Clinical features and outcomes of young patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas treated with a risk-based strategy: A report from Children's Oncology Group study ARST0332.

BACKGROUND: In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited. METHODS: We analyzed patients less than 30 years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low-risk patients were treated with surgery alone. Intermediate-/high-risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12 weeks of chemoradiotherapy. RESULTS: Estimated 5-year event-free and overall survival were 90% and 100% low risk (n = 80), 55% and 78% intermediate risk (n = 15), and 25% and 25% high risk (n = 4). In low-risk patients, only local recurrence was seen in 10%; none with margins greater than 1 mm recurred locally. Sixteen of 17 intermediate-/high-risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate-/high-risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low-risk (surgery alone) patients would have received radiotherapy ± chemotherapy. CONCLUSIONS: Most low-risk patients with completely resected POG low-grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1 mm may be sufficient to prevent local recurrence. Patients with intermediate- and high-risk low-grade NRSTS have outcomes similar to patients with high-grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low-risk NRSTS curable with surgery alone.

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney.

AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

BACKGROUND: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS. METHODS: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m2 per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164. FINDINGS: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9-7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0-93·8) and 96·2% (93·2-99·2) in the low-risk group; 65·0% (58·2-71·8) and 79·2% (73·4-85·0) in the intermediate-risk group; and 21·2% (11·4-31·1) and 35·5% (23·6-47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group). INTERPRETATION: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.

Magnetic resonance and computed tomography imaging features of epithelioid sarcoma in children and young adults with pathological and clinical correlation: a report from Children's Oncology Group study ARST0332.

OBJECTIVE: To correlate imaging features of epithelioid sarcoma in children and young adults enrolled in Children's Oncology Group study ARST0332 with clinical and pathological findings. MATERIALS AND METHODS: Fifteen patients (6 males; median age 16.1 years, range 6.5-24.8 years) with epithelioid sarcoma enrolled in ARST0332 had preoperative imaging (MRI, n=10; CT, n=5) that was reviewed by two radiologists who recorded numerous features including presence and percentage of tumor necrosis, presence of surrounding edema, and lymph node involvement. Discrepancies between reviewers were adjudicated by concurrent re-review. We correlated imaging findings with histological assessment of percentage tumor necrosis, proximal- vs. classic-type histology, lymph node involvement and recurrence. RESULTS: Eleven patients (11/15, 73%) had proximal-type histology tumors. Ten of 14 tumors (71%) had imaging evidence of necrosis. Among the nine tumors with imaging and histological estimates of percentage necrosis, agreement was within 30% (in six tumors there was ≤10% difference between pathology and imaging). All 10 tumors imaged with MRI had surrounding edema. Four patients had biopsy-proven nodal involvement; all had necrotic nodes on imaging. There were four false-positives for nodal involvment by imaging. Twelve patients (12/15, 80%) had recurrences (local only, n=1; local and distant, n=1; distant only, n=10). CONCLUSION: Proximal-type histology was prevalent in this young cohort with preoperative imaging. Necrosis is common in primary tumors and involved nodes. There is good agreement between histological and imaging estimates of primary tumor necrosis. Surrounding tumor edema is common in this tumor, which is known to spread along fascial planes.

MRI and CT of Low-Grade Fibromyxoid Sarcoma in Children: A Report From Children's Oncology Group Study ARST0332.

OBJECTIVE: The purpose of this article is to determine the MRI and CT features of low-grade fibromyxoid sarcoma in children. MATERIALS AND METHODS: We retrospectively analyzed images of 11 pediatric patients with low-grade fibromyxoid sarcoma from a phase 3 clinical trial of nonrhabdomyosarcoma soft-tissue sarcoma (Children's Oncology Group Protocol ARST0332). MRI and CT were performed in 10 and four patients, respectively. Location, size, margin, and composition on imaging were correlated with pathologic findings. RESULTS: Tumors were located in the extremities in nine patients, and one tumor each was located in the tongue and lung. Tumors were deep in seven patients and superficial in four patients. All tumors were well defined, solitary, and nonmetastatic at presentation. Tumors were complex solid-cystic in eight patients and completely solid in three patients. On T1-weighted images, all tumors had at least some areas hypointense to muscles, and six had a split-fat sign. On STIR or T2-weighted images, eight tumors had areas hypointense to adjacent muscle, and eight tumors had fluid signal intensity. On contrast-enhanced MRI studies, eight tumors had thick enhancing internal septations, and three had peripheral nodular gyriform enhancement. When we correlated imaging to pathologic findings, areas with hypointense signal intensity on both T1- and T2-weighted images were likely related to fibrous component; areas with fluid signal intensity on T2-weighted images were likely related to myxoid component. On CT, all four tumors were hypodense to muscle, and one tumor showed punctate calcific foci. CONCLUSION: Low-grade fibromyxoid sarcoma is hypodense to muscle on CT. MRI may identify both fibrous and myxoid components of this rare pediatric soft-tissue sarcoma.

A conditional mouse model of synovial sarcoma: insights into a myogenic origin.

Synovial sarcoma is an aggressive soft-tissue malignancy marked by a unique t(X;18) translocation leading to expression of a chimeric SYT-SSX fusion protein. We report here a mouse model of synovial sarcoma based on conditional expression of the human SYT-SSX2. Using this model, we have identified myoblasts as a potential source of synovial sarcoma. Remarkably, within the skeletal muscle lineage, while expression of the oncoprotein in immature myoblasts leads to induction of synovial sarcoma with 100% penetrance, its expression in more differentiated cells induces myopathy without tumor induction. We also show that early widespread expression of the fusion protein disrupts normal embryogenesis, causing lethality.

Syndrome-associated soft tissue tumours.

Soft tissue neoplasms may be associated with a variety of genetic disorders and malformation syndromes, especially when they arise in children, adolescents and early adulthood. This review summarizes the principal histopathological types of soft tissue tumours which occur in various syndromes, with an emphasis on pathological features, genetic aspects and considerations for the diagnostic pathologist.

Imaging features of alveolar soft-part sarcoma: a report from Children's Oncology Group Study ARST0332.

OBJECTIVE: There are few studies in the literature regarding the imaging features of alveolar soft-part sarcoma (ASPS). We performed a comprehensive assessment of the imaging characteristics of this rare tumor to determine whether there are features that suggest the diagnosis. MATERIALS AND METHODS: Twenty-two subjects with ASPS underwent pretherapy imaging as part of enrollment in Children's Oncology Group protocol ARST0332 for the treatment of nonrhabdomyosarcoma soft-tissue sarcomas: 16 patients underwent MRI; three, CT; and three, both MRI and CT. Two radiologists retrospectively reviewed the imaging studies by consensus and recorded tumor location, size, contour, internal architecture, signal characteristics, presence of flow voids, and enhancement patterns. RESULTS: The 12 females and 10 males in the study group ranged in age from 8 to 23 years 7 months (mean, 15 years 8 months). The most common anatomic site was the lower extremity (12/22, 55%) followed by the upper extremity (4/22, 18%). The maximal tumor diameter ranged from 2.3 to 20.0 cm (median, 5.9 cm). All tumors imaged with MRI had flow voids (19/19, 100%), and 19 (19/22, 86%) had large peripheral vessels, lobulated margins, and nodular internal architecture. Unenhanced T1-weighted MRI was available for 18 tumors: 14 (14/18, 78%) appeared slightly hyperintense to muscle. Of the 16 tumors imaged with contrast material, 11 (11/16, 69%) showed intense enhancement and five (5/16, 31%), moderate enhancement. Six tumors (6/16, 38%) had a thick enhancing peripheral rim with a nonenhancing center consistent with necrosis. CONCLUSION: The imaging features of ASPS include flow voids, large peripheral vessels, internal nodularity, and lobulated margins. Contrast administration produces intense to moderate enhancement, sometimes with a thick enhancing peripheral rim around central necrosis. Extremity tumors with these imaging features in a child or young adult should suggest the diagnosis of ASPS.

The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective.

CONTEXT.­: Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. OBJECTIVE.­: To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. DATA SOURCES.­: The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. CONCLUSIONS.­: Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.

Infantile fibrosarcoma (IFS; also known as cellular congenital mesoblastic nephroma, CMN, when in the kidney) is a rare, undifferentiated tumour often characterized by the ETV6-NTRK3 fusion transcript. Our goal was to identify downstream pathways, diagnostic markers and potential therapeutic targets for IFS/CMN. Global gene expression, reverse-phase protein array and ETV6-NTRK3 fusion analyses were performed on 14 IFS/CMN and compared with 41 other paediatric renal tumours. These analyses confirm significant receptor tyrosine kinase (RTK) activation, with evidence of PI3-Akt, MAPK and SRC activation. In particular, GAB2 docking protein, STAT5-pTyr-694, STAT3-pSer-729 and YAP-pSer-127 were elevated, and TAZ-pSer-89 was decreased. This provides mRNA and proteomic evidence that GAB2, STAT activation and phosphorylation of the Hippo pathway transcription co-activators YAP and TAZ contribute to the RTK signal transduction in IFS/CMN. All IFS/CMN tumours displayed a distinctive gene expression pattern that may be diagnostically useful. Unexpectedly, abundant ETV6-NTRK3 transcript copies were present in only 7/14 IFS, with very low copy number in 3/14. An additional 4/14 were negative by RT-PCR and absence of ETV6-NTRK3 was confirmed by FISH for both ETV6 and NTRK3. Therefore, molecular mechanisms other than ETV6-NTRK3 fusion are responsible for the development of some IFS/CMNs and the absence of ETV6-NTRK3 fusion products should not exclude IFS/CMN as a diagnosis.

Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-ß, COX2 and sex steroid receptors.

Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and non-steroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor-ß (TGFß) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFß superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFß family signaling pathways, ß-catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co-expression were explored via correlational statistical analyses. In addition to ß-catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFß signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor-ß receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor-ß was present in all cases studied. Transforming growth factor-ß signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor-ß and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

ß-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors.

Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence of activated ß-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing ß-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, metastatic, multifocal primitive renal epithelial tumors that have the histologic and staining characteristics of the epithelial component of human WT. These highly malignant tumors have increased activation of the phosphatidylinositol 3-kinase-AKT and extracellular signal-regulated kinase pathways, increased expression of total and nuclear ß-catenin, and increased downstream targets of this pathway, such as c-Myc and survivin. Thus, we developed a novel mouse model in which activated K-RAS synergizes with canonical Wnt/ß-catenin signaling to form metastatic primitive renal epithelial tumors that mimic the epithelial component of human WT.

Solitary, multifocal and generalized myofibromas: clinicopathological and immunohistochemical features of 114 cases.

AIMS: To report a large series of solitary and multiple myofibromas with systematic clinicopathological correlations. METHODS AND RESULTS: We report on 114 patients with myofibromas, 97 of which were solitary and 17 multifocal. The age at presentation ranged from newborn to 70 years. All multifocal myofibromas and 91% of solitary myofibromas occurred in children. The head and neck region was the most common site (n = 43), followed by the trunk (n = 24), lower limbs (n = 14), upper limbs (n = 11), and viscera (n = 4). Solitary and multifocal myofibromas stained positively for smooth muscle actin (SMA) in 95% and 92% of cases, muscle-specific actin (MSA) in 75% and 50% of cases, and desmin in 10% and 14% of cases, respectively. Regressive features were seen in 34 solitary myofibromas and in nine multifocal myofibromas. Most patients were treated with complete excision (n = 79) or partial excision (n = 12). There were no recurrences after treatment. CONCLUSIONS: Solitary and multiple myofibromas are benign tumours that predominantly occur in infancy and childhood. Myofibromas occur especially in the head and neck region, and are characterized by SMA and, to a lesser extent, MSA expression. The clinical course is self-limiting, and local excision appears to be sufficient.

Nuclear p63 expression in osteoblastic tumors.

Expression of the p63 tumor suppressor protein has been reported in the mononuclear stromal cells of giant cell tumor of the bone, which may represent osteoblast-precursor cells. Only a limited number of osteoblastic tumors have been studied for p63 expression thus far. We therefore examined whether p63 may serve as a marker for osteoblastic differentiation in osteosarcomas or as a differential diagnostic marker to distinguish osteoblastoma from osteosarcoma. Immunohistochemical stains for p63 were performed on a tissue microarray containing 71 chemotherapy naïve biopsy samples of osteosarcoma, 21 whole sections of osteosarcoma, and 8 osteoblastomas. Nuclear p63 was detected in seven of eight osteoblastomas but was restricted to stromal cells within primitive, immature-appearing areas of osteoid deposition. Although only 7 of 71 (10 %) biopsy samples of osteosarcoma represented on the tissue microarray were positive for p63, 7 of 21 (33 %) osteosarcomas were positive when whole tissue sections were evaluated. Although p63 is detected in most osteoblastomas, it is also observed in a significant subset of osteosarcomas, severely limiting its utility in distinguishing between benign and malignant osteoblastic tumors. The relatively low prevalence of p63 expression in osteosarcoma would also seem to preclude its use as a marker of osteoblastic differentiation in skeletal sarcomas.

IgG4 plasma cells in inflammatory myofibroblastic tumor: inflammatory marker or pathogenic link?

Inflammatory myofibroblastic tumor is a rare mesenchymal neoplasm that harbors an anaplastic lymphoma kinase (ALK) gene rearrangement in the majority of cases. It is composed of fibroblastic-myofibroblastic cells with a characteristic inflammatory infiltrate that consists predominantly of plasma cells. In contrast, IgG4-related sclerosing disease is a recently described multisystem disorder with a histological appearance similar to inflammatory myofibroblastic tumor. The plasma cell infiltrate is characteristic in IgG4-related sclerosing disease and has been studied as a tool to render this diagnosis. Histologically, the two disorders overlap, although there are significant clinical differences. This study analyzes the histological appearance of 36 inflammatory myofibroblastic tumors, compares them with IgG4-related sclerosing disease, and assesses the plasma cell profile using immunohistochemistry to determine the range and proportion of IgG4 plasma cells. The majority of patients were children and young adults, mainly with solitary masses and no clinical manifestations of IgG4-related sclerosing disease. ALK-1 positivity was present in 23 cases (64%). None showed obliterative phlebitis or prominent lymphoid aggregates. Of 36 inflammatory myofibroblastic tumors, 15 cases showed an IgG4/IgG ratio ≥0.10, a cutoff described in the literature as supportive of IgG4-related sclerosing disease and up to 33 IgG4-positive plasma cells per high-power field indicating a mild-to-moderate increase as compared with IgG4-related sclerosing disease. Currently, the diagnostic recognition of inflammatory myofibroblastic tumor is based on clinicopathological features and diagnostic adjuncts, such as ALK-1 reactivity and genetic tests. Although inflammatory myofibroblastic tumor and IgG4-related sclerosing disease are distinct entities, a subset of inflammatory myofibroblastic tumors exhibit an IgG4/IgG ratio that is within the range for IgG4-related sclerosing disease. Therefore, the ratio alone cannot be used as a reliable discriminator between these two entities and other clinical and pathologic features must always be taken into account.

Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.

Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.

Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

PURPOSE: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR). METHODS AND MATERIALS: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D). RESULTS: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection. CONCLUSIONS: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.

Foamy cell angiosarcoma: a rare and deceptively bland variant of cutaneous angiosarcoma.

Cutaneous angiosarcoma can sometimes mimic other benign and malignant lesions, thereby presenting a difficult differential diagnosis. In the two cases of cutaneous angiosarcoma presented herein, extensive foamy cell alteration of tumor cells resembled a reactive xanthogranulomatous process. Foamy cell angiosarcoma is an unusual and deceptively benign morphologic variant of cutaneous angiosarcoma. Critical features for diagnosis include the presence of a deep, permeative, sometimes 'scaffolding' growth pattern and subtle areas of vascular formation.