Bone sarcoma: success through interdisciplinary collaboration

PurposeOsteosarcoma and Ewing sarcoma are the most frequent malignant bone tumours of childhood and adolescence. This review summarizes the oncologist’s view of these diseases and their treatment.MethodsA non-systematic literature review was performed, the personal impressions and experience of the authors is described.ResultsLocal therapy and chemotherapy, each on their own, will not cure patients with malignant bone sarcomas. Together, they present a highly efficacious combination. While the most effective drugs were defined decades ago, progress since then has been limited. It is hoped that substances shown to be active in relapsed disease will be forwarded into even more efficacious frontline treatments. Good palliative therapy is necessary when cure is no longer an option.ConclusionClose interdisciplinary collaboration is the key to successful treatment of bone sarcomas in paediatric patients.     

Carcinomas of the Thyroid with Ewing Family Tumor Elements (CEFTEs): A Diagnostic Challenge Before Surgery

Carcinomas of the thyroid with Ewing family tumor elements (CEFTEs) are small cell thyroid tumors characterized by epithelial differentiation and EWSR1-FLI1 rearrangements. In contrast to primary thyroid Ewing sarcomas, these rare tumors have a favorable prognosis. CEFTEs may co-exist with papillary thyroid carcinoma (PTC) foci and are thought to arise from either PTCs or main cells of solid cell nests (SCN). Due to their rare occurrence, characteristic clinical presentations, preoperatory sonographic (US) findings, and fine-needle aspiration (FNA) cytologic features were ill-defined until now. We report a case of a 40-year-old male who was referred to the thyroid clinic for a progressively enlarging, hard, painless, cervical mass. US examination revealed a hypoechoic nodule with lobulated margins and scant intranodular vascular signals of the right thyroid lobe. Evidence of extracapsular spread was not identified. FNA provided a Bethesda V cytology classification on conventional smears. Repeat FNA sampling with the use of a CytoFoam Core allowed a preoperative diagnosis consistent with undifferentiated thyroid carcinoma. Total thyroidectomy without lymph node dissection was performed. Histologic examination with subsequent molecular studies provided the diagnosis of papillary carcinoma of the thyroid with Ewing family tumour elements (CEFTEs). No additional treatment was rendered and the patient showed no evidence of local or distant disease by clinical examination, US, and ¹⁸FDG-TAC/PET after 6 months of follow-up. This is the first reported case of CEFTE with complete clinical, US, cytologic, and immunohistochemical preoperatory assessment.     

Primary Sarcomas of the Larynx: A Clinicopathologic Study of 27 Cases

Primary sarcomas of the larynx are rare and are associated with diagnostic and treatment challenges. Studies of these tumors are limited, and most examples have been reported as small series. To further increase our understanding of laryngeal sarcomas, we reviewed our experience of an adult cohort. A retrospective search for laryngeal sarcomas from our pathology archives and consultation files of one of the authors was performed. We studied 27 primary laryngeal sarcomas that included 25 males, and 2 females, with a mean age of 60 years (range 33–85). The cases included conventional chondrosarcoma (16), well-differentiated liposarcoma (2), clear cell chondrosarcoma (1), leiomyosarcoma (2), high grade myxofibrosarcoma (2), high grade myofibroblastic sarcoma (1), low-grade myofibroblastic sarcoma (1), malignant granular cell tumor (1), and Kaposi sarcoma (1). Data on treatment and follow-up was available in 17 and 16 cases, respectively. 12 patients underwent partial laryngeal resection; five had total laryngectomy, and the patient with Kaposi sarcoma received combined highly active antiretroviral therapy and chemotherapy. Three patients developed local recurrence, and two patients developed metastases. The remaining patients with follow up had a favorable outcome and were disease-free after treatment. The important differential diagnosis of spindle cell sarcoma is sarcomatoid squamous cell carcinoma, and their distinction often requires extensive sampling of the mucosal surface and immunohistochemical analysis. The mainstay of treatment for laryngeal sarcomas is surgical removal, with the extent dictated by tumor type and grade. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.     

Ewing sarcoma of the jejunum: A case report and literature review

BACKGROUNDEwing sarcomas (ESs) are highly aggressive malignancy and are predominant in the long bones of extremities of children and young adults with a slight male predilection and rarely presents at extra skeletal locations.CASE SUMMARYA 55-year-old woman came to our hospital after finding elevated tumor biomarkers during her physical examination. Her enhanced computed tomography scan showed a jejunal mass. The patient underwent laparoscopic enterectomy. The mass was later diagnosed as ES, evidenced by fluorescence in situ hybridization whereby the GLP ES breakpoint region 1 probe was used, showing that more than 10% of the cells showed a red-green-yellow signal proving the breakpoint rearrangement of the ES breakpoint region 1 gene in chromosome 22.CONCLUSIONWe describe a case of localized ES at the jejunum in China based on the literature.     

Sarcomas of the vagina and uterus: the Intergroup Rhabdomyosarcoma Study

During a 12-year period (1972-1984), 43 patients with sarcomas of the female genital tract were admitted to the Intergroup Rhabdomyosarcoma Study (IRS), including 31 with primary tumors of the vagina; and 12 with tumors of the uterus, including the cervix. Thirty-four of these can be evaluated on the basis of periods of observation from 18 months to 12 years. Primary tumors of the uterus were a distinct group, distinguished from those arising in the vagina by patient age-range and probably by prognosis, as well as site. Patients with vaginal tumors, with a mean age of 1.8 years, responded to a multimodality approach employing combinations of chemotherapy (vincristine sulfate and actinomycin D, or the aforementioned two drugs with cyclophosphamide +/- doxorubicin hydrochloride), irradiation, and/or surgery, with only one tumor-related death, among 24 evaluable patients. In contrast, among the patients with primary uterine tumors, in which the mean age was greater than 14 years, four of ten evaluable patients died secondary to tumor relapse or progression.     

含洛铂方案的新辅助化疗在骨肉瘤及尤因肉瘤中的疗效观察

背景：化疗是骨肉瘤及尤因肉瘤最主要的治疗手段之一,目前化疗疗效已进入平台期,选择低毒高效的化疗药物及方案是关键。目的：观察含洛铂（LBP）方案的新辅助化疗对骨肉瘤及尤因肉瘤的疗效及不良反应。方法：2011年10月至2012年10月收治经病理学检查确诊为原发恶性骨肿瘤患者22例,其中骨肉瘤13例,尤因肉瘤9例;男17例,女5例,年龄9～23岁,平均18.3岁;Enneking分期：ⅡA期3例,ⅡB期19例。给予LBP-多柔比星（AMD）方案交替异环磷酰胺（IFO）方案（LBP 30mg/m2,AMD 60mg/m2;IFO12g/m2;全身静脉给药）的新辅助化疗,后行保肢手术治疗。采用RECIST评价标准评价其疗效,并观察不良反应。结果：22例中完全缓解（CR）1例,部分缓解（PR）18例,疾病稳定（SD）3例,总有效率（RR）为86.4%。随访3～14个月,平均9.2个月,1例脊柱骨肉瘤患者术后5个月复发,其余患者未发现复发或转移征象。主要不良反应为限制性骨髓抑制,化疗间歇期患者恢复快,无明显肾功能异常及过敏反应。结论：骨肉瘤及尤因肉瘤接受含LBP方案的新辅助化疗的近期疗效满意,不良反应可耐受,值得进一步临床研究。     

Selected Diagnostically Challenging Pediatric Soft Tissue Tumors

Many benign and malignant soft tissue tumors in children are challenging and their diagnosis requires knowledge of their vast diversity, histopathological complexity, and immunohistochemical, cytogenetic, and molecular characteristics. The importance of clinical and imaging features cannot be overstated. Soft tissue sarcomas account for 15% of all pediatric malignancies after leukemia/lymphoma, central nervous system tumors, neuroblastoma and Wilms tumor. This article discusses selected challenging pediatric soft tissue tumors with an update on recently described entities.     

Adamantinoma-Like Ewing Sarcoma Mimicking Basal Cell Adenocarcinoma of the Parotid Gland: A Case Report and Review of the Literature

Adamantinoma-like Ewing sarcoma (AES) is a rare variant of the Ewing family of tumors that resembles classic adamantinoma of bone. AES shows epithelial differentiation and a more complex immunohistochemical expression profile with keratin and basal marker immunoreactivity and can resemble a variety of carcinomas. We report an unusual case of an AES of the parotid gland that mimicked a basal cell adenocarcinoma. Like basal cell adenocarcinoma, this AES showed a nested basaloid proliferation with peripheral palisading in tumor nests with ‘basaloid’ epithelial differentiation as highlighted by cytokeratin AE1/3 and p40 positivity. However, unlike most basal cell adenocarcinomas, this tumor demonstrated high grade morphology, showed no true ductal or myoepithelial component, and also showed a tendency towards neuroectodermal phenotype with focal rosette formation, CD99 and weak synaptophysin immunoreactivity. EWSR1 and FLI1 fluorescence in situ hybridization confirmed the presence of a translocation supporting the diagnosis of AES. This is the first case of AES presenting as a primary parotid mass highlighting the potential to be mistaken for primary salivary gland carcinomas, which in addition to basal cell adenocarcinoma include other basaloid tumors such as adenoid cystic carcinoma.

Electronic supplementary material

The online version of this article (doi:10.1007/s12105-014-0558-0) contains supplementary material, which is available to authorized users.     

Modified Staging System for Extremity Soft Tissue Sarcomas

Background: The establishment of a universally acceptable staging system for soft tissue sarcomas has been hampered by the low incidence, various grading systems, and lack of consensus regarding the value of different prognostic factors. We aimed to evaluate prognostic factors in patients with extremity soft tissue sarcomas and to test the validity of the AJCC/UICC staging system.Methods: Prospectively collected data from 316 previously untreated patients with primary extremity soft tissue sarcomas treated at a single institution between 1989 and 1995 were studied. The influence of clinical and pathological factors on local recurrence, distant metastasis, and disease-specific survival was analyzed by univariate and multivariate techniques.Results: Large tumor size and high histological grade were independent adverse prognostic factors for distant metastasis. Large size, high grade, and positive microscopic surgical margins were independent adverse prognostic factors, and liposarcoma histology was an independent favorable prognostic factor for disease-specific survival. Within each histological grade, there was a progressive decline in survival with increasing tumor size, as reflected by an almost linear increase in hazard ratios. Similarly, there was a progressive fall in survival with increasing grade within each size group (<5 cm, 5 to 10 cm, 10 to 15 cm, and =15 cm). AJCC staging did not correlate well with prognosis. Survival for intermediate-grade tumors smaller than 5 cm (stage IIA) was better than that for low-grade tumors larger than 5 cm (stage IB) (86% vs. 73%). Survival for high-grade tumors smaller than 5 cm (stage IIIA) was better than that for intermediate-grade tumors larger than 5 cm (stage IIB) (72% vs. 57%). A modified staging system was formulated based on the additive influence of size and grade on the estimated hazard ratios for disease-specific survival, as follows: stage IA, G1T1; stage IB, G1T2 or G2T1; stage IIA, G1T3 or G2T2 or G3T1; stage IIB, G1T4 or G2T3 or G3T2; stage IIIA, G2T4 or G3T3; stage IIIB, G3T4; and stage IV, M1 (G1, G2, G3 = low, intermediate, and high grade; T1, T2, T3, T4 = tumor size < 5 cm, 5–10 cm, 10–15 cm, and >15 cm, respectively). The 5-year disease-specific survivals of stages IA, IB, IIA, IIB, IIIA, and IIIB were 100%, 83%, 74%, 61%, 39%, and 18%, respectively. The 5-year disease-specific survival for stages I, II, III, and IV were 90%, 67%, 31%, and 6% respectively. The survival difference between each stage was statistically significant (P < .001).Conclusion: Histological grade and tumor size are equally important determinants of distant metastases and survival. The AJCC/UICC staging system is based primarily on the grade of the tumor, with size used to subgroup each stage. A staging system for extremity soft tissue sarcomas with equal emphasis on grade and size is proposed that correlates extremely well with prognosis.     

Angiogenesis and Ewing sarcoma--relationship to pulmonary metastasis and survival

Background/Purpose

Intratumoral angiogenesis quantified by microvessel density (MVD) has been shown to be a strong prognostic indicator in a number of malignant tumors. Its association with prognosis in Ewing sarcoma has not been previously studied. The aim of our study was to investigate the relationship between angiogenesis and clinical outcome in Ewing sarcoma.

Methods

Twenty-seven patients with Ewing sarcoma were included in a retrospective immunohistochemical study. Sections from diagnostic biopsies were immunostained using anti-von Willebrand factor antibody and microvessels were counted at 400× magnification on three microscopic fields per patient. Microvessel density was correlated with overall and disease-free survival as a continuous variable using univariate regression analysis and as a dichotomous variable by Kaplan-Meier and log-rank analysis. Correlation between clinicopathologic variables and the degree of angiogenesis was tested using χ² test.

Results

Increasing MVD was not confirmed to be a poor prognostic factor in univariate analysis. Also, statistically significant difference was not found in overall survival or disease-free survival between patients with high (>31.6 vessels per field) and low (≤31.6 vessels per field) microvessel counts. Finally, there was no difference regarding the metastatic rate between patients with high and low microvessel counts.

Conclusions

Our results did not confirm increasing angiogenesis quantified by MVD to be predictive of prognosis or pulmonary metastasis in Ewing sarcoma. The diffuse pattern of distribution of microvessels found in Ewing sarcoma may be responsible for the observed lack of prognostic significance of angiogenesis. Future work is required to assess the prognostic importance of MVD in this disease.     

Expression of p53 and Proliferation Index as Prognostic Factors in Gastrointestinal Sarcomas

Background:Sarcomas arising in the gastrointestinal (GI) tract are rare tumors. Molecular markers could be associated with prognosis in these types of tumors.Methods:We performed a retrospective analysis of adult patients with sarcomas arising in the GI tract at the National Institute of Medical Sciences in Mexico City and the University of Alabama at Birmingham Hospital. All histological types were included. Patient, tumor, and treatment factors were analyzed, with overall survival as the main outcome variable. Expression of p53 and cellular proliferation antigen Ki-67 was also analyzed. Statistical analysis was performed by log-rank test and Cox regression. Significance was defined as P < .05.Results:Forty-seven patients were analyzed. The median patient age was 53 years (range, 16–82 years). Twenty-five patients (53%) were women. The stomach was the most common site of presentation. The mean tumor size was 14 cm (2–45 cm). A complete resection was achieved in 40 patients. With a median follow-up of 30 months, the actuarial 3-year survival was 68%. Univariate analysis identified overexpression of p53 and Ki-67, high tumor grade, tumor size >10 cm, and incomplete resection as significant negative prognostic factors. Hispanic race and good performance status were significantly associated with prolonged survival. On multivariate analysis, overexpression of p53 was the only independent negative prognostic factor.Conclusions:Overexpression of p53 is the strongest predictor of poor prognosis in patients with sarcomas of the GI tract.     

Soft-tissue sarcomas of the extremities in patients of pediatric age

Purpose The extremity site is a peculiar location for soft-tissue sarcomas (STS) of children and adolescents. Here we report the experience of the Pediatric Oncology Unit of the Istituto Nazionale Tumori of Milan, Italy, concerning 204 patients with STS of the limbs treated between 1977 and 2006. Methods The study series included 52 patients with rhabdomyosarcoma (RMS)(65% of which were of the alveolar subtype), nine with extraosseous Ewing sarcoma and 143 with non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS), 38% of which were synovial sarcoma. Patients were treated with a multimodality approach including surgery, chemotherapy, and radiotherapy. Results For the RMS patients, the 5-year event-free survival (EFS) rate was 37.1%, with distant metastases being the main cause of treatment failure. The outcome was particularly poor for patients with large invasive tumors, hand/foot involvement and/or nodal or distant metastases, and for patients who were not given radiotherapy. For the extraosseous Ewing sarcoma cases, 5-year EFS was 74%. For the NRSTS cases, the 5-year EFS was 72.6%: tumor size and local invasiveness, tumor grade, malignant peripheral nerve sheath tumor (MPNST) histology, and distant metastases were the main prognostic factors. Discussion While the limbs are the most common sites of NRSTS and are often characterized by a more favorable prognosis than for axial tumors, the clinical features of extremity RMS often differ from those of RMS of other sites, with a higher incidence of unfavorable prognostic factors (e.g., alveolar subtype) and consequently unsatisfactory treatment results. The treatment of these patients is complex and necessarily multidisciplinary, and it demands not only adequate experience of treating children and adolescents in clinical trials, but also particular skills in the field of orthopedic surgery.     

Magnetic resonance image findings of primary intradural Ewing sarcoma of the cauda equina: case report and review of the literature

Background contextInvolvement of the cauda equina in Ewing sarcoma (ES) is extremely rare, and only few cases are reported in literature. However, ES of cauda equina shares some neuroradiological features with other neoplasms that can involve the intradural space. Therefore, differential diagnosis with other tumors of cauda equina should be considered by neuroradiologists and neurosurgeons to provide appropriate treatment.PurposeTo present a rare case of intradural extramedullary primary ES.Study designCase report.MethodsWe report a case of a 44-year-old woman presenting with the rapid onset of cauda equina syndrome. Radiological analysis showed multiple intradural masses, extending from L1 to S3 level. After radical surgery, lesions were histologically defined as ES. We present a literature review, analyzing magnetic resonance image (MRI) features of primary intradural ES of the cauda equina.ResultsFour cases of primitive ES arising from the cauda equina have been reported in the literature.ConclusionsBecause of the low number of reported cases, it is not possible to describe pathognomonic MRI findings for intradural ES of the cauda equina. However, few tumors show similar MRI features. Therefore, despite its rarity, intradural ES should be taken into account in the differential diagnosis of spinal tumors involving cauda equina.     

Indeterminate pulmonary nodules are not associated with worse overall survival in Ewing Sarcoma

AimLung metastases are a negative prognostic factor in Ewing sarcoma, however, the incidence and significance of sub-centimetre pulmonary nodules at diagnosis is unclear. The aims of this study were to (1): determine the incidence of indeterminate pulmonary nodules (IPNs) in patients diagnosed with Ewing sarcoma (2); establish the impact of IPNs on overall and metastasis-free survival and (3) identify patient, oncological and radiological factors that correlate with poorer prognosis in patients that present with IPNs on their staging chest CT.Materials & methodsBetween 2008 and 2016, 173 patients with a first presentation of Ewing sarcoma of bone were retrospectively identified from an institutional database. Staging and follow-up chest CTs for all patients with IPN were reviewed by a senior radiologist. Clinical and radiologic course were examined to determine overall- and metastasis-free survival for IPN patients and to identify demographic, oncological or nodule-specific features that predict which IPN represent true lung metastases.ResultsFollowing radiologic re-review, IPN were found in 8.7% of patients. Overall survival for IPN patients was comparable to those with a normal staging chest CT (2-year overall survival of 73.3% [95% CI 43.6–89] and 89.4% [95% CI 81.6–94], respectively; p = 0.34) and was significantly better than for patients with clear metastases (46.0% [95% CI 31.9–59]; p < 0.0001). Similarly, there was no difference in metastasis-free survival between ‘No Metastases’ and ‘IPN’ patients (p = 0.16). Lung metastases developed in 40% of IPN patients at a median 9.6 months. Reduction of nodule size on neoadjuvant chemotherapy was associated with worse overall survival in IPN patients (p = 0.0084).ConclusionIPN are not uncommon in patients diagnosed with Ewing sarcoma. In this study, we were unable to detect a difference in overall- or metastasis-free survival between patients with IPN at diagnosis and patients with normal staging chest CTs.     

Primary Ewing sarcoma of the petrous temporal bone: an exceptional cause of facial palsy and deafness in a nursling

BACKGROUND: Primary Ewing sarcoma affecting the skull base in general and the petrous bone in particular is extremely rare with only 4 reports of Ewing sarcoma arising in the petrous temporal bone in the international medical literature. METHODS: The authors report for the first time a case of a primary Ewing sarcoma of the petrous temporal bone in a 5-month-old nursling, which became apparent with a complete peripheral facial palsy and ipsilateral surdity. RESULTS: The neoformation was treated by systemic chemotherapy and radiation of the tumor region. The diagnostic steps, therapy, and development of the child are described in detail; the literature concerning Ewing sarcoma originating from the skull in general and from the petrous temporal bone in particular is reviewed. CONCLUSIONS: The highlights of this case are an extremely uncommon location, an unusual age of presentation, as well as a unique set of symptoms.     

Pathology of paediatric bone tumours

Primary bone tumours account for less than 0.2% of all neoplasms but malignant bone tumours represent the third most common cause of cancer deaths in children and adolescents. The rarity of bone tumours in itself is a diagnostic challenge but is compounded by the number of tumour subtypes on top of which the imaging and histological features of degenerative and reactive processes, and benign bone tumours can simulate bone sarcomas. Furthermore, even in children bone lesions may represent metastatic disease. Hence the assessment of a bone tumour in a child or adolescent should be performed in a specialist referral bone tumour centre which has access to a multidisciplinary team and molecular diagnostic tests: the latter provides greater diagnostic accuracy. It is now appreciated that germline alterations occur more commonly than previously recognised in children and young adults presenting with osteosarcoma and Ewing sarcoma. Awareness of this is important as genetic counselling and screening may be appropriate. In this article epidemiology, radiology, pathology, genetics, treatment and prognosis of most commonly encountered bone tumours among the paediatric population are reviewed.     

Vascular Endothelial Growth Factor and Soft Tissue Sarcomas: Tumor Expression Correlates With Grade

Introduction: Vascular endothelial growth factor (VEGF), an endothelial–specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor.Methods: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 g/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier.Results: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining.Conclusions: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.Presented at the 53rd Annual Cancer Symposium of the Society of Surgical Oncology Poster Session, New Orleans, Louisiana, March 16-19, 2010434_2001_Article_260.