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Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription., Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined., Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity., Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

Fibrous lesions of infancy and childhood are a heterogeneous group of entities composed predominantly of fibroblasts and myofibroblasts, ranging from reactive lesions to neoplasms with a range of malignant potential. Although rare, their correct recognition by histopathology is important clinically as they exhibit a wide range of behaviors and may be associated with distinct underlying syndromes. Contributions from molecular diagnostics have enabled more accurate diagnosis, and have changed our concepts of some tumor types. In this review, we discuss the clinicopathologic spectrum of fibroblastic and myofibroblastic lesions of childhood and adolescence.

We present clinicopathologic data on 10 pulmonary myxoid sarcomas, which are defined by distinctive histomorphologic features and characterized by a recurrent fusion gene, that appear to represent a distinct tumor entity at this site. The patients [7 female, 3 male; aged 27 to 67 y (mean, 45 y)] presented with local or systemic symptoms (n=5), symptoms from cerebral metastasis (1), or incidentally (2). Follow-up of 6 patients showed that 1 with brain metastasis died shortly after primary tumor resection, 1 developed a renal metastasis but is alive and well, and 4 are disease free after 1 to 15 years. All tumors involved pulmonary parenchyma, with a predominant endobronchial component in 8 and ranged from 1.5 to 4 cm. Microscopically, they were lobulated and composed of cords of polygonal, spindle, or stellate cells within myxoid stroma, morphologically reminiscent of extraskeletal myxoid chondrosarcoma. Four cases showed no or minimal atypia, 6 showed focal pleomorphism, and 5 had necrosis. Mitotic indices varied, with most tumors not exceeding 5/10 high-power fields. Tumors were immunoreactive for only vimentin and weakly focal for epithelial membrane antigen. Of 9 tumors, 7 were shown to harbor a specific EWSR1-CREB1 fusion by reverse transcription-polymerase chain reaction and direct sequencing, with 7 of 10 showing EWSR1 rearrangement by fluorescence in situ hybridization. This gene fusion has been described previously in 2 histologically and behaviorally different sarcomas: clear cell sarcoma-like tumors of the gastrointestinal tract and angiomatoid fibrous histiocytomas; however, this is a novel finding in tumors with the morphology we describe and that occur in the pulmonary region.

Clear cell sarcoma is a rare translocation-related sarcoma. There have been few studies documenting the response rate and progression-free survival in clear cell sarcoma patients treated with palliative chemotherapy. The prospectively maintained databases of two referral centres were searched to identify clear cell sarcoma patients treated with chemotherapy. Twenty-four patients were treated with palliative first-line chemotherapy with a median age of 30 years at diagnosis. There were 18 men and 6 women. One (4%) achieved a partial response and 9 (38%) had stable disease. Fourteen patients (58%) progressed on therapy. The median progression-free survival was 11 weeks (95% CI, 3–20 weeks). The median overall survival from commencing first-line chemotherapy was 39 weeks (95% CI, 34–45 weeks). Second-line chemotherapy was administered to 12 patients, 11 (92%) of these progressed and one (8%) had stable disease. Of the 5 patients treated with third-line chemotherapy, 4 (80%) progressed and one (20%) had stable disease. One patient received fourth-line chemotherapy and maintained stable disease for 4 months. Conventional chemotherapy has minimal activity in clear cell sarcoma as documented by the response rate of 4% and median progression-free survival of 11 weeks in this retrospective series. These data provide a reference for response and outcome in the assessment of novel agents in this histological subtype.

Primitive round cell neoplasms (small round cell tumors) of soft tissue are a diverse group of malignant tumors composed of monotonous undifferentiated cells with high nuclear-cytoplasmic ratio. Many occur more frequently, although not exclusively, in childhood. As tumors with primitive round cell morphology are seen in virtually every basic tumor category, the diagnosis of small round cell neoplasms requires the use of ancillary diagnostic techniques: immunohistochemistry and often molecular genetics. The principal tumors in this group include Ewing sarcoma/primitive neuroectodermal tumor, desmoplastic small round cell tumor, alveolar rhabdomyosarcoma, poorly differentiated synovial sarcoma, neuroblastoma, and ganglioneuroblastoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Standard systemic treatment options for patients with advanced sarcoma are limited. Depending on the histological subtype, patients receive differing lines of therapy usually consisting of doxorubicin, ifosfamide and/or trabectedin. After progression on conventional therapies, some patients are offered more experimental options including Phase I clinical trials. The aim of this study was to evaluate the clinical benefit for sarcoma patients treated within the Phase I Unit of a single referral centre., Methods: The response, toxicity and outcome of sarcoma patients treated within Phase I clinical trials at the Royal Marsden between August 1998 and December 2010 were analysed., Results: One hundred and thirty-three patients were treated. The median number of prior systemic therapies was 3 (range 0-6). The median age of these patients was 48.0 years (range 12.5-81.9), with a male/female ratio of 71/62. One patient (0.8%) achieved a complete response and 2 (1.6%) partial responses. The non-progression rate at 3 and 6 months was 31.5% (95% CI, 23.4-39.6%) and 11.0% (95% CI 5.6-16.5%), respectively. The median progression-free survival was 2.1 months (95% CI, 1.7-2.5), and median overall survival was 7.6 months (95% CI, 4.8-10.4). Twenty-four (18.0%) patients experienced grade 3 or 4 toxicity, and 16 (12.0%) stopped trial treatment due to toxicity., Conclusion: Phase I clinical trials could be considered a therapeutic option in sarcoma patients with no remaining standard treatment due to the low risk of toxicity and the potential for clinical benefit.

Aims: Glypican-3 (GPC3) is a membrane-bound heparan sulphate proteoglycan. Glypicans are predominantly expressed during development in cell- and tissue-specific manners and act as co-receptors for many heparin-binding growth factors, playing important roles in cell growth and differentiation. GPC3 expression has been linked to several visceral malignancies, but its role in sarcomas is unexplored. Rhabdomyosarcomas (RMS), the most common paediatric soft tissue sarcomas (STS), are aggressive tumours that frequently show histological overlap with other STS. Immunohistochemistry was performed on tissue microarrays to study GPC3 expression in paediatric RMS and a variety of the more common spindle cell and pleomorphic adult sarcomas., Methods: 642 tumour samples encompassing alveolar and embryonal RMS and adult STS (fibrosarcoma, synovial sarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma) were stained with anti- GPC3, and percentage expression in tumour cells was scored on a scale of 0 to +3., Results: GPC3 immunostaining was positive (+1 to +3 expression) in 34.7% (74/213) of RMS samples (15/60 alveolar, 54/143 embryonal, 5 RMS not otherwise specified), but negative or negligible in all other sarcoma samples., Conclusions: This is the first study of GPC3 in a large series of sarcomas, and highlights expression of GPC3 in RMS but not other STS. As glypicans are rarely expressed in mature tissue, GPC3 may be a therapeutic target in RMS, and as the protein can be shed from the cell surface, it may have future application as a biomarker for this disease.

Background: The pattern of distribution of cervical nodal involvement from primary parotid carcinomas has not been extensively described., Methods: All cases of parotid carcinoma over a 10-year period treated at our institution were reviewed. Data from the patients with cervical metastases were analyzed. These findings were pooled with previously published data on topography of cervical lymph nodes from parotid carcinomas., Results: Of 80 cases, 15 had cervical metastases (N+) in our series. When pooled with the data from all other reports, a total of 66 N+ cases were available for analysis. Twenty-eight percent of cases had involvement of level I, 59% had level II, 52% had level III, 38% had level IV, and 41% had level V. There were frequent skip metastases to level V but all were ipsilateral., Conclusion: The diffuse distribution of cervical nodal metastases does not support a high echelon neck dissection or radiotherapy fields limited to the upper chain in the management of cervical nodal disease., (Copyright © 2010 Wiley Periodicals, Inc.)

We studied 5 cases of dedifferentiated liposarcoma with meningothelial-like whorls and metaplastic bone formation, assessing morphology and immunohistochemical expression of a panel of antigens (CDK4, MDM2, and p16 proteins, desmin, smooth muscle actin, h-caldesmon, CD34, AE1/AE3, epithelial membrane antigen, claudin-1, S100 protein, CD21, CD35, CD117, β-catenin, vimentin, and MIB1). The specimens were from the retroperitoneum (3), pelvis (1) or paratesticular region (1), and all 5 specimens comprised exclusively or predominantly dedifferentiated liposarcoma. All 5 dedifferentiated liposarcomas showed prominent metaplastic bone, 3 produced cartilage, and 1 also had osteosarcomatous tissue. The whorls comprised concentric distributions of spindle or epithelioid cells. All cases expressed smooth muscle actin, 3 strongly, whereas 4 cases showed at least focal claudin-1 positivity. In all cases, the whorls expressed at least 2 of CDK4, MDM2, and p16. The presence of 2 morphologic subsets and the immunohistochemical findings suggest that the whorls in these dedifferentiated liposarcomas exhibit divergent myofibroblastic and possibly perineurial differentiation. The CDK4, MDM2, and p16 expression in the whorls suggests that they share a similar genetic background to well-differentiated and dedifferentiated liposarcoma, and that additional genetic events are causal to their distinct morphology.

Epithelioid angiosarcomas are rare aggressive neoplasms that occur most frequently in deep soft tissues. Primary cutaneous lesions are rare, and there are discrepant findings in the literature regarding their behavior. In this study, we report a series of 13 cases of primary cutaneous epithelioid angiosarcoma and analyze their clinicopathologic features. The tumors arising in the conventional settings for cutaneous angiosarcoma (ie, in the head and neck region of elderly patients, and those occurring postradiation or associated with lymphedema) were excluded. Primary cutaneous epithelioid angiosarcoma occurred in adults (mean age, 66 y) with an equal sex distribution, and presented as solitary (n=10) or multiple (n=3) nodules ranging in size from 8 to 80 mm, with a predilection for the limbs (n=10). Histopathologically, the tumors comprised infiltrative sheets of atypical epithelioid cells within the dermis with or without the involvement of the subcutis. Vascular channel formation and intracytoplasmic lumina were seen, at least focally, in most cases. Mitoses were readily identified and necrosis was seen in 40% of the cases. The tumors were immunoreactive for vascular markers, with CD31 and FLI-1 offering the highest sensitivity. Pancytokeratin was positive in two thirds of the cases, and epithelial membrane antigen was positive in one-quarter of the cases. There was rare focal expression of Melan-A (n=2) and smooth muscle actin (n=3). Follow-up information was available for 11 patients. Six patients died of metastatic disease after a median follow-up of 12 months (range, 3 to 36 mo), and 1 patient died of unrelated causes. These findings suggest that primary cutaneous epithelioid angiosarcoma occurring outside the conventional settings of angiosarcoma is a highly aggressive malignant tumor with mortality rates in excess of 55% after 3 years.

Background: Pharyngeal diverticulum or Zenker's diverticulum carcinoma is a rare malignancy with a poor prognosis. Carcinoma arising in a recurrent pharyngeal diverticulum is even rarer, with only 1 such case reported in the English-language literature. We report 2 patients with pharyngeal diverticulum carcinoma exhibiting an unusual presentation and good long-term, disease-free survival with normal speech and swallowing., Methods: A 70-year-old man with a carcinoma in a recurrent pharyngeal diverticulum excised 20 years previously and a 65-year-old man with a neck mass as the only presentation of pharyngeal diverticulum carcinoma., Results: Our patients were treated with open resection, laryngeal preservation, and postoperative radiotherapy (PORT), resulting in long-term tumor control and disease-free survival of 5 and 15 years (longest reported), respectively., Conclusion: One-stage diverticulectomy with or without radiotherapy is the treatment of choice and can provide long-term control and survival., (© 2009 Wiley Periodicals, Inc. Head Neck, 2011.)

Aim: To evaluate the cross-sectional radiological appearances and to review the clinical presentation and outcome of patients with leiomyosarcomas of the inferior vena cava (IVC LMS). These are rare aggressive tumours that present late with non-specific symptoms and have a poor prognosis., Materials and Methods: From January 2002 to December 2008, the radiological images of 23 sequential patients with pathologically proven IVC LMS were independently reviewed by two experienced radiologists. The clinical presentation, treatment including surgical details, and outcome were recorded., Results: There were 19 females and four males with a mean age of 53 years. CT typically demonstrated a large, lobulate, non-calcified heterogeneous mass with peripheral enhancement. T1-weighted magnetic resonance imaging (MRI) images demonstrated a mass with a low signal intensity and T2-weighted MRI images demonstrated a mass with a high signal intensity. Clinical presentation included leg oedema, back and abdominal pain with almost 50% of patients presenting with metastases. Eleven patients underwent ablative surgery. The mean survival time of all patients in the study was 34 months and that of the 11 post-surgical patients was 56 months., Conclusion: There are a variety of diagnostic features on both computed tomography (CT) and MRI which aid the diagnosis of this unusual vascular neoplasm. CT is vital in determining the location of the tumour within the IVC and MRI accurately depicts its extent and the potential for surgical resectability, which offers the only chance of survival., (Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Controversy surrounds the biopsy method of choice for the histological diagnosis of soft tissue sarcoma. The objective of this study was to evaluate the diagnostic accuracy of core needle biopsy (CNB) in patients referred with the suspicion of a soft tissue sarcoma., Methodology: Previously undiagnosed patients (n = 530) with a suspected soft tissue tumour (STT) who underwent CNB at initial presentation were identified. Specific end-points were the ability to differentiate benign from malignant tumours, soft tissue from non-STT, and for sarcomas to define subtype and grade., Results: Of the 530 patients, 426 patients (80.4%) with soft tissue tumours were identified, of which 225 (52.8%) were malignant and 201 (47.2%) benign. In the remaining 104 patients, tumours masquerading as STT were diagnosed. CNB could differentiate soft tissue sarcomas from benign soft tissue tumours with an accuracy of 97.6%. High grade were differentiated from low grade sarcomas with an accuracy of 86.3%. Tumour subtype was accurately assigned in 89.5% of benign tumours and 88.0% of sarcomas., Conclusion: CNB is simple, safe and can accurately diagnose benign and malignant soft tissue tumours. It can reliably identify other tumours masquerading as sarcoma. CNB should be the method of choice to obtain a histological diagnosis in suspected STT., (J. Surg. Oncol. 2010;102:523-529. © 2010 Wiley-Liss, Inc.)

Pleuropulmonary synovial sarcoma is a rare malignancy that often presents like any other thoracic tumor with symptoms such as chest pain or cough. Here we describe 4 young adults who underwent surgery for apparently benign recurrent pneumothoraces and who, unexpectedly, were found upon histologic and molecular examination of the resection specimen to have cystic primary pleuropulmonary synovial sarcoma. These cases highlight (a) the importance of cytogenetic analysis in making the diagnosis, as confusion with other spindle cell sarcomas or cystic neoplasms can occur and (b) the importance of thorough examination of all resected tissue in cases of recurrent pneumothorax.

Purpose: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN)., Experimental Design: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored., Results: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months)., Conclusions: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN., ((c) 2010 AACR.)

Background: Leiomyosarcomas of the urinary bladder (LMS-UB) are rare, usually aggressive neoplasms. Owing to their rarity, only a limited number of cases with clinical follow-up information have been published. There is no current consensus on LMS-UB grading, and it is unknown whether the widely accepted Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) and National Cancer Institute (NCI) grading systems of soft-tissue sarcomas are applicable to LMS-UB., Methods: The authors studied 34 well-characterised LMS-UB and compared the prognostic power of the FNCLCC and NCI systems with that of one published grading scheme for LMS-UB (Mayo). All available slides from 34 LMS-UB were retrieved and evaluated with regards to degree of differentiation, mitotic rate/10 high-powered fields (HPF), and % necrosis. Cases were graded using published criteria for the FNCLCC, NCI and Mayo schemes. Follow-up information was obtained., Results: The tumours occurred in 17 females and 17 males, ranging from 31 to 91 years (median 65), and measured 2-12 cm in size. One tumour was well differentiated, 17 tumours were moderately differentiated, and 16 tumours were poorly differentiated. Mitotic rates ranged from 1 to >30/10 HPF (median 12/10 HPF), and tumours showed 0-60% necrosis (median 25%). FNCLCC grades were 1 (3), 2 (12) and 3 (19). NCI grades were 1 (2), 2 (11) and 3 (21). Mayo grades were low (7) and high (27). FNCLCC and NCI grades were identical in 23/34 cases (68%). Four cases were FNCLCC/NCI grade 2 or 3 and Mayo low-grade. Clinical follow-up was available for 25 of 34 patients (74%). Clinical follow-up of > or =12 months was available for 17 of these 25 cases (68%) with a median follow-up duration of 52 months (range 12-120 months). Adverse outcome was seen in nine of these 17 patients (53%). Seven of the eight cases (88%) with a clinical follow-up duration of <12 months died of their disease. Overall, adverse outcome was documented in 16 of 25 (64%) cases. Metastatic disease was seen in 13 of 25 (52%) cases, with the lungs being the most common site of metastasis (62%). Adverse outcome was noted in 15 of 23 (65%) of FNCLCC grade 2 or 3 LMS-UB, as compared with zero of two (0%) FNCLCC grade 1 tumours (p=0.15), in 15 of 23 (65%) NCI grade 2 or 3 LMS-UB, versus zero of two (0%) NCI grade 1 sarcomas (p=0.17) and in 13 of 20 (65%) Mayo high grade LMS-UB, as opposed to two of five (40%) low-grade lesions (all results not statistically significant)., Conclusions: The authors conclude that LMS-UB occurs in older adults of either sex and is characterised by aggressive behaviour, with adverse outcome in >60% of cases. Certain advantages of the FNCLCC system may support its more widespread adoption for future studies.

Objective: Solitary fibrous tumors are rare soft-tissue tumors of submesothelial origin with variable malignant potential. Most of these tumors originate within the thoracic cavity, but they can occur in a variety of sites, including the abdomen, pelvis, and soft tissues and muscles. The purpose of this study was to review the imaging findings with clinicopathologic correlation in 34 cases., Conclusion: The finding of a large, solid, vascular tumor, particularly with prominent feeding vessels or a visible fatty component, should alert the radiologist to the possible diagnosis of solitary fibrous tumor. Percutaneous biopsy carries minimal risk and should be used for definitive diagnosis of these lesions, which in many cases are curable with surgery. The prognosis is good for patients with benign tumors but variable for those with malignant tumors.

Background: Rhabdomyosarcomas (RMSs) are primarily paediatric sarcomas that resemble developing skeletal muscle. Our aim was to determine the effects of microRNAs (miRNA) that have been implicated in muscle development on the clinical behaviour of RMSs., Methods: Expression levels of miR-1, miR-206, miR-133a and miR-133b were quantified by RT-PCR in 163 primary paediatric RMSs, plus control tissues, and correlated with clinico-pathological features. Correlations with parallel gene expression profiling data for 84 samples were used to identify pathways associated with miR-206. Synthetic miR-206 was transfected into RMS cell lines and phenotypic responses assessed., Results: Muscle-specific miRNAs levels were lower in RMSs compared with skeletal muscle but generally higher than in other normal tissues. Low miR-206 expression correlated with poor overall survival and was an independent predictor of shorter survival in metastatic embryonal and alveolar cases without PAX3/7-FOXO1 fusion genes. Low miR-206 expression also significantly correlated with high SIOP stage and the presence of metastases at diagnosis. High miR-206 expression strongly correlated with genes linked to muscle differentiation and low expression was associated with genes linked to MAPkinase and NFKappaB pathway activation. Increasing miR-206 expression in cell lines inhibited cell growth and migration and induced apoptosis that was associated with myogenic differentiation in some, but not all, cell lines., Conclusion: miR-206 contributes to the clinical behaviour of RMSs and the pleiotropic effects of miR-206 supports therapeutic potential.

Aims: Diagnosis of soft tissue sarcomas can be difficult. It can be aided by detection of specific genetic aberrations in many cases. This study assessed the utility of a molecular genetics/cytogenetics service as part of the routine diagnostic service at the Royal Marsden Hospital., Methods: A retrospective audit was performed over a 15-month period to evaluate the diagnostic usefulness for soft tissue sarcomas with translocations of fluorescence in situ hybridisation (FISH) and reverse-transcriptase PCR (RT-PCR) in paraffin-embedded (PE) material. Results were compared with histology, and evaluated., Results: Molecular investigations were performed on PE material in 158 samples (total 194 RT-PCR and 174 FISH tests), of which 85 were referral cases. Synovial sarcoma, Ewing sarcoma and low-grade fibromyxoid sarcoma were the most commonly tested tumours. Myxoid liposarcoma showed the best histological and molecular concordance, and alveolar rhabdomyosarcoma showed the best agreement between methods. FISH had a higher sensitivity for detecting tumours (73%, compared with 59% for RT-PCR) with a better success rate than RT-PCR, although the latter was specific in identifying the partner gene for each fusion. In particular, referral blocks in which methods of tissue fixation and processing were not certain resulted in higher RT-PCR failure rates., Conclusions: FISH and RT-PCR on PE tissue are practical and effective ancillary tools in the diagnosis of soft tissue sarcomas. They are useful in confirming doubtful histological diagnoses and excluding malignant diagnoses. PCR is less sensitive than FISH, and the use of both techniques is optimal for maximising the detection rate of translocation-positive sarcomas.

Purpose: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses., Experimental Design: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity., Results: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease., Conclusions: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent., (Copyright 2010 AACR.)

Background: Angiosarcomas comprise less than 1% of all sarcomas, arising from endothelial cells of blood or lymph vessels. Chronic immunosuppression increases the risk of many malignancies and an association between the development of angiosarcoma with an immunosuppressed state is established. A few cases have been reported of angiosarcomas arising in the post-renal transplant patient. Specifically, there have been six cases of an angiosarcoma arising in arteriovenous (AV) fistulae in this patient population. We describe a further case and review the relevant literature with specific emphasis on a possible mechanism for the development of angiosarcoma in the post-transplant patient., Case Presentation: We report the case of a 48-year-old male who developed an angiosarcoma in a ligated native AV fistula. The lesion arose on the background of immunosuppression following a successful ABO-incompatible renal transplant for chronic renal failure., Conclusion: Angiosarcomas are extremely rare tumours but should be considered as a differential diagnosis for an evolving mass near the site of an AV fistula. Diagnosis relies on an index of suspicion and obtaining a definitive histological diagnosis. Both clinicians and patients should be aware that an evolving mass within or around an AV fistula should prompt urgent biopsy., ((c) 2010 Wiley-Liss, Inc.)

The role of radiofrequency ablation (RFA) in metastatic sarcoma is not well defined. The aim of this study was to evaluate the efficacy and safety of RFA in a series of sarcoma patients. A retrospective search of a prospectively maintained database identified 13 gastrointestinal stromal tumour (GIST) patients and 12 with other histological subtypes treated with RFA. All the GIST patients received RFA for metastatic disease in the liver: 12 of these responded to the first RFA procedure and one achieved stable disease. Two GIST patients received RFA on two occasions to separate lesions within the liver and both responded to the second RFA procedure. Of the other subtypes: 7 underwent RFA to liver lesions, 5 of these responded to RFA, one progressed and 1 was not assessable for response at the time of analysis. All 5 patients with lung metastases achieved a response following their first RFA procedure. RFA was effective and well tolerated in this series of sarcoma patients. RFA may have a role in patients with GIST who have progression in a single metastasis but stable disease elsewhere. Further larger studies are required to better define the role of this technique in this patient population., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Local recurrence after surgical resection is the main cause of disease-related mortality in patients with primary retroperitoneal sarcoma (RPS). This study analysed predictors of local recurrence and disease-specific survival., Methods: A prospective database was reviewed to identify patients who underwent surgery for primary RPS between 1990 and 2009. Patient demographics, operative outcomes and tumour variables were correlated with local recurrence and disease-specific survival. Multivariable analysis was performed to evaluate predictors for local recurrence and disease-free survival., Results: Macroscopic clearance was achieved in 170 of 200 patients. The median weight of tumours was 4.0 kg and median maximum diameter 27 cm. Resection of adjacent organs was required in 126 patients. The postoperative mortality rate was 3.0 per cent. Seventy-five patients developed local recurrence during follow-up. At 5 years the local recurrence-free survival rate was 54.6 per cent and the disease-specific survival rate 68.6 per cent. Inability to obtain macroscopic clearance at resection and high-grade tumours were significant predictors for local recurrence and disease-specific survival., Conclusion: Complete macroscopic excision should be the goal of surgical resection. Ability to resect a RPS completely and tumour grade are the most important predictors of local recurrence and overall survival., (Copyright 2010 British Journal of Surgery Society Ltd.)

Purpose: To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene., Patients and Methods: The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets., Results: Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome., Conclusion: The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.

Low-grade fibromyxoid sarcoma is a soft tissue sarcoma with recurrent and low metastatic potential, which has characteristic FUS-CREB3L2 or FUS-CREB3L1 fusions. Perineurioma is a peripheral nerve sheath neoplasm, which is usually benign. Low-grade fibromyxoid sarcoma and perineurioma can appear morphologically similar, particularly in small biopsy specimens, and distinction between the 2 entities is important for appropriate treatment. Low-grade fibromyxoid sarcoma is negative for most immunohistochemical markers, whereas perineuriomas stain variably for epithelial membrane antigen, CD34 and claudin-1, a tight-junction associated protein. We studied 15 cases of genetically proven low-grade fibromyxoid sarcoma that at least focally resembled perineurioma, with antibodies to claudin-1 and epithelial membrane antigen. Of these, 11 showed positivity for epithelial membrane antigen and all 15 were positive for claudin-1; in all cases, expression of claudin-1 was equal to or greater than the corresponding epithelial membrane antigen expression. This study emphasizes that claudin-1 is significantly expressed in low-grade fibromyxoid sarcomas. This has implications toward the accurate diagnosis of both tumors, and, as positivity for claudin-1 in low-grade fibromyxoid sarcoma is not previously documented, suggests that there might be underdiagnosis of low-grade fibromyxoid sarcoma. Although positivity for claudin-1 remains useful as an adjunct marker for perineurioma, it should be taken in context with clinical findings, morphology, and the additional immunoprofile.

Sarcomas are a rare, complex group of childhood and adult neoplasms with differentiation towards mesenchymal tissue, which may arise almost anywhere in the body. Although pathologically diverse, they frequently exhibit similar clinical presentations and radiological features. Correct histopathological diagnosis is therefore crucial, but there is overlap between histological patterns of malignant tumours, between benign and malignant lesions, and with non-mesenchymal tumours. Immunohistochemistry and molecular genetic techniques, the latter to detect tumour-specific alterations, add significantly to histological interpretation, but several groups of tumours still lack reliable immunohistochemical markers or reproducible genetic changes. The classification of sarcomas is incomplete and continues to evolve, and although the biology of many remains relatively poorly understood, our increasing insight into molecular events occurring in these tumours is certain to aid future diagnosis and therapy. This paper aims to give a broad overview of several of the main soft tissue sarcomas from a clinicopathological perspective, discussing laboratory diagnosis and the use and limitations of ancillary investigations, including recent developments in molecular diagnosis.

Background: Extra-thoracic solitary fibrous tumours (ESFTs) have traditionally been regarded as indolent neoplasms similar to their intra-thoracic counterparts. However there has been some evidence that a subset of more aggressively malignant tumours exist. We examined our experience with these rare tumours in an effort to clarify their clinico-pathological behaviour and relate this to their histopathological findings., Patients/methods: All patients with a histopathological diagnosis of solitary fibrous tumour (SFT) who presented to the Royal Marsden Hospital between 1998 and 2006 were reviewed. Clinico-pathological data were recorded for all cases and subset analysis performed to compare rates of locoregional recurrence, distant metastases and death., Results: There were 33 cases included in the study. 18 cases had malignant features on histological examination. Locoregional recurrent disease was more common in those with malignant histopathological findings compared to those with benign histopathology (6/18 vs 0/15 p 0.021). Distant metastatic disease was more common in those with malignant histopathological findings (7/18 vs 1/15 p 0.046) and these patients were at increased risk of death (10/18 vs 0/15 p<0.01). The presence of malignant histopathology was the only factor to affect survival with no benign cases dying of disease and malignant cases having a median survival of 59 months (p 0.003)., Conclusion: In our experience ESFTs have a higher rate of malignant behaviour than that classically described. Those tumours with atypical or malignant features on histological examination have poor prognosis and should be managed and followed up in the same manner as other high-grade soft tissue tumours.

Nuclear immunoreactivity for beta-catenin is a useful adjunct for diagnosis of adult desmoid-type fibromatoses, many of which exhibit mutations within the APC/beta-catenin (Wnt) pathway. Pediatric fibromatoses represent a heterogeneous group of lesions that are diagnostically challenging, especially on biopsy. We studied beta-catenin expression in a variety of pediatric fibroblastic and myofibroblastic lesions. Immunohistochemical nuclear expression of beta-catenin was assessed in 100 tumors. High-level expression of beta-catenin was found in 42% of usual-type or deep fibromatoses (21 of 50). Such expression was not seen in any of the other lesions, including fibrous hamartoma of infancy (0 of 18), juvenile hyaline fibromatosis (0 of 7), infantile digital fibromatosis (0 of 6), myofibromatosis (0 of 5), lipofibromatosis (0 of 4), calcifying aponeurotic fibroma (0 of 3), palmar-plantar fibromatosis (0 of 2), fibromatosis colli (0 of 1), or torticollis (0 of 1). High-level beta-catenin staining is seen in deep "adult-type" fibromatoses occurring in children, although to a lesser frequency than in adult fibromatoses. This indicates that a subset of deep fibromatoses in childhood shares similar mechanisms of tumorigenesis with those in adults. beta-catenin is not expressed in other common pediatric fibroblastic and myofibroblastic lesions, and the Wnt pathway does not appear to play a role in their pathogenesis.

A 41-year-old female patient with neurofibromatosis type 1 (NF-1) presented with a breast lump and anaemia related to gastrointestinal bleeding. She was found to have malignant myoepithelioma of the breast and simultaneously multiple gastrointestinal stromal tumours (GISTs) of the small bowel. Molecular studies showed a silent germline mutation in exon 9 of the KIT gene of both tumours. The common gene mutations characteristic of sporadic GISTs were not identified in these tumours, consistent with the literature, suggesting that gene mutations in GISTs are either absent or late events in patients with NF-1.

This report describes a tumour in the ileum with clinical features initially suggestive of a gastrointestinal stromal tumour (GIST). Histopathological examination revealed a biphasic tumour in which the spindle cell component showed immunohistochemical evidence of smooth muscle differentiation but without the characteristic profile of a GIST. A well-differentiated epithelial component was also present, comprising glandular structures with immunohistochemical features suggestive of Mullerian differentiation. Similar glandular differentiation has been described in uterine leiomyomas but not, to our knowledge, in tumours associated with the small bowel. None of the characteristic mutations of GISTs were identified in this case. There were no overt features of malignancy but, because of the unusual nature of the case, we assessed the biological behaviour as uncertain.

Background: Radiation-induced sarcoma (RIS) is a rare late complication of therapeutic irradiation with a reputation for aggressive pathology and poor outcome., Methods: We retrospectively reviewed histopathological features, surgery and outcome in 67 patients with RIS treated between 1990 and 2005 at a single tertiary referral center., Results: Previous breast cancer was the most common indication for radiotherapy. The median interval from irradiation to development of RIS of was 11 years (3-36 years). Median tumour size was 7 cm with 56% classified as high grade, 31% intermediate grade and 13% low grade. The commonest histology was leiomyosarcoma. The only relationship for histology with site was for angiosarcoma (n=9), all of which developed on the chest wall/breast after irradiation for breast cancer. Of 67 patients, 34 underwent potentially curative surgery, and microscopically clear margins were achieved in 75% of cases. Pedicled or free tissue transfer was required in 12 patients and abdominal or chest wall mesh reconstructions were required in 8 patients. No patient received adjuvant radiotherapy but 7 received adjuvant/neoadjuvant chemotherapy. Median follow up is 53 months. Median sarcoma specific survival was 54 months (2- & 5-year survival: 75% & 45%). The local relapse rate was 65%. Negative histopathological margins were a significant predictor of sarcoma specific survival (HR 3.0 95% CI 1.1-8.6 p=0.04). Grade and size of tumour approached, but did not attain significance., Conclusion: RIS is a biologically aggressive tumour with high rates of local relapse despite aggressive attempts at curative surgery.

Ganglioneuromatosis of the gastrointestinal tract is a rare condition that has an established association with the multiple endocrine neoplasia syndrome, type IIb. Its occurrence in neurofibromatosis, in which the large intestine is usually affected, is much rarer. We report a case of diffuse ganglioneuromatosis of the small bowel, found incidentally during surgery for a malignant peripheral nerve sheath tumor arising in the retroperitoneum in a 32-year-old man with neurofibromatosis type 1, and review previously reported cases.

Background. Ewing's sarcoma of extraskeletal origin is uncommon and that is of primary renal origin in adults are rare. There is no consensus on the optimal management of Ewing's tumors of renal origin. Methods. A retrospective review of the clinical features, treatment, and outcome of adult patients with primary renal extra-skeletal Ewing's sarcoma who were treated at the Royal Marsden hospital from January 1993-December 2007 is reported. Results. Seven adult patients with primary renal Ewing's sarcoma were identified. All four patients with nonmetastatic disease had radical nephrectomy and received adjuvant chemotherapy +/- radiotherapy. Two developed metastatic disease while on adjuvant chemotherapy, and one patient relapsed after 55 months. The three patients with metastatic disease at presentation did not have nephrectomy and were treated with chemotherapy. All three patients had disease progression with a dismal outcome. Only one patient in the whole group is alive and disease free. The median overall survival was 62.8 months, and the median disease-free survival in patients with nonmetastatic disease after combined modality treatment was 30.3 months. Conclusion. Primary adult renal Ewing's sarcoma is an aggressive tumor with a propensity for early metastasis. Radical nephrectomy with adjuvant combination chemotherapy produced the best results but the outlook remained poor with only one patient experiencing long disease-free survival.

Aims. A study was performed to determine areas of diagnostic discrepancy in the reporting of cases of soft tissue tumours referred to a specialist sarcoma unit. This was to pinpoint common discrepancies and to determine their causes. Methods and Results. We compared the sarcoma unit's histopathology reports with referring reports on 349 specimens from 277 patients with suspected or proven soft tissue tumours in a one-year period. Conclusions. Diagnostic agreement was found in 256 of 349 cases (73.4%), with minor diagnostic discrepancy in 55 cases (15.7%) and major discrepancy in 38 cases (10.9%). Benign/malignant discordances accounted for only 5% of all discrepancies (5 cases). The most common discrepancies occurred in tumour classification, including diagnosis of gastrointestinal stromal tumour and leiomyosarcoma and the subtyping of spindle cell sarcomas, as well as in tumour grading that could conceivably lead to changes in clinical management. Major diagnostic discrepancies leading to management change occurred in a relatively select range of tumour groups, and almost all discrepancies occurred due to differences in tumour interpretation between general or nonsoft tissue pathologists, and pathologists at the specialist unit. The findings support guidelines by the National Institute for Health and Clinical Excellence that diagnostic review of soft tissue tumours should be performed by specialist soft tissue pathologists.

Biphasic tumors of the seminal vesicle are rare. We report a further case in a 61-year-old man of a seminal vesicle epithelial-stromal tumor with focally atypical epithelial and stromal cells, the latter displaying a smooth muscle immunophenotype. In addition, this was associated with 2 synchronous malignant neoplasms, chromophobe renal cell carcinoma and small lymphocytic lymphoma, both of which were detected incidentally after clinical presentation because of the seminal vesicle mass.

Introduction: Clear cell sarcoma (CCS) is a rare tumour with a propensity for local recurrence and nodal metastasis. About 300 cases have been reported, thus further clarification regarding the course and outcome of the disease is required., Methods: Patients with a histopathologic diagnosis of CCS were identified from prospective histopathology and sarcoma databases and supplemented with a retrospective analysis of the patients' hospital records., Results: Between 1990 and 2005, a total of 72 patients with a diagnosis of CCS were identified, 35 having been referred for management and 37 having been referred for histopathologic opinion. The median age was 39 years (range 5-90 years). Of the 35 patients referred to the Royal Marsden Hospital for management, 23% developed local recurrence or in-transit metastases at a median of 9 months (2-79 months) after resection of the primary, and nodal or distant metastatic disease was seen in 63% after 14 months (range 0-177 months). Five- and 10-year survival were 52% and 25%, respectively., Conclusions: CCS has a number of similarities with melanoma, particularly in its peripheral distribution and propensity for nodal disease. Wide excision with clear margins offers the best chance of cure. Local recurrence and regional metastases are common, and are almost always followed by distant metastases and death.

Background and Aims: To report our experience and review the literature of thyroid cancer obstructing the great veins in the neck, highlighting clinical aspects and response to treatment., Methods: Clinical data were collected from the thyroid cancer register and from follow-up clinic visits of patients referred to the Thyroid Unit at the Royal Marsden Hospital. A Medline literature search was conducted between 1980 and 2007., Results: Of 1448 patients with thyroid cancer on our cancer register and treated in our unit over the last 60 years, we identified five patients, four women and one man, aged 43 - 81 years with a median follow up of 28 (24-78) months in whom tumour had occluded the great veins in the neck. All patients underwent total thyroidectomy and all subsequently received ablative 131I with the exception of patient 3 whose post-operative isotope scan shown no significant 131I uptake. External beam radiotherapy to the neck and upper mediastinum was used for residual disease control in the 5 patients. The median survival was 28 months and the disease-free survival was 24 months. One patient remains asymptomatic but with disease 53 months after initial presentation. Survival in this small series is significantly better than that previously reported for this condition., Conclusion: A multimodality therapeutic approach comprising surgery, radioiodine and external beam radiotherapy may give the best results for patients in whom thyroid cancer is occluding the great veins.

Retrorectal (presacral) dermoid cysts are rare entities, also described as mature cystic or monodermal teratomas. We present a unique case arising in a 64-year-old man, in which the lining squamous epithelium showed marked expansion by Paget disease of extramammary type, and discuss the clinical, radiologic, and pathologic findings.

Angiomatoid fibrous histiocytoma is a neoplasm of intermediate biologic potential most often arising in the extremities of children and young adults. Its rarity may lead to misdiagnosis as either a reactive lesion or a benign or higher-grade tumor. Originally described as a type of malignant fibrous histiocytoma, its differentiation remains enigmatic, with precise histogenesis still only hypothesized. Its morphology is distinct, as a circumscribed lesion with sheets of bland spindle to ovoid cells, peripheral lymphoplasmacytic infiltrate, and blood-filled cystic cavities, and half of the cases show strong desmin expression. Cytogenetically, 2 specific translocations, t(12:16)(q13:p11) and more recently t(12:22)(q13:q12), have been characterized. The literature on angiomatoid fibrous histiocytoma is reviewed, particularly with regard to recent molecular genetic developments and differentiation, and its morphology, immunohistochemistry, and differential diagnosis are summarized.

Toxic megacolon is a rare consequence of infection with Entamoeba histolytica. We present such a patient in whom the course of disease may have been influenced by heavy loperamide use. Loperamide and other anti-motility agents have been implicated previously in the pathogenesis of toxic megacolon in patients with infectious gastroenteritis.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. A granulomatous form of the condition is recognized. Renal involvement is rare. The authors present the first case of CVID with biopsy-proven noncaseating renal granulomas, in association with hypercalcemia. The mechanism of hypercalcemia in granulomatous disorders, and the difficulty of differentiating granulomatous CVID from sarcoidosis, are discussed.

Background: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria., Methods: We assessed incidence of P. falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand. During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P. falciparum malaria., Findings: Early detection and treatment controlled P. falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990). A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94. Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P. falciparum malaria in the study area. In-vitro susceptibility of P. falciparum to mefloquine has improved significantly (p=0.003)., Interpretation: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance. We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.