this study is to examine the prognostic significance of tumor-associated macrophages in sarcomas. EXPERIMENTAL DESIGN: Global gene expression profiling data of a series of soft tissue tumors were analyzed for macrophage-associated gene expression. Immunohistochemistry on tissue microarrays containing leiomyosarcoma cases with known clinical outcome was used to verify the presence of macrophages and to examine the relationship between tumor-associated macrophages and clinical outcome. RESULTS: Gene expression profiling revealed high-level expression of several macrophage-associated genes such as CD163 and CD68 in a subset of leiomyosarcomas, indicating the presence of variable numbers of tumor-infiltrating macrophages. This was confirmed by CD68 and CD163 immunostaining of a tissue microarray containing 149 primary leiomyosarcomas. Kaplan-Meier survival analysis showed that high density of tumor-infiltrating macrophages as identified by CD163 or CD68 staining is associated with a significantly worse disease-specific survival in nongynecologic leiomyosarcomas, whereas leiomyosarcomas arising from the gynecologic tract showed no significant association between macrophage infiltration and survival. The presence of tumor necrosis did not correlate significantly with outcome. CONCLUSIONS: An increased density of CD163- or CD68-positive tumor-infiltrating macrophages is associated with poor outcome in nongynecologic leiomyosarcomas. This may help the clinical management of patients with leiomyosarcomas.     

Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma.

PURPOSE: Hypoxia is associated with malignant progression and poor outcome in several human tumors, including soft tissue sarcoma. Recent studies have suggested that carbonic anhydrase (CA) IX is an intrinsic marker of hypoxia, and that CA IX correlates with poor prognosis in several types of carcinoma. The aim of this study was to quantify the extent of CA IX expression and to investigate whether CA IX is a marker for poor prognosis in soft tissue sarcoma patients at high risk of developing metastasis. EXPERIMENTAL DESIGN: Archival paraffin-embedded blocks were retrieved from 47 patients with deep, large, high-grade soft tissue sarcoma. Sections from two separate and representative tumor areas were immunostained for CA IX, and the CA IX-positive area fraction was quantified by image analysis, excluding areas of normal stroma and necrosis that were identified from serial H&E-stained sections. Patients were then subject to survival analysis. RESULTS: CA IX-positive area fractions of viable tumor tissue varied significantly between tumors (range, 0-0.23; median, 0.004), with positive membranous CA IX staining in 66% (31 of 47) of the tumors. Patients with CA IX-positive tumors had a significantly lower disease-specific and overall survival than patients with CA IX-negative tumors (P = 0.033 and P = 0.044, respectively). CONCLUSIONS: These data suggest that CA IX, a potential intrinsic marker of hypoxia, predicts for poor prognosis in patients with deep, large, high-grade soft tissue sarcoma. Larger studies are required to determine whether CA IX has independent prognostic value in this group of tumors.     

基于免疫基因集的软组织肉瘤分类研究

目的:基于免疫基因集的生物信息学方法,鉴定和识别软组织肉瘤的免疫特征亚型。方法:从TCGA数据库和GEO数据库下载软组织肉瘤基因表达谱数据,分别对两个数据集进行单样本基因集富集分析及层次聚类分析,鉴定软组织肉瘤的免疫分型。使用ESTIMITE方法评估和定量软组织肉瘤的肿瘤微环境评分。CIBERSOFT反卷积算法计算软组织肉瘤免疫细胞亚群占比。对高和低免疫亚型进行生存分析。最后,通过GSEA算法,对高免疫亚型和低免疫亚型进行京都基因与基因组百科全书数据库通路富集分析。结果:基于单样本基因集富集分析及层次聚类分析,鉴别了两种新的软组织肉瘤免疫亚型。肿瘤微环境分析结果显示高和低免疫亚型具有不同的免疫微环境。CIBERSORT反卷积算法证实了高和低免疫亚型具有不同的免疫细胞亚群比例。生存分析曲线能较好的区分两种不同免疫亚型的患者。京都基因与基因组百科全书数据库通路富集分析结果显示,高免疫亚型富集了大量与免疫相关的通路。结论:本研究鉴定的两种免疫亚型可指导软组织肉瘤患者进行分型,并帮助识别对免疫治疗有反应的患者,具有一定的临床应用价值。