Clear cell sarcoma of tendons and aponeuroses: a study of 75 patients

BACKGROUND: Clear cell sarcoma (CCS) of tendons and aponeuroses (malignant melanoma of soft parts) is a rare melanocytic soft tissue sarcoma. The objective of this study was to determine the clinical features, prognostic factors, and optimal treatment policy for patients with this rare disease. METHODS: Seventy-five consecutive patients with histologically confirmed CCS who received treatment between 1980 and 2004 were analyzed retrospectively. RESULTS: There were 41 men and 34 women, and the median age was 36 years. Sixty-five tumors were located in the extremities, and 10 tumors were located in the trunk. The median tumor size was 4 cm. Seventy-one patients underwent surgical excision, and 56 patients received chemotherapy. Sixteen patients developed local recurrences, and 52 patients developed metastasis. The overall patient survival rates was 47% at 5 years and 36% at 10 years. Univariate analysis showed that sex (P = .018), tumor size (P = .001), tumor depth (P = .002), TNM classification (P = .001), and surgical margin (P = .042) were significant prognostic factors. Among the 52 patients who presented with localized disease, sex (P = .023), tumor size (P = .002), tumor depth (P = .011), TNM classification (P = .004), and chemotherapy (P = .032) were identified as significant prognostic factors. Multivariate analysis showed that tumor size remained an independent prognostic factor in both groups. CONCLUSIONS: The current results supported the contention that early diagnosis and initial wide excision are essential for a favorable outcome of CCS. The role of chemotherapy for CCS should be investigated further.     

Clear cell sarcoma (melanoma of soft parts): The Royal Marsden Hospital experience

Introduction

Clear cell sarcoma (CCS) is a rare tumour with a propensity for local recurrence and nodal metastasis. About 300 cases have been reported, thus further clarification regarding the course and outcome of the disease is required.

Methods

Patients with a histopathologic diagnosis of CCS were identified from prospective histopathology and sarcoma databases and supplemented with a retrospective analysis of the patients' hospital records.

Results

Between 1990 and 2005, a total of 72 patients with a diagnosis of CCS were identified, 35 having been referred for management and 37 having been referred for histopathologic opinion. The median age was 39 years (range 5–90 years). Of the 35 patients referred to the Royal Marsden Hospital for management, 23% developed local recurrence or in-transit metastases at a median of 9 months (2–79 months) after resection of the primary, and nodal or distant metastatic disease was seen in 63% after 14 months (range 0–177 months). Five- and 10-year survival were 52% and 25%, respectively.

Conclusions

CCS has a number of similarities with melanoma, particularly in its peripheral distribution and propensity for nodal disease. Wide excision with clear margins offers the best chance of cure. Local recurrence and regional metastases are common, and are almost always followed by distant metastases and death.     

Metastatic soft tissue sarcoma: current treatment landscape and future perspectives

Introduction: The therapeutic armamentarium for advanced soft tissue sarcoma (STS) has increased over the last few years. Doxorubicin monotherapy or in combination is now the established first line treatment. Beyond first line treatment, no standard therapy has been established. Novel drugs have reached the late-clinical stage development demonstrating to be effective in controlled studies. While these novel treatments can be beneficial to a subset of patients, even producing long lasting remissions, a significant fraction of the STS population derives limited benefit. This is due to the fact that STS is a very heterogeneous disease with different histopathologic features, biological characteristics and clinical behaviour.

Areas covered: The primary aim of this review is to summarize data from recent phase III clinical trials in unselected STS population, and to discuss their impact on the current clinical practice. Phase I-II trials of special interest are discussed as well.

Expert commentary: Although our efforts in this research task are ongoing, the integration of biological therapies, the anti-angiogenesis targeted treatments as well as immunotherapy that may further improve the long term control of advanced STS are of special clinical interest. Clinical management of advanced STS should be tailored to each patient in order to optimize therapy.     

Clear cell sarcoma of soft tissue: A retrospective review and analysis of 31 cases treated at Istituto Ortopedico Rizzoli

Introduction

Clear cell sarcoma (CCS) of soft tissue is a rare melanocytic soft tissue sarcoma with different cytogenetic and natural history than that of melanoma. Objective of this study was to determine outcome predictors in patients treated in our Institute. This objective included the effectiveness of surgical intervention and disease progression after surgery.

Materials and methods

Thirty-one patients were diagnosed at our institute with clear cell sarcoma through tissue pathology and immunohistochemistry. Patients received multimodality treatment (surgery, radiotherapy and chemotherapy). Five-year survival rates and prognostic predictors were determined.

Results

Sixteen patients were males and 15 females with a median age of 37 years (8–72-years). Twenty-eight tumors were located in extremities and 3 in the trunk area. Eight patients had metastases at their first presentation (6 local lymph nodes and 2 pulmonary metastases). Five and ten-year disease-specific survival rates were 56% and 41%. Two-year disease-specific survival rates for lymph node and pulmonary metastasis groups were 40% and 0%. All metastatic patients died within 5 years follow-up. Five and ten-year disease-specific survival rates for localized tumor cases were 72% and 53%. Male gender, less than 30-years of age, trunk tumor location and size greater than 5 cm were poor prognostic factors according to univariate analysis. Tumor location in the trunk was the only negative prognostic determinant in multivariate model.

Conclusions

Although surgical treatment may be beneficial for tumors without systemic involvement, new chemotherapeutic agents and molecular targeted therapy should be implemented to improve the oncologic outcome in both early and late stage disease.     

透明细胞肉瘤的临床治疗与预后分析

目的 探讨透明细胞肉瘤的临床特点及治疗方法,分析治疗效果及影响因素.方法 对1990年-2009年连续治疗的38例病理证实透明细胞肉瘤的患者进行回顾性分析.结果 全部病例随访时间4-242个月（平均34个月）.发生转移26例,局部复发9例.全部病例的5年复发率23.7%,5年和10年转移率分别为61.0%和68.4%,转移风险累积明显大于局部复发（P=0.004）.转移、局部复发、死亡的中位时间为分别为13个月,19个月和20个月.全部病例的5年、10年生存率分别为47%、36%.单因素分析结果显示性N（P=0.018）,肿瘤大小（P=0.001）,肿瘤深度（P=0.002）,TNM分期性（P=0.001）及手术切缘（P=0.042）可能成为预后因素.而化疗（P=0.18）、放疗（P=0.06）与肿瘤预后无明显相关.在多变量分析中,只有肿瘤大小（P=0.021）成为独立的预后因素.结论 早期诊断和首次广泛切除是改善透明细胞肉瘤预后的关键.肿瘤大小与转移关系密切,是影响预后的重要因素.     

Massive parallel sequencing in sarcoma pathobiology: state of the art and perspectives

Sarcomas are an aggressive and highly heterogeneous group of mesenchymal malignancies with different morphologies and clinical behavior. Current therapeutic strategies remain unsatisfactory. Cytogenetic and molecular characterization of these tumors is resulting in the breakdown of the classical histopathological categories into molecular subgroups that better define sarcoma pathobiology and pave the way to more precise diagnostic criteria and novel therapeutic opportunities.

The purpose of this short review is to summarize the state-of-the-art on the exploitation of massive parallel sequencing technologies, also known as next generation sequencing, in the elucidation of sarcoma pathobiology and to discuss how these applications may impact on diagnosis, prognosis and therapy of these tumors.     

A Case Series of Metastatic Malignant Gastrointestinal Neuroectodermal Tumors and Comprehensive Genomic Profiling Analysis of 20 Cases

Malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare soft tissue sarcoma, therefore often misdiagnosed and has no available standard treatment. Here, we report 3 cases of metastatic GNET with variable clinical courses. Our small case series as well as extensive literature review, further support that GNET is a spectrum of diseases with variable inherent biology and prognosis. Surgical management in the setting of recurrent/metastatic disease may be appropriate for GNET with indolent nature. Response to systemic treatments including chemotherapy and targeted treatments is variable, likely related to heterogenous biology as well. Furthermore, we retrospectively identified 20 additional GNET cases from Foundation Medicine’s genomic database and expanded on their clinicopathological and genomic features. Comprehensive genomic profiling (CGP) with DNA and RNA sequencing of this cohort, in the course of clinical care, demonstrated recurrent EWSR1 chromosomal rearrangements and a sparsity of additional recurrent or driver genomic alterations. All cases had low tumor mutational burden (TMB) and were microsatellite stable.     

Small cell lung cancer: state of the art and future perspectives

Small cell lung cancer accounts for less than 20% of all lung cancer. The management of this distinct tumor entity differs from the more common non-small cell lung cancer. Primary prevention of smoking exposure remains the most important public health measure. Although small cell lung is an exquisitely chemosensitive disease it remains ultimately fatal for the great majority of patients. Combination chemotherapy regimens have improved response rate and survival of the last three decades. The combination of cisplatin and etoposide has been considered the standard therapy for over a decade. More intensive triplet combination chemotherapy and high-dose chemotherapy have shown improved response rates and survival. Early concomitant and accelerated radiotherapy improves survival in limited stage disease. This review summarizes the current state of the art and future perspectives in detection, staging and standard therapy of small cell lung cancer. Particular emphasis is given to the importance of concomitant and accelerated radiotherapy and consideration of dose-intensive combination chemotherapy regimens.     

State-of-the-art management of nasopharyngeal carcinoma: current and future directions

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer. Approximately 70% of patients with newly diagnosed NPC present with locally advanced disease. Phase III clinical trials support the addition of chemotherapy to radiotherapy for the initial treatment of these patients. Once metastatic disease develops, practices become varied. Further experience needs to be gained with both targeted therapies and immunotherapy to gauge whether they will improve treatment outcomes in NPC.     

CIAPIN1 inhibits the growth and proliferation of clear cell renal cell carcinoma

Our previous studies indicated a direct correlation with loss of CIAPIN1 and carcinogenesis of tumor in human gastric cancer. Here we presented that the expression of CIAPIN1 was absent or significantly decreased in 102 cases of clear cell renal cell carcinoma (CCRCC) tissues (P < 0.05). Up-regulating CIAPIN1 by adenoviral vectors exhibited significant inhibition of CCRCC-derived cell growth in vitro and in vivo with G1 cell cycle arrest. Simultaneously, CIAPIN1-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4, p-Rb and VEGF, but up-regulation of p27^Kip1 and Rb.     

儿童肾透明细胞肉瘤临床病理分析及文献复习

目的：探讨儿童肾透明细胞肉瘤（ clear cell sarcoma of the kidney,CCSK）的临床病理特点与鉴别诊断。方法：观察1例儿童肾透明细胞肉瘤的病理学形态、特殊染色及免疫表型特征并复习有关文献。结果：片内显示为小细胞肿瘤,呈弥漫性分布,部分细胞丰富,密集,部分区域细胞排列较松散,以分枝状纤维血管间质分隔肿瘤细胞呈不规则索状和小团状为结构特征,细胞呈圆形、多角形或梭形,细胞核呈圆形、卵圆形或棒状,核染色质呈细颗粒状,核膜较薄,核仁不明显。网状纤维染色：网状纤维密布于单个或小团肿瘤细胞之间。Masson三色：肿瘤间质小血管周纤维组织呈绿色。免疫组化染色：Vim、Bcl2和CD99（＋）,其他（-）。结论：CCSK是少见的小儿恶性肾肿瘤,诊断主要依赖于病理学,熟悉CCSK典型形态学特征以及合理应用特殊染色和免疫组化有助于同肾母细胞瘤、PNET和先天性中胚叶肾瘤等鉴别。     

Clinical insights into small cell lung cancer: Tumor heterogeneity,diagnosis, therapy,and future directions

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.     

EWS-ATF1融合基因在透明细胞肉瘤中的表达及其诊断意义

目的: 探讨在透明细胞肉瘤(CCS)石蜡包埋组织中检测EWS-ATF1融合基因的可行性及EWS-ATF1融合基因表达在透明细胞肉瘤诊断中的意义。 方法: 收集1992年～2006年期间确诊的26例CCS石蜡包埋组织标本,20例非CCS石蜡包埋组织标本为对照组,β-肌动蛋白和β₂微球蛋白作为内参照,用逆转录聚合酶链反应(RT-PCR)和巢式PCR检测EWS-ATF1融合基因的表达;过氧化物酶染色(SP)方法对26例CCS石蜡组织标本进行免疫组化染色,检测S-100、HMB-45蛋白的表达。 结果: 26例标本中,有22例β-肌动蛋白阳性;24例β₂微球蛋白阳性,其中20例EWS-ATF1融合基因阳性(16例EWS-ATF1Ⅰ型,4为EWS-ATF1Ⅲ型),余4例EWS-ATF1融合基因阴性。对照组均未检测到EWS-ATF1融合基因的表达。26例CCS石蜡组织标本中S-100及HMB-45的总阳性率分别为79.2%和70.8%。 结论: 在CCS石蜡包埋组织中运用RT-PCR检测EWS-ATF1融合基因是可行的,可作为辅助诊断和鉴别诊断的有力工具。     

Sarcomas of the head and neck in adult patients: current concepts and future perspectives

Sarcomas comprise a heterogeneous and biologically diverse group of malignant neoplasms having as a common denominator their origin from mesenchymal cells. Head and neck sarcomas account for 4 to less than 20% of total body sarcomas depending on the criteria, such as age of patients (pediatric vs adult population), type of sarcomas (soft-tissue vs bony sarcomas) and site of location. Although head and neck sarcomas occur infrequently in adults, in the pediatric population one in three sarcomas will occur in the head and neck region. Most head and neck sarcomas are of the soft-tissue type, with only 20% being of bony or cartilaginous origin. Sarcomas display a diverse array of histologies and a wide spectrum of clinical behavior, ranging from relatively slow growing lesions to aggressive locally and regionally destructive tumors with the potential for systemic metastases. Osteosarcomas, rhabdomyosarcomas, pleomorphic sarcomas (malignant fibrous histiocytomas), fibrosarcomas and angiosarcomas are among the most common histologic types of sarcoma found in the head and neck. Surgery has been the primary therapeutic approach for the management of head and neck sarcomas. Survival rates for head and neck sarcomas suggest worse outcomes than for their extremity counterparts. Lymph node metastasis only occurs in 3–10% of sarcomas of the head and neck. An improvement in local disease control has recently been suggested with the combined use of surgery and radiotherapy. Conflicting results have been reported on the benefit from the use of chemotherapy as an adjuvant or neoadjuvant regimen, especially for high-grade sarcomas in long-term survival or local disease control. Encouraging results have recently been reported with the use of molecular targeted therapies with tyrosine kinase inhibitors and antiangiogenetic agents.     

Establishment and characterisation of a human clear cell sarcoma model in nude mice

We have established a new experimental model of human clear cell sarcoma, UM-CCS1, using serial subcutaneous transplantation of intact tumour tissue in nude mice. The heterotransplanted nude mouse tumours retained characteristic morphological features of the primary clear cell sarcoma. Immunohistochemical analysis showed the retained expression patterns of S-100 protein, melanoma-associated antigen HMB-45 and vimentin in the xenografts as compared to the primary tumour. DNA index showed low variations both between the xenografts in the same passage and between the serial passages. Cytogenetic analysis of the primary tumour and the xenografts showed the unbalanced translocation der(6)t(6;12)(p23;q13). Based on the combined genetic data a reasonable interpretation of our findings is that there was a complex chromosomal rearrangement resulting in a cytogenetically cryptic EWS-ATF1 fusion gene. Analysis of cell kinetics using in vivo incorporation of iododeoxyuridine and flow cytometry showed generally short potential doubling time (T(pot)) of the xenografts. Volume doubling time showed low variations without correlation with T(pot). The retained phenotypic and genotypic characteristics of the primary tumour and the morphological and structural stability over time makes the model suitable for studies on the tumour biology and treatment of clear cell sarcoma.     

Current status and future perspectives of immune checkpoint inhibitors in extensive-stage small cell lung cancer

Small-cell lung cancer (SCLC) is a type of neuroendocrine neoplasms with high aggressiveness and poor prognosis. Chemotherapy has been the standard first-line therapy for SCLC over the past several decades. In recent years, results of randomized phase III CASPIAN and IMpower-133 trials indicated that the combination of immune checkpoint inhibitors (ICIs) with platinum-etoposide chemotherapy improved the overall survival (OS) of patients with extensive stage small-cell lung cancer (ES-SCLC), which has transformed the treatment model for ES-SCLC. ICIs combined with chemotherapy has become the new first-line standard treatment of ES-SCLC with the latest research results from CASPIAN and ASTRUM-005 studies. This review summarizes the recent progress of ICIs in the treatment of ES-SCLC and expounds the mode and efficacy of immunotherapy for ES-SCLC. Future research focused on exploring basic SCLC biology and identifying novel predictive biomarkers in response to ICIs in ES-SCLC is essential. Double-ICIs treatment strategies, bispecific antibodies, and ICIs combined with other therapies, such as chemotherapy, radiotherapy, and targeted therapy, represent a new modality and show great promise for the treatment of ES-SCLC, which should achieve greater therapeutic effects through multiple synergistic mechanisms.