Article

Management of Abdominal Ewing’s Sarcoma: A Single Institute Experience

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Abstract

Ewing’s sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are a rare group of tumors commonly arising from bones, uncommonly from soft tissues, and rarely from abdomen. The aim of the study was to analyze the outcome (recurrence-free survival[RFS]), patient characteristics, role of FDG-PET (fluorodeoxyglucose positron emission tomography) computerized scan, chemotherapy and radiation, and prognostic factors. We retrospectively studied patients diagnosed with abdominal ES/PNET and treated surgically between June 2005 and November 2019. Ten patients were included in the study, with a median age of 36.5 years (19–46 years). The median follow-up was 25 months (3–178 months). The site of origin was the retroperitoneum, small bowel, and abdominal wall in six, two, and two patients, respectively. 70% of patients were treated with induction chemotherapy. R0 resection was achieved in 90% of patients. With chemotherapy, there was significant reduction in tumor size (p = 0.034) with non-significant reduction in SUV max (p = 0.31). The 1- and 2-year RFS were 88.90% and 76.20%, respectively. Pathological peritoneal metastasis and ability to achieve R0 resection were prognostic factors affecting RFS. These patients must be offered multimodality treatment. Induction chemotherapy significantly reduces the tumor size. Pathological peritoneal metastasis and ability to achieving R0 resection significantly affect survival.

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... Retroperitoneal EES comprises ≈20-30% of those cases [98,99]. Due to its rarity, only case reports and small case series exist for retroperitoneal EES [100][101][102][103][104][105][106][107]. Management of retroperitoneal EES is inferred from studies on all Ewing sarcomas or EESs that included non-retroperitoneal sites. ...
... For instance, Lynch et al. investigated 978 EES and 1682 IES patients, observing that combination therapy with chemotherapy and local therapy (radiation or surgery) was strongly associated with survival for EES (HR 0.42, 95% CI [0.31, 0.55] p < 0.001), while surgery alone, radiation alone, or chemotherapy alone were not [109]. Additionally, other smaller case series, have confirmed the importance of multimodal therapy for EES, with a focus on chemotherapy followed by surgery ± radiation [91,93,107,121]. ESFTs are known to be radiosensitive, but the role of radiation has decreased in the past two decades, likely due to improvements in chemotherapeutic regimens [99]. ...
... For instance, Lynch et al. investigated 978 EES and 1682 IES patients observing that combination therapy with chemotherapy and local therapy (radiation or surgery) was strongly associated with survival for EES (HR 0.42, 95%CI [0.31, 0.55] p < 0.001), while surgery alone, radiation alone, or chemotherapy alone were not [109]. Additionally, other smaller case series, have confirmed the importance of multimodal therapy for EES, with a focus on chemotherapy followed by surgery ± radiation [91,93,107,121] ESFTs are known to be radiosensitive, but the role of radiation has decreased in the past two decades, likely due to improvements in chemotherapeutic regimens [99]. In our centre, neo-or adjuvant radiation for retroperitoneal EES still plays an important role to help sterilize surgical margins, or to facilitate sparing critical structures that are abutting, but not invaded by tumour (e.g., the femoral nerve). ...
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With the exception of well-differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma, solitary fibrous tumour, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma, the majority of the ≈70 histologic subtypes of retroperitoneal sarcoma are defined as ‘ultra-rare’ sarcomas, with an incidence of ≤1–5/1,000,000 persons/year. For most of these ultra-rare RPS subtypes, diagnosis and treatment follows international guidelines for the management of more common RPS histologies, with en bloc surgical resection as the mainstay of curative treatment, and enrolment in clinical trials where possible. Because the treatment of RPS is heavily driven by histology, the surgeon must be familiar with specific issues related to the diagnosis and management of ultra-rare sarcoma subtypes. Expert radiological and surgeon reviews are required to differentiate similarly presenting tumours where surgery can be avoided (e.g., angiomyolipoma), or where upfront systemic therapy is indicated (e.g., extraosseous Ewing’s sarcoma). Thus, the management of all retroperitoneal sarcomas should occur at a sarcoma referral centre, with a multidisciplinary team of experts dedicated to the surgical and medical management of these rare tumours. In this focused review, we highlight how diagnosis and management of the ultra-rare primary RPS histologies of malignant perivascular epithelioid cell tumour (PEComa), extraosseous Ewing sarcoma (EES), extraosseous osteosarcoma (EOS), and rhabdomyosarcoma (RMS) critically diverge from the management of more common RPS subtypes.
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Background: To investigate the value of positron emission tomography (PET) and PET/computed tomography (CT) using fluorine-18-fluorodeoxyglucose (F-FDG) in the diagnosis, staging, restaging and recurrence monitoring of Ewing sarcoma family of tumors (ESFTs), a meta-analysis was performed through systematically searching PubMed, Embase, and Cochrane Central library to retrieve articles. Methods: After screening and diluting out the articles that met inclusion criteria to be used for statistical analysis the pooled evaluation indexes including sensitivity, specificity, and diagnostic odd ratio (DOR) as well as the summary receiver operating characteristic curve (SROC) were calculated involving diagnostic data (true positive, false positive, false negative, and true negative) extracted from original studies. Results: Screening determined that out of 2007, 23 studies involving a total of 524 patients were deemed viable for inclusion in the meta-analysis. The results of the analysis showed that the sensitivity and specificity were at 86% and 80%, respectively. Additionally, a satisfactory accuracy of F-FDG PET and PET/CT was observed in detecting ESFT recurrence, lung metastasis, and osseous metastasis. Conclusion: This meta-analysis suggests that F-FDG PET and PET/CT with an extremely high accuracy could be considered a valuable method for detecting distant metastasis and post-operational recurrence of ESFT, which might have a profound impact on the development of treatment protocols for ESFT.
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Objective: The existing literature of 18 F-FDG PET/CT in Ewing sarcoma investigates mixed populations of patients with both soft tissue and bone primary tumors. The aim of our study was to evaluate whether the maximum standardized uptake value (SUVmax) obtained with 18F-FDG PET/CT before and after induction chemotherapy can be used as an indicator of survival in patients with Ewing sarcoma originating exclusively in the skeleton. Materials and Methods: A retrospective database search from 2004-2011 identified 28 patients who underwent 18 F-FDG PET/CT before (SUV1, n= 28) and after (SUV2, n=23) induction chemotherapy. Mean follow up was 3.3 years and median follow up for survivors was 6.3 years (range: 2.6-9.8 years). Multivariate and univariate Cox proportional hazard model was used to assess for correlation of SUV1, SUV2, and the change in SUVmax with overall survival (OS) and progression-free survival (PFS). Results: Mean SUVmax was 10.74 before (SUV1) and after 4.11 (SUV2) induction chemotherapy. High SUV1 (HR = 1.05, 95% CI: 1.0-1.1, P = 0.01) and SUV2 (HR =1.2, 95% CI: 1.0-1.4, P = 0.01) were associated with worse OS. A cut off point of 11.6 was identified for SUV1. SUV1 higher than 11.6 had significantly worse OS (HR = 5.71, 95% CI: 1.85 - 17.61, P = 0.003) and PFS (HR = 3.16, 95% CI: 1.13 - 8.79, P = 0.03, P < 0.05 is significant). Conclusion: 18F-FDG PET/CT can be used as a prognostic indicator for survival in primary Ewing sarcoma of bone.
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The molecular genetic changes that have been described in sarcomas over the past era have aided our understanding of their pathogenesis. The majority of sarcomas carry nonspecific genetic changes within a background of a complex karyotype. These constitute the challenges in sarcoma research for unraveling a putative multistep genetic model, such as for chondrosarcoma, and finding targets for therapeutic strategies. Approximately 15-20% of mesenchymal tumors carry a specific translocation within a relatively simple karyotype. The resulting fusion products act either as transcription factors upregulating genes responsible for tumor growth, as for instance in Ewing sarcoma, or translocate a highly active promoter in front of an oncogene driving tumor formation, as for instance in aneurysmal bone cyst. In addition, a small subset of mesenchymal tumors have specific somatic mutations driving oncogenesis. The specific genetic changes unraveled so far had great impact on the classification of bone and soft tissue tumors. In addition, these changes can assist the pathologist in the differential diagnosis of some of these entities, especially within the groups of small blue round cell tumors and spindle cell tumors, if performed in specialized centers. While a putative association between certain fusion products and outcome is still under debate, the role of predicting response of targeted therapy has been well established for KIT and PDGFRA mutations in gastrointestinal stromal tumors.
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Ewing sarcoma is most commonly a bone tumour which has usually extended into the soft tissues at the time of diagnosis. Exceptionally, this tumour can have an extraskeletal origin. Clinical or imaging findings are non-specific and diagnosis is based on histology. We report a case of an extraskeletal Ewing sarcoma developed in the soft tissues of the abdominal wall in a 35-year-old woman who presented a painful abdominal wall tumefaction. Ultrasongraphy and computed tomography showed a large, well-defined soft tissue mass developed in the left anterolateral muscle group of the abdominal wall. Surgical biopsy was performed and an extraskeletal Ewing sarcoma was identified histologically.
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Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
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"Undifferentiated tumor" refers to a heterogeneous group of neoplasms with little or no evidence of differentiation on routine light microscopic morphology. To identify the true identity of undifferentiated tumors by immunohistochemical analysis. Review of the pertinent literature and the authors' experience. For treatment and prognostic evaluation, it is crucial to delineate whether an undifferentiated neoplasm is epithelial, mesenchymal, melanocytic, or hematopoietic in nature. Application of a screening panel to demonstrate the expression of markers of major lineages is fundamental for determination of the broad category of neoplasia. Because poorly differentiated carcinomas and in particular sarcomatoid carcinomas are known to be heterogeneous in their antigen expression, several epithelial markers in combination may be required to establish the carcinomatous nature of tumor. A diagnostic misinterpretation as a consequence of occasional aberrant or unexpected antigen expression is best avoided by using a broad panel that includes both antibodies that are anticipated to be positive and those that are expected to be negative. In this treatise, the immunohistochemical dissection of undifferentiated tumors on the basis of their morphologic features is outlined, supplemented with algorithmic immunohistochemical analysis for each morphologic category of small round cell tumors, carcinomatous tumors, sarcomatous (or sarcoma-like) tumors, and tumors with histologically overlapping features, including hematolymphoid malignancies, melanoma, and sarcomas with epithelioid appearance. The utility of several organ- or tissue-specific markers in the context of undifferentiated tumors is reviewed.
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Context.—“Undifferentiated tumor” refers to a heterogeneous group of neoplasms with little or no evidence of differentiation on routine light microscopic morphology. Objective.—To identify the true identity of undifferentiated tumors by immunohistochemical analysis. Data Sources.—Review of the pertinent literature and the authors' experience. Conclusions.—For treatment and prognostic evaluation, it is crucial to delineate whether an undifferentiated neoplasm is epithelial, mesenchymal, melanocytic, or hematopoietic in nature. Application of a screening panel to demonstrate the expression of markers of major lineages is fundamental for determination of the broad category of neoplasia. Because poorly differentiated carcinomas and in particular sarcomatoid carcinomas are known to be heterogeneous in their antigen expression, several epithelial markers in combination may be required to establish the carcinomatous nature of tumor. A diagnostic misinterpretation as a consequence of occasional aberrant or unexpected antigen expression is best avoided by using a broad panel that includes both antibodies that are anticipated to be positive and those that are expected to be negative. In this treatise, the immunohistochemical dissection of undifferentiated tumors on the basis of their morphologic features is outlined, supplemented with algorithmic immunohistochemical analysis for each morphologic category of small round cell tumors, carcinomatous tumors, sarcomatous (or sarcoma-like) tumors, and tumors with histologically overlapping features, including hematolymphoid malignancies, melanoma, and sarcomas with epithelioid appearance. The utility of several organ- or tissue-specific markers in the context of undifferentiated tumors is reviewed.
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Background The current multidisciplinary approach in the treatment of Ewing sarcoma has improved cure rates, with contemporary dose‐dense chemotherapy attaining 5‐year event‐free survival (EFS) of 73% in localized cases. Dose‐intense and dose‐dense chemotherapy is difficult in the majority of resource‐limited settings with limited access to optimal supportive care. We report on patients with Ewing sarcoma treated on EFT‐2001, a nondose‐dense chemotherapy protocol. Procedure A retrospective analysis was conducted of patients (<15 years) with Ewing sarcoma treated with curative intent during January 2013‐June 2017 with an institutional ethics committee‐approved nondose‐dense protocol (EFT‐2001). Local therapy was planned after 9‐12 weeks of chemotherapy with metastatic sites addressed with radiotherapy. The study assessed outcomes and prognostic factors. Results We analysed 200 patients with M:F ratio of 1.27:1 and metastases in 41 patients (20.5%). At a median follow up of 41.5 months (range 4.5‐81.8 months), respective 3‐year EFS and overall survival (OS) of the whole cohort is 65.3% (95% confidence interval [CI]: 58.1‐71.7%) and 79.3% (95% CI: 72.8‐84.5%); for localized and metastatic cohort, 70.9% (95% CI: 62.9‐77.5%) and 82.8% (95% CI: 75.7‐89.0%); and for metastatic cohort, 42.8% (95% CI: 28.0‐58.6%) and 65.3% (95% CI: 47.7‐78.3%). Presence of residual disease (morphologic/metabolic) on positron emission tomography‐computed tomography scan done 3 months post definitive radiotherapy (hazard ratio [HR] 7.92 [95% CI: 3.46‐18.14]) and delay in any form of local control >4 months (HR 3.42 [95% CI: 1.32‐8.89]) affected outcomes. Nonrelapse mortality during treatment was 6.5%, mainly due to cardiomyopathy (3.0%) and bacterial sepsis (1.5%). Cardiotoxicity was seen in 11.5% of patients. Conclusions Nondose‐dense chemotherapy provides good outcomes with manageable toxicities in a multidisciplinary treatment approach, while reducing cumulative drug exposures in the developing world where dose‐intense or dose‐dense chemotherapy could potentially increase toxicity, and hence seems a feasible approach in resource‐limited settings. Presence of any residual disease post definitive radiotherapy or delay in local control portends poor outcome.
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Round cell tumors of bone are a divergent group of neoplasms that largely constitute Ewing sarcoma/primitive neuroectodermal tumor, small cell osteosarcoma, Langerhans cell histiocytosis, mensenchymal chondrosarcoma, and hematopoietic malignancies including lymphoma and plasmacytoma/myeloma, along with metastatic round cell tumors including neuroblastoma, rhabdomyosarcoma, and small cell carcinoma. These lesions share many histomorphologic similarities and often demonstrate overlapping clinical and radiologic characteristics, but typically have a diverse clinical outcome, thus warranting differing therapeutic modalities/regimens. Recent advances in molecular and cytogenetic techniques have identified a number of additional novel entities, including round cell sarcomas harboring CIC-DUX4 and BCOR-CCNB3 fusions, respectively. These novel findings have not only enhanced our understanding of the pathogenesis of round cell tumors, but also allowed us to reclassify some entities with potential therapeutic and prognostic significance. This article provides an overview focusing on recent molecular genetic advances in primary, nonhematologic round cell tumors of bone.
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The Ewing family of tumors (Ewing's sarcoma and primitive neuroectodermal tumor [PNET]) is the second most common malignant bone tumor (after osteogenic sarcoma) in children and adolescents. These tumors can also occur in soft tissue, presenting in a manner similar to rhabdomyosarcoma. Nearly half of all patients with Ewing's family tumors are between 10 and 20 years of age, and 70% are under the age of 20, with a slight male predominance. The annual incidence in the United States is 2.1 cases per million children. 81 A similar incidence of these tumors occurs throughout the world in countries composed mostly of whites or persons of Hispanic origin; however, these tumors are extremely rare in black children and children of Asian origin. 15,36 The reason for this striking difference in incidence according to racial background is unknown. Ewing's tumor was originally described in 1921 by James Ewing as an endothelioma. 14 Over the past decade it has become clear that Ewing's sarcoma, in fact, derives from a primitive neuroectodermal cell with variable differentiation. Classical Ewing's sarcoma is a poorly differentiated small round blue cell tumor, whereas, on the other end of the scale, PNET shows quite discernible differentiation. Both share the same histochemical staining profile and a unique characteristic translocation t(11;22) or a variation of the same within the tumor cell. Virtually all Ewing's tumors contain the chromosomal marker.
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The Ewing's family of tumors (EFT) comprises a molecularly defined group of "small round blue cell tumors", consisting of Ewing's sarcoma of bone (ESB), extraosseous Ewing's sarcoma (EES), peripheral primitive neuroectodermal tumor (pPNET), and Askin's tumor. Characteristic translocations that disrupt the EWSR1 gene located at 22q12 create novel fusion genes that are central to the pathogenesis. The EFT also shares certain clinical characteristics, such as a peak incidence during the teenage years, a tendency to spread rapidly, and responsiveness to the same chemotherapeutic regimens and radiation therapy. Nearly all patients have occult disseminated disease at diagnosis; hence, chemotherapy is routinely used. Improvements in multimodality treatment have had a dramatic impact on outcomes. EES/pPNET has been reported in a variety of sites, including the pancreas, though this is extremely rare. We describe a case of pancreatic EES/pPNET in a 35-year-old woman and provide a brief review of the relevant literature.
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To evaluate the outcome of children with an extraosseous Ewing tumor (EOE) according to treatment. Children with EOE were treated either with the strategy used for malignant mesenchymal tumors (MMTs) by the International Society of Pediatric Oncology (SIOP) or with the French Society of Pediatric Oncology (SFOP) regimen used for osseous Ewing tumors (OET). The MMT strategy included vincristine/actinomycin for small and resected tumors or ifosfamide/vincristine/actinomycin for unfavorable sites or unresectable tumors. Surgical excision was to be attempted after four courses, followed by local irradiation in case of residue. Osseous Ewing (OE) protocol included three courses of cyclophosphamide/doxorubicin followed either by two similar courses in case of good response or two courses of ifosfamide/etoposide in case of no response. After resection of the primary, treatment included conventional chemotherapy in case of good histologic response and high-dose chemotherapy and radiotherapy for poor response. All diagnosis specimens were reviewed by the panel. Between 1989 and 1999, 63 patients were registered. Characteristics of patients treated by both protocols were similar. Five-year overall survival (OS) and event-free survival (EFS) of those treated with the OE protocol are 83% and 75%, respectively, which is significantly better than the OS and EFS of those treated with the MMT strategy (59% and 44%, respectively; P = .04 and .008, respectively). The size of the primary and the type of protocol influenced patients' EFS. In multivariate analysis, only the regimen had an impact on OS and EFS. Our study shows that patients with EOE should be treated with OE regimens, probably because of the use of anthracyclines.
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The aim of this study was to identify whether there was any difference in patient, tumour, treatment or outcome characteristics between patients with skeletal or extra-skeletal Ewing’s sarcoma. We identified 300 patients with new primary Ewing’s sarcoma diagnosed between 1980 and 2005 from the centres’ local database. There were 253 (84%) with skeletal and 47 (16%) with extra-skeletal Ewing’s sarcomas. Although patients with skeletal Ewing’s were younger (mean age 16.8 years) than those with extra-skeletal Ewing’s sarcoma (mean age 27.5 years), there was little difference between the groups in terms of tumour stage or treatment. Nearly all the patients were treated with chemotherapy and most had surgery. There was no difference in the overall survival of patients with skeletal (64%) and extra-skeletal Ewing’s sarcoma (61%) (p = 0.85), and this was also the case when both groups were split by whether they had metastases or not. This large series has shown that the oncological outcomes of Ewing’s sarcoma are related to tumour characteristics and patient age, and not determined by whether they arise in bone or soft tissue.
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Ewing sarcoma-primitive neuroectodermal tumors (ES/PNET) constitute a family of neoplasms characterized by a continuum of neuroectodermal differentiation. ES/PNET of the uterus is rare. There are 43 cases published in the English literature as far as we know. We describe an additional case. A 56-year-old woman presented with a 2-month history of irregular menopausal vaginal bleeding. After surgical excision, microscopic, immunohistochemical and electron microscopic examination suggested the diagnosis of ES/PNET. The patient underwent combined chemotherapy consisting of ifosfamide, etoposide, and cisplatin. She was alive with no evidence of recurrence or metastasis after 41 months of the initial operation. In spite of the rarity of ES/PNET, we should consider it in the differential diagnosis of small cell neoplasms of the uterus.
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This report describes a unique clinicopathologic entity characterized as a malignant small cell tumor of the thoracopulmonary region in 20 children and adolescents (average age 14.5 years). There was a female predilection (75%) for this tumor which appeared to originate in the soft tissues of the chest wall or the peripheral lung. The neoplasm tended to recur locally and did not seem to disseminate as widely as some of the other small cell tumors of childhood (rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma and malignant lymphoma). However, the median survival was only 8 months. Electron microscopy of 3 cases suggested a neuroepithelial derivation, but, at the present, the histogeneis remains a subject for further investigation.
Article
This article reviews the pathologic features and the behavior of 39 small, round, or oval cell sarcomas occurring in the soft tissues and considered histologically indistinguishable from Ewing's sarcoma of bone. The tumors affected chiefly young adults (median age 20 years) and most commonly involved the soft tissues of the lower extremity and the paravertebral region. Microscopically, they consisted of solidly packed small, round, or ovoid cells of great uniformity, arranged in sheets or lobules separated by strands of fibrous connective tissue. The nucleus of the tumor cells contained finely divided chromatin, a distinct nuclear membrane, and frequently a minute nucleolus. The scanty ill-defined cytoplasm contained varying amounts of glycogen. Sometimes the histologic picture was dominated by a "peritheliomatous" pattern, or by large areas of necrosis or hemorrhage. Followup data ranging from 1 month to 14 years were available in 35 of the 39 cases (93%). Of these, 13 were alive and 22 had died. In the majority of the fatal cases, the clinical course was rapid; metastatic lesions developed within a few months after the primary tumor was excised. The lungs and the skeleton were the two most common sites of metastasis. Cure may be achieved by wide local excision of the tumor at an early stage of the disease, combined with radiation therapy and chemotherapy.
Article
Two hundred fourteen eligible patients with previously untreated, localized Ewing's sarcoma of bone were randomized on IESS-II to receive Adriamycin (ADR; doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, vincristine, and dactinomycin by either a high-dose intermittent method (treatment [trt] 1) or a moderate-dose continuous method (trt 2) similar to the four-drug arm of IESS-I. Patient characteristics (sex, primary site, type of surgery) were stratified at the time of registration; these and other patient characteristics (age, time from symptoms to diagnosis, race) were distributed similarly between treatments. Surgical resection was encouraged, but not mandatory. Local radiation therapy was the same as for IESS-I. The median follow-up time is 5.6 years. The overall outcome was significantly better on trt 1 than on trt 2. At 5 years, the estimated percentages of patients who were disease-free, relapse-free, and surviving were 68%, 73%, and 77% for trt 1 and 48%, 56%, and 63% for trt 2 (P = .02, .03, and .05, respectively). The major reason for treatment failure for both treatment groups was the development of metastatic disease. The lung was the most common site of metastases followed by bone sites. The combined incidence of severe or worse toxicity (67%) was comparable between the treatments; however, severe or worse cardiovascular toxicity was significantly greater on trt 1. Tne only treatment-associated deaths (N = 3) were on trt 1 and were cardiac-related.
Article
A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).
Article
Peripheral neuroepithelioma of soft tissue belongs to the group of peripheral neuroectodermal tumors (PNETs), but because of its clinical, biological, and morphological characteristics, it differs from other small, round-cell sarcomas that appear in children (neuroblastoma) or in the thoracopulmonary region (Askin's tumor) and bone (peripheral neuroectodermal sarcoma of bone). We report ten new cases of such PNET variety, based on their histologic, immunohistochemical, and electron microscopic findings. In all of these cases, the clinicopathologic correlations demonstrated high malignancy, with an ominous outcome in nine cases. The mean age of the patients was 32.6 years and there was a clear male predominance (eight men, two women). Histologically, the presence of Homer-Wright rosettes is mandatory for diagnosis, being complemented with positive immunohistochemistry for several neural immunomarkers using paraffin-embedded material. Neuron-specific enolase, E-36, HNK-1, and chromogranin neural markers proved to be positive in a high number of cases, but other markers (S-100 protein, synapto-physin, GFA protein, and neurofilaments [70 kilodalton]) were absent. Electron microscopy confirmed the presence of neural structures, both by scanning and transmission electron microscopy.
Article
The clinical presentation of the disease and the results of treatment in 42 patients with malignant peripheral neuroectodermal tumors (MPNT) entered into the Cooperative Ewing's, soft tissue, and neuroblastoma trials of the German Society of Pediatric Oncology were retrospectively analyzed. Within the Ewing's sarcoma trial, patients with chest wall lesions were particularly analysed for MPNT features. The period of observation ranged from 15 to 86 months; the median relapse-free time was 24 months. There were 28 male and 14 female patients, the median age of patients was 15 years (range, 9 months-23 years). Thirty-two patients had localized disease (M0), and ten patients presented with primary metastases (M1). The predominant location of the tumors was the thoracopulmonary region, followed by the extremities, the abdominal/pelvic, and head and neck region. Thirty-one of 42 tumors involved the adjacent bone. The disease-free survival according to Kaplan-Meier life-table analysis was 56% +/- 11% for Stage M0 patients at 3 years. Nine of ten patients with M1 disease showed progression of their disease. Most patients had combined modality treatment with surgery, chemotherapy and radiation therapy. Best results were obtained with extensive surgery. Radiation doses ranged from 20 to 60 Gy and could not be correlated with the outcome of the disease. Most recurrences occurred at the site of the primary tumor. In patients with primary chemotherapy after biopsy-proven diagnosis, the responsiveness of this disease to chemotherapy could be demonstrated. Combination chemotherapy containing anthracyclines and high doses of alkylating agents appeared superior.
Article
There has been an explosion of new knowledge regarding the Ewing family of tumors over the past 5 to 10 years. Classical Ewing's sarcoma and PNET are now known to be the same tumor with variable differentiation, defined by a translocation between the EWS gene on chromosome 22 with one of three ETS-like genes, especially the FLI-1 gene on chromosome 11. Molecular techniques used to identify this translocation along with the knowledge that the protein product of the MIC2 gene is highly expressed on the cell surface have greatly improved our diagnostic abilities in this family of tumors. Controversy still exists as to whether surgery improves event-free survival when compared with radiotherapy in Ewing's sarcoma. The high second tumor rate, if nothing else, has started moving many physicians to preferentially use surgery when the functional results are predicted to be reasonable. The addition of ifosfamide and etoposide to standard therapy in Ewing's sarcoma has improved survival for patients without metastases at presentation. However, outcome for patients with metastases or who develop metastases while on therapy or shortly thereafter remains poor. Preliminary reports of better outcome with megatherapy are interesting but not yet definitive. The decades ahead will probably see marked changes in therapy for Ewing's sarcoma. The unique translocation seen in virtually all of these tumors is a potential target for a "magic bullet" therapy, because the protein product of this translocation is present only in the malignant cells. Hopefully either immune modulation against this unique protein or further knowledge of how to use antisense genes will move us toward exquisitely targeted therapy in the Ewing family of tumors.
Article
We report the treatment and outcome of patients with peripheral primitive neuroectodermal tumor (PNET) and extraosseous Ewing's tumor (EOE) using Ewing's-directed therapy, including an ifosfamide and etoposide window. Seventeen pediatric patients with peripheral PNET (n = 14) or EOE (n = 3) were enrolled between 1988 and 1992 on our institutional Ewing's protocol. Induction therapy comprised a 9-week "window" of ifosfamide and etoposide, followed by 9 weeks of therapy with cyclophosphamide and Adriamycin (Adria Laboratories, Columbus, OH). Response assessment after 17 weeks was followed by surgery and/or radiotherapy (doses based on tumor size and response to induction), repeat evaluation, and maintenance chemotherapy with alternating courses of vincristine/dactinomycin, ifosfamide/etoposide, and cyclophosphamide/Adriamycin for a total of 45 weeks. At diagnosis, 8 patients had large lesions (>8 cm) and 3 had pulmonary metastases (1 with large tumor). Surgical resection was performed at diagnosis for 9 patients and after induction therapy for 5. During window therapy, all of the 9 evaluable patients responded (8 partial, I objective), and no patient without measurable disease developed disease progression. Responses were maintained or improved during subsequent induction in six of the patients with residual disease. Fourteen patients received local radiotherapy. At 49 to 94 months after diagnosis, 12 patients are disease-free (1 in second remission), 4 have died, and 1 is alive with disease. The five-year overall and progression-free survival rates are 77 +/- 13% and 62 +/- 16%, respectively. The use of consistent Ewing's-directed combined-modality therapy for patients with soft tissue peripheral PNET/EOE results in survival similar to that of patients with osseous Ewing's tumor. The combination of ifosfamide and etoposide appears active and should be incorporated in future treatment protocols.
Article
Ewing's sarcoma usually is identified as a primary malignancy of bone affecting children and young adults. Extraskeletal Ewing's sarcoma is rare, and very few data are available addressing optimal surgical and oncologic treatment modalities. The authors chose to review retrospectively 24 patients with extraskeletal Ewing's sarcoma treated at the study institution with modern multimodality therapies. Anatomic location, tumor size, patient age at diagnosis, stage of disease at the time of diagnosis, surgical margins, radiation dose, and the type and dose of chemotherapy were documented for every patient. Follow-up averaged 64 months for surviving patients. The overall 5-year survival rate was 61% and the disease free survival rate was 54%. A multivariate analysis found that younger age at the time of diagnosis was associated with improved 5-year survival and disease free survival (P = 0.008 and P = 0.005, respectively). Patients who underwent wide resection and less-than-wide resection had better overall survival (P = 0.001 and P = 0.015, respectively) and disease free survival (P = 0.002 and P = 0.024) compared with those who underwent no attempt at surgical resection. Patients who underwent a wide resection had an improved overall survival compared with those who underwent a less-than-wide resection (P = 0.045). The size of the lesion (P = 0.277) and the presence of metastatic disease at the time of diagnosis (P = 0.219) were not found to be significant prognostic factors. Age and surgical treatment were found to be important prognostic variables in the treatment of extraskeletal Ewing's sarcoma. No other variables, such as tumor size, tumor location, stage of disease, or radiation therapy, were found to improve survival. Surgical resection should be considered for all patients with extraskeletal Ewing's sarcoma.
Article
The primitive neuroectodermal tumor (PNET) is an extremely aggressive soft tissue neoplasm that occurs in children and adolescents. We retrospectively reviewed our therapeutic experience with a multidisciplinary approach, combining surgery, chemotherapy, and radiation therapy. Treatment of PNET was carried out in compliance with the soft tissue protocol (CWS) from the German Society of Pediatric Oncology. Biopsy-proven diagnosis was followed by chemotherapy, which in all cases led to partial remission, allowing excision of the remainder of the tumor without mutilation. After excision, irradiation of the tumor site and two further sequences of chemotherapy were performed. When PNET of the paravertebral region caused symptoms of paralysis and immediate surgery was required, postoperative chemotherapy, a second-look operation, and irradiation were undertaken. Between 1986 and 1998 we treated 13 patients (median age 15 years). In five patients the PNET originated from the chest wall and in eight patients from the paravertebral and retroperitoneal region. Five patients died after 20 months on average, and the remaining eight patients are in full remission after 7, 16, 46, 55, 70, 74, 75, and 115 months, respectively. Close cooperation between surgeons and their pediatric and radiotherapy colleagues is obligatory when treating PNET. Chemotherapy as the first stage is mandatory to avoid a mutilating surgical procedure and intraoperative tumor cell dissemination.
Article
Extraskeletal Ewings sarcoma is a tumour of neuroectodermal origin sharing close similarities with Ewings sarcoma of bone. We report the case of a 21 year old 16 week pregnant woman presenting with vomiting and weight loss and found to have an extraskeletal Ewings sarcoma of the small bowel. In a review of the literature there are no previous reports of extraskeletal Ewings sarcoma occurring in the small bowel. The diagnosis of extraskeletal Ewings sarcoma and the complicated management of a young pregnant woman with a malignant tumour are described.
Article
Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is an extraordinarily rare primary tumor in the kidney and can be mistaken for a variety of other round cell tumors, including blastema-predominant Wilms' tumor (WT). Approximately 90% of ES/PNET have a specific t(11;22), which results in a chimeric EWS-FLI-1 protein. Immunohistochemistry for the carboxy-terminus of FLI-1 is sensitive and highly specific for the diagnosis of ES/PNET. WT-1, the WT-associated tumor suppressor gene, is overexpressed in WT but not in ES/PNET. No study has examined FLI-1 or WT-1 expression in renal ES/PNET. The clinicopathologic features of 11 renal ES/PNET were studied along with immunohistochemistry for cytokeratin, desmin, CD99, FLI-1, and WT-1. WT were also immunostained for CD99 (5 cases), FLI-1 (10 cases), and WT-1 (9 cases). The patients (6 men, 5 women) ranged from 18 to 49 years of age (mean, 34 yr). The mean tumor size was 11.8 +/- 3.8 cm (mean +/- standard deviation). Presenting symptoms included abdominal/flank pain and/or hematuria. Grossly, all tumors showed necrosis and hemorrhage, and 4 had cystic change. Microscopically, all tumors showed vaguely lobular growth, primitive round cells, and variable rosette formation. Epithelial, myogenous, or cartilaginous differentiation was not seen. Immunohistochemical results on the renal ES/PNET were cytokeratin (2/8 focal), desmin (0/9), CD99 (8/8), FLI-1 (5/8), and WT-1 (0/8). In comparison, the WT only rarely expressed CD99 (1/5) and did not express FLI-1 (0/10), but were usually WT-1-positive (7/9). Follow-up on 8 cases (mean, 28 mo; range, 6-64 mo) showed 4 lung and pleural metastases, 1 bone metastasis, liver metastasis, 2 local recurrences, and 5 deaths from disease (median time to death, 16.8 mo). No case had distant metastatic disease at presentation. Adjuvant therapy included chemotherapy (8 cases), radiation (3 cases), and bone marrow transplantation (1 case). Our study affirms a unique proclivity of renal ES/PNET for young adults and that it is a highly aggressive neoplasm, with rapid death in many cases, usually after the development of treatment-resistant lung metastases. These tumors must be distinguished from blastema-predominant WT and other primitive renal tumors that require different therapy. FLI-1 and WT-1 immunohistochemistry may be valuable in this differential diagnosis, given the known immunophenotypic overlap between ES/PNET and blastema-predominant WT with regard to CD99, cytokeratin, and desmin. The accurate distinction between these two entities has clear prognostic and therapeutic implications.
Article
This report describes a rare case of Ewing sarcoma (ES) of the small intestine. The patient was a 9-year-old girl with progressive abdominal distension. Computed tomography showed a large mass in the small bowel. Histopathologic examination of the resected tumor showed ES with typical histologic, immunohistochemical, and ultrastructural features. The tumor recurred in the pelvic cavity 18 months after the original surgery. Molecular study of the recurrent tumor confirmed a diagnostic EWS-FLI1 gene fusion. This patient illustrates the unique occurrence of ES in the small intestine.
Article
To establish outcome and optimal timing of local control for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the chest wall. Patients < or =30 years of age with ES/PNET of the chest wall were entered in 2 consecutive protocols. Therapy included multiagent chemotherapy; local control was achieved by resection, radiotherapy, or both. We compared completeness of resection and disease-free survival in patients undergoing initial surgical resection versus those treated with neoadjuvant chemotherapy followed by resection, radiotherapy, or both. Patients with a positive surgical margin received radiotherapy. Ninety-eight (11.3%) of 869 patients had primary tumors of the chest wall. Median follow-up was 3.47 years and 5-year event-free survival was 56% for the chest wall lesions. Ten of 20 (50%) initial resections resulted in negative margins compared with 41 of 53 (77%) negative margins with delayed resections after chemotherapy (P = 0.043). Event-free survival did not differ by timing of surgery (P = 0.69) or type of local control (P = 0.17). Initial chemotherapy decreased the percentage of patients needing radiation therapy. Seventeen of 24 patients (70.8%) with initial surgery received radiotherapy compared with 34 of 71 patients (47.9%) who started with chemotherapy (P = 0.061). If a delayed operation was performed, excluding those patients who received only radiotherapy for local control, only 25 of 62 patients needed radiotherapy (40.3%; P = 0.016). The likelihood of complete tumor resection with a negative microscopic margin and consequent avoidance of external beam radiation and its potential complications is increased with neoadjuvant chemotherapy and delayed resection of chest wall ES/PNET.
Article
Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time. A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide. The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons. The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
Article
Response to neoadjuvant chemotherapy is a significant prognostic factor for the Ewing sarcoma family of tumors (ESFTs). [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is a noninvasive imaging modality that accurately predicts histopathologic response in several malignancies. To determine the prognostic value of FDG PET response for progression-free survival (PFS) in ESFTs, we reviewed the University of Washington Medical Center experience. Thirty-six patients with ESFTs were evaluated by FDG PET. All patients received neoadjuvant and adjuvant chemotherapy. FDG PET standard uptake values before (SUV1) and after (SUV2) chemotherapy were analyzed and correlated with chemotherapy response, as assessed by histopathology in surgically excised tumors. Thirty-four patients had both SUV1 and SUV2. The mean SUV1, SUV2, and ratio of SUV2 to SUV1 (SUV2:1) were 7.9 (range, 2.3 to 32.8), 2.1 (range, 0 to 4.3), and 0.36 (range, 0.00 to 1.00), respectively. Good FDG PET response was defined as SUV2 less than 2.5 or SUV2:1 < or = 0.5. FDG PET response by SUV2 or SUV2:1 was concordant with histologic response in 68% and 69% of patients, respectively. SUV2 was associated with outcome (4-year PFS 72% for SUV2 < 2.5 v 27% for SUV2 > or = 2.5, P = .01 for all patients; 80% for SUV2 < 2.5 v 33% for SUV2 > or = 2.5, P = .036 for localized at diagnosis patients). SUV2:1 < or = 0.5 was not predictive of PFS. FDG PET imaging of ESFTs correlates with histologic response to neoadjuvant chemotherapy. SUV2 less than 2.5 is predictive of PFS independent of initial disease stage.
Article
This is a review of extraosseous Ewing's sarcoma (ES) which includes a new, extremely rare case. The literature was examined with respect to determining the locations of extraosseous ESs, the incidence per site and in total and the criteria which confirm the similarity between extraosseous and osseous ES. ES sites were detected in several organs and tissues, mainly in the trunk, extremities and the retroperitoneal region. Studies confirmed that osseous and extraosseous ES are identical chromosomally and histologically. ES of the small intestine, described here, has not been previously documented in the literature. Along with the other different documented sites, a new location of primary extraosseous ES is also reported here.
Article
Primitive neuroectodermal tumor (PNET) of the kidney is a rare entity, the diagnosis usually being made at histopathology. Few cases reported in literature revealed a variable presentation and an aggressive behavior. The purpose of our study was to review our experience in diagnosis and the management of patients with renal PNET. The records of 16 patients of renal PNET treated between 1995 and 2003 were reviewed retrospectively and our data compared with the literature. There were 10 male and 6 female patients with median age of 27 years. At presentation, 10 patients (63%) had localized disease, 5 (31%) had metastatic disease and 1 (6%) had locally advanced disease. The presence of Homer-Wright type rosettes on hematoxylin and eosin staining and CD99 (cluster differentiation) products positivity on immunohistochemistry supported the diagnosis. Radical nephrectomy was performed in operable cases and all patients received chemotherapy. Nine patients received adjuvant radiotherapy to the renal bed. Median follow-up was 31 months (range 4 to 92). Overall median survival was 40 months with 3- and 5-year survival of 60% and 42%, respectively. The diagnosis of renal PNET must be considered in young patients presenting with renal mass. Standard therapy consists of combination of surgical resection, postoperative irradiation and chemotherapy. Chemotherapy regimen used is either RCT II (round cell tumor) protocol or EFT 2001 (Ewing's family of tumors) protocol. However, further studies are required to validate the appropriate chemotherapy protocol.
Article
This study presents a case of Ewing sarcoma and primitive neuroectodermal tumor arising in the esophagus of a 44-year-old woman who presented with progressive dysphagia. Imaging studies demonstrated a polypoid lesion in the esophagus. The tumor was characterized by corded and pseudopapillary architecture, cytologic monotony, and low proliferative activity. Immunohistochemical stains were positive for CD99, neuron-specific enolase, vimentin, cyclin D1, p53, and FLI1 gene product. Fluorescence in situ hybridization demonstrated a 22q12 translocation, associated with primitive neuroectodermal tumor in the tumor cells, whereas reverse transcription polymerase chain reaction conformed expression of Ewing sarcoma/FLI1 fusion transcript in the patient's bone marrow aspirate. Although this is a rare site for this type of tumor to occur, primitive neuroectodermal tumor should be considered in the differential diagnosis of mesenchymal tumors of the esophagus. Genetic analysis is crucial to establish the diagnosis and can be successfully performed on formalin-fixed, paraffin-embedded material and hematopoietic tissue.
Primitive neuroectodermal tumor of the liver: a case report
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Outcomes with nondose-dense chemotherapy for Ewing sarcoma: a practical approach for the developing world. Pediatr Blood Cancer
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Analysis of prognostic factors in extraosseous Ewing sarcoma family of tumors: review of St. Jude Children’s Research Hospital experience
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Primary Ewing’s sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases
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Malignant peripheral neuroectodermal tumors. a retrospective analysis of 42 patients
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