Current topics in the diagnosis and treatment of malignant fibrous histiocytoma

Malignant fibrous histiocytoma (MFH) is a tumor about which much remains unknown. The cell origin, molecular mechanism of pleomophism and mechanism of pleomorphic change in a cell undergoing malignant change have not been elucidated. MFH-like histological changes are observed in many bone and cartilage sarcomas, and some renal cell carcinomas and malignant lymphomas. These changes occur in many subtypes of sarcomas such as osteogenic sarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, and liposarcoma. MFH has been regarded as one tumor classification from its special histopathological features. In clinical pathological studies these tumors are divided into low-grade fibrous tumors and fibrous histiocytic tumors. With the establishment of molecular biological diagnostic methods, MFH-like histological features can be seen in changes in cellular differentiation of many sarcomas. Patients with MFH often have repeated recurrences before a diagnosis is made, and the tumor is partially resected. Furthermore, distance metastasis develops and the prognosis is poor. The sensitivity of MFH to radiotherapy and chemotherapy is insufficient, and evidence is lacking for adjuvant treatment. Rescue following initial treatment failure is extremely difficult. Local control of 70% to 90% can be achieved if a correct diagnosis is made, and a curative wide resection or salvage wide resection are done early. For treatment of bone and soft tissue sarcoma, a correct diagnosis and initial treatment are extremely important. MFHs are rare tumors that occur in every part of the body. Many cases need to be accumulated in joint clinical studies across fields according to organ and specialty, and effective treatment method developed. We need to advance the standardization of treatment for MFH, and eliminate wrong initial treatment through the active provision of information.     

Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy in recent years. The aim of this study is to evaluate the PD-1/PD-L1 expressions in sarcomas and to determine association between PD-1/PD-L1 expressions and clinical/pathological properties in some sarcoma subtypes. Formalin-fixed, paraffin-embedded tissue samples from 65 cases with sarcomas were analyzed. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions in tumor tissue and microenvironment, separately. PD-1 expression in tumor tissue and microenvironment was detected in 11 (17 %) and 8 (12 %) cases, respectively. PD-L1 expression in tumor tissue and microenvironment was detected in 19 (29 %) and 20 cases (30 %), respectively. None of the 5 Ewing sarcomas involving bone showed PD-1/PD-L1 expression, while 2 of 3 cases with Ewing sarcomas involving soft tissue showed PD-1 and PD-L1 expression. Among 5 cases with Kaposi sarcoma, four showed PD-1 and/or PD-L1 expression in tumor or microenvironment. PD-1/PD-L1 expressions were detected 3 of 6 cases with pleomorphic sarcoma, 2 of 4 cases with peripheral nerve sheath tumors and 1 of 4 cases with synovial sarcoma. Interestingly, strongest PD-1/PD-L1 expressions in our study group were detected in 2 sarcoma cases with the history of giant cell tumor. PD-1 and PD-L1 expressions are up to 30 % of the cases with sarcomas. It may be rational to target programmed death pathway in Kaposi sarcoma, pleomorphic sarcoma and peripheral nerve sheath tumors. Strong expression of PD-1/PD-L1 in cases with previous giant cell bone tumor has been found to be interesting and must be studied in giant cell tumor samples.     

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas.     

Radiological and pathological response following pre-operative radiotherapy for soft-tissue sarcoma

Purpose

To report radiological and pathological response to neo-adjuvant radiotherapy for extremity and trunk soft-tissue sarcomas.

Materials/methods

Fifty patients were identified retrospectively. All patients had MRI imaging pre and post neo-adjuvant external beam radiotherapy. Tumor volumes were measured in 3D on T1 Gadolinium enhanced sequences. Pathological treatment response was quantified in terms of percentage of treatment-related necrosis for each case.

Results

Histopathologic responses to treatment varied from 0% to 100%. The median pathological treatment response was 67.5% for low-grade sarcomas and 50% for high-grade sarcomas. The median decrease in tumor volume was 13.8% for non-myxoid low-grade sarcomas, 82.1% for myxoid liposarcomas and <1% for high-grade sarcomas. A partial response on MRI (volume reduction ? 50%) was highly predictive of a good pathological response (p < 0.001). Patients with stable disease on imaging or volumetric progression had wide ranging pathological responses.

Conclusions

Soft-tissue sarcomas show significant pathological treatment responses in the form of hyaline fibrosis, necrosis and granulation tissue. Despite this, there is minimal early volumetric response to radiation, especially for high-grade tumors. Although radiological partial response was predictive of pathological response, the significance of radiological progression was unclear. Myxoid liposarcoma tumor type was predictive of both pathological and radiological tumor response.     

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.     

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.     

Do stem-like cells play a role in drug resistance of sarcomas?

Stem cells are defined by their unique characteristics, which include their abilities to self-renew and differentiate. Normal somatic stem cells have been isolated from various tissues such as bone marrow, adipose tissue, mammary glands and the nervous system. They are considered naturally resistant to chemotherapeutic agents because they express high levels of membrane transporter molecules, detoxifying enzymes and DNA repair proteins. Several recent studies have identified the presence of side populations in various cancer tissues, the so-called ‘cancer stem cells’, which are defined as the counterparts of stem cells in tumor tissues. These cancer stem cells possess stem-like properties, such as self-renewal and differentiation abilities, as well as playing a role in tumor initiation. Most sarcomas, which are thought to originate from mesenchymal stem cells, are highly malignant and approximately 30–40% of them show local and/or distant relapse (metastasis), even in the case of relatively chemosensitive tumors such as osteosarcomas and Ewing sarcomas. Several studies have suggested the presence of stem-like cell populations in sarcomas, based on their tumorigenicity and drug resistance. This review explores the issues of drug resistance of cancer stem cells in sarcomas and the possibilities of targeting cancer stem cells for the future treatment of sarcomas.     

Future directions for immunotherapeutic intervention against sarcomas

PURPOSE OF REVIEW: To discuss advances in immunotherapy as pertaining to systemic therapy for sarcomas. RECENT FINDINGS: Developments in immunology will have direct relevance to studies in sarcomas and other cancers in the near future. Vaccines employing peptides are the backbone of many studies today due to issues of cost and ease of production, but intact or transfected whole tumor cells or antigen-pulsed or transfected dendritic cells are now being investigated as the immunogenic principle in sarcomas and other cancers. The importance of dendritic cells in generating immune responses is better appreciated than ever, as is the role of CD4+ CD25+ regulatory T cells in mediating immune responses. Enhancing costimulatory signals to T cells using anti-CD152 (CTLA4) and other antibodies or expanding anti-tumor cytotoxic T lymphocytes ex vivo are other means to enhance immunity to sarcoma-specific antigens. SUMMARY: As of 2006, few studies are examining the utility of immunotherapy in sarcomas. However, a detailed understanding of the remarkable mechanics of how an immune response is mounted and how T cell activation and/or proliferation can be halted by the tumor will be central to properly design new studies of immunological agents against sarcomas and other cancers.     

口腔颌面部肉瘤中ki-67表达的研究

[目的]探讨口腔颌面部肉瘤细胞增殖活性与临床病理学特征的关系.[方法]采用S-P免疫组化法检测51例口腔颌面部间叶组织肿瘤中ki-67表达情况.[结果]口腔肉瘤中ki-67标记指数(ki-67 labeling index,ki-67LI)明显高于口腔良性间叶组织肿瘤(P＜O.05).ki-67LI与口腔颌面部肉瘤的病理学分级、淋巴转移或远处转移密切相关.复发肉瘤ki-67u虽明显高于原发肉瘤,但未发现有统计学意义(P＞0.05).[结论]ki-67可能是研究口腔颌面部肉瘤生物学行为的一个有用指标.     

New developments in the pathology and molecular biology of retroperitoneal sarcomas

Retroperitoneal sarcomas (RPS) refer to a heterogeneous group of malignancies of mesenchymal origin developing from retroperitoneal tissues and vessels. The most frequent RPS are well differentiated/dedifferentiated liposarcomas and leiomyosarcomas, but other rare histological subtypes can be observed. Over the last decade, significant advances have been made in the pathological and molecular characterization of sarcomas. These advances have led to major changes in their diagnostic management as well as in the development of new therapeutic strategies based on tumor biology and microenvironment. This review describes the current knowledge and recent findings in the pathology and molecular biology of the most frequent RPS subtypes.     

指突状树突状细胞肉瘤诊治探讨

目的：探讨树突状细胞肉瘤的临床特征、诊断、治疗和预后。方法：对1例指突状树突状细胞肉瘤进行临床病理特点分析,CHOP（环磷酰胺、表阿霉素、长春地辛、地塞米松）方案化疗并观察疗效,复习文献总结国内树突状细胞肉瘤诊治情况。结果：临床表现为全身淋巴结肿大,颈部呈巨大肿块,两肺弥漫性微小结节,伴盗汗、轻度贫血。病理结果示淋巴结结构破坏,瘤细胞成梭形,形成束状,交错状排列。免疫组化S-100（＋）、Vimentin（＋）、Fascin（＋）、Lyso（＋）、Ki-67（＋）,部分肿瘤细胞CD68（＋）。经CHOP方案化疗后达到部分缓解。Langerhans细胞肉瘤罕见,呈高度恶性表现,常累及多个器官,目前国内仅3例报道。指突状树突状细胞肉瘤国内共报道6例,年龄19～41岁（中位33岁）,颈部淋巴结好发,手术后无病生存时间2～15月（中位10月）,18月总生存率40%（2/5）。滤泡树突状细胞肉瘤18例,年龄16～63岁（中位37岁）,发病部位1/3以上在结外,无病生存时间5～72月（中位11.5月）,18月总生存率100%（6/6）。结论：树突状细胞肉瘤诊断依赖病理和免疫组化;治疗尚需规范,可采取手术、放疗、化疗相结合的方案。     

软组织肉瘤治疗进展

肉瘤是一组少见的具有不同临床和病理特征的间叶来源的肿瘤。整体上肉瘤可分为两大类,软组织来源的肉瘤和骨肉瘤。肉瘤大约占成人恶性肿瘤的1%,占儿童恶性肿瘤的15%。软组织肉瘤包含50多种不同的组织学亚型,最常见的亚型包括未分化多形性肉瘤、胃肠间质瘤、脂肪肉瘤、平滑肌肉瘤、滑膜肉瘤和恶性外周神经鞘瘤等。手术是软组织肉瘤最主要的治疗方法,但术后复发率高,预后差,化疗疗效仍不理想。随着人们对其生物学行为认识的加深,近些年涌现的一系列新型靶向药物取得了不错的疗效。总之,软组织肉瘤的治疗需根据疾病的组织学亚型、分子遗传学特点、分期及预后因素采取包括手术、放疗、化疗以及分子靶向治疗在内的个体化治疗模式。      

Sarcomas of the fallopian tube: disentangling a rare entity

Sarcomas of the fallopian tube are exceedingly rare malignancies. They have been considered the most lethal of all gynaecological malignancies with high metastatic potential, frequent recurrences and cancer-related deaths. The reported pathological types of the fallopian tube sarcomas are malignant mixed mullerian (mesodermal) tumours or carcinosarcomas, leiomyosarcomas, rhabdomyosarcomas, liposarcomas, and synovial sarcomas. The rarity of these sarcomas and their often aggressive clinical course has resulted in a relatively limited amount of literature. Thus a single hospital or specialist cannot gain sufficient experience with these tumours. This review article tries to elucidate this uncommon malignancy, in a systematic way, focusing on the different pathological types, epidemiology, risk factors, diagnosis, survival, and different therapeutic modalities (surgery, chemotherapy, and radiotherapy).     

Clinical experience with intravenous radiosensitizers in unresectable sarcomas

Traditionally, adult bone and soft tissue sarcomas have been considered to be "radioresistant." Because of this philosophy, patients who present with locally advanced, unresectable sarcomas often are treated in a palliative fashion, usually with low-dose radiotherapy. Over the last 6 years, 29 patients with unresectable primary or metastatic sarcomas were treated using a combination of intravenous chemical radiosensitizers and high-dose irradiation. Twenty-two of 29 patients achieved clinical local control, with six patients having a complete clinical response. The time to tumor response is often several months or longer, which is in contrast to other tumor histologies (carcinomas, lymphomas), where tumor response usually occurs over several weeks. Several large tumors have shown only a minimal tumor response, yet were found to be sterilized in posttreatment biopsy or autopsy examination. Of 15 patients with primary sarcomas without metastases, 11 patients (73%) remain free of local tumor progression from 12 to 83 months. Adult high-grade sarcomas can be controlled with high-dose radiotherapy and intravenous radiosensitizers, although the precise role of these agents is unclear.     

Genetic predictors for drug resistance in soft tissue sarcoma: a review of publications in 2004

PURPOSE OF REVIEW: Sarcomas are generally managed through a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Metastatic tumor cells frequently develop resistance to cytotoxic agents. Several molecular mechanisms of drug resistance have been uncovered recently. RECENT FINDINGS: Among genes governing the apoptosis pathway, overexpression of the bcl2 family or mutations of p53 have recently been reported to be involved in drug resistance in sarcoma. The multidrug resistance genes are involved in the efflux of chemotherapeutic agents. Identification of members of this family of genes may predict resistance for developing new strategies. Several histologic subtypes of sarcomas have specific mechanisms of resistance. Methotrexate is one of the four active drugs for osteosarcoma and penetrates in tumor cell through specific carrier (reduced folate carrier) whose levels of expression or changes in amino acid sequence correlate to resistance to methotrexate. Specific molecular alteration defining nosological entities among sarcoma also correlates to drug resistance. Thirty percent of human sarcomas are characterized by specific translocations that may predict, for specific subtypes, survival and response to treatment. Finally, gastrointestinal tumors harbor specific activating mutations in KIT or PDGFRA genes, which are responsive to imatinib. Specific mutations of the KIT and PDGFRA genes have now repeatedly been found correlated to response or resistance to imatinib. SUMMARY: The molecular alterations present in tumor cells predict influence sensitivity or resistance to chemotherapy. Ultimately, this may delineate specific therapeutic strategies for both cytotoxic and targeted therapies in sarcomas.     

骨来源恶性肿瘤临床疗效的评估

  目的  通过现有实体瘤临床评估体系,对骨来源恶性肿瘤术前化疗前后的影像学资料进行总结,对比病理学评估结果,进一步提出并完善适合骨来源恶性肿瘤疗效的临床评估体系。  方法  回顾性分析自2014年6月至2017年3月就诊于北京大学人民医院的190例连续病例,最后纳入研究157例,通过病理学Huvos分级将病例进行分组,对术前化疗前后的临床资料（肿瘤最大径变化、代谢参数的变化,以及一些公认的描述性参数）进行差异性检验及通过受试者工作曲线（receiver operating characteristic curve,ROC）计算肿瘤各项参数的变化率对术前化疗病理反应的ROC曲线下面积,并判断病理学分级的截点。  结果  对原发肢体骨包含软组织包块的病例,判断坏死率为100%、90%及50%的最大径变化率截点分别为86%、50.7%和0.02%,骨扫描的T/B值变化率对坏死率预测效果不好,而PET/CT的SUVmax变化率对应坏死率为90%和50%的截点分别为60.7%和31.4%;而骨性边界变清晰及骨性密度增高为90%以上的病理学特异性表现形式。对不含软组织包块的原发纯骨内病变的病例,尚未发现有意义的临床评估指标。对中轴骨（包括颌面骨、脊柱及骨盆等）的病灶,由于病例数少,临床评估的截点目前区分度不大。  结论  本研究对骨来源肿瘤的疗效临床评估提出了更具体的定义和不同病理学分级的界值,该临床评估体系的完善需通过前瞻、多中心、大宗数据进一步验证和讨论。      

High expression of neuropeptide Y1 receptors in ewing sarcoma tumors

PURPOSE: Peptide receptors are frequently overexpressed in human tumors, allowing receptor-targeted scintigraphic imaging and therapy with radiolabeled peptide analogues. Neuropeptide Y (NPY) receptors are new candidates for these applications, based on their high expression in specific cancers. Because NPY receptors are expressed in selected sarcoma cell lines and because novel treatment options are needed for sarcomas, this study assessed the NPY receptor in primary human sarcomas. EXPERIMENTAL DESIGN: Tumor tissues of 88 cases, including Ewing sarcoma family of tumors (ESFT), synovial sarcomas, osteosarcomas, chondrosarcomas, liposarcomas, angiosarcomas, rhabdomyosarcomas, leiomyosarcomas, and desmoid tumors, were investigated for NPY receptor protein with in vitro receptor autoradiography using (125)I-labeled NPY receptor ligands and for NPY receptor mRNA expression with in situ hybridization. RESULTS: ESFT expressed the NPY receptor subtype Y1 on tumor cells in remarkably high incidence (84%) and density (mean, 5,314 dpm/mg tissue). Likewise, synovial sarcomas expressed Y1 on tumor cells in high density (mean, 7,497 dpm/mg; incidence, 40%). The remaining tumors expressed NPY receptor subtypes Y1 or Y2 at lower levels. Moreover, many of the sarcomas showed Y1 expression on intratumoral blood vessels. In situ hybridization for Y1 mRNA confirmed the autoradiography results. CONCLUSIONS: NPY receptors are novel molecular markers for human sarcomas. Y1 may inhibit growth of specific sarcomas, as previously shown in an in vivo mouse model of human ESFT. The high Y1 expression on tumor cells of ESFT and synovial sarcomas and on blood vessels in many other sarcomas represents an attractive basis for an in vivo tumor targeting.     

~(18)F-FDG PET和~(18)F-FDG PET/CT在肉瘤临床评估中的应用价值

正电子发射断层显像术(positron-emission tomography, PET)作为一种功能显像方法,在肿瘤诊断、分级、分期及疗效评估中的应用日益广泛.将~(18)F-氟脱氧葡萄糖(~(18)F-fluorodeoxyglucose, ~(18)F-FDG)PET检查获得的代谢信息与其他病理学分级方法相结合,有助于进一步明确肉瘤的病理学分级及预测预后.~(18)F-FDG PET在寻找肉瘤患者的骨转移灶和肺转移灶方面要优于其他影像学方法,因此可用于临床分期及再分期.肿瘤-本底比值(tumor-to-background ratio, TBR)和标准摄取值(standardized uptake value, SUV)作为~(18)F-FDG PET定量分析中的2个重要参数,均有助于评价肿瘤的化疗反应.~(18)F-FDG PET提供的重要信息有助于临床治疗效价比达最大化.本文就~(18)F-FDG PET和~(18)F-FDG PET/CT在肉瘤中的临床应用价值进行综述.