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Pseudoendocrine sarcoma (PES) is a recently described neoplasm typically arising in paravertebral soft tissues. Histologically, PES resembles well-differentiated neuroendocrine tumors but lacks expression of epithelial/neuroendocrine markers, and most show aberrant nuclear β-catenin positivity. We describe the clinicopathological and molecular features and DNA methylation profile of one PES. A resected paraspinal soft tissue mass in a 52-year-old man showed a neuroendocrine-like neoplasm, negative for keratin, and synaptophysin and showing diffuse nuclear β-catenin expression. Targeted NGS confirmed a CTNNB1 (p.S37C) mutation. Whole genome methylation analysis showed no match to any methylation class in the central nervous system tumor (versions 11b6 and 12b6) or sarcoma classifier (calibrated scores of ≤0.3), but clustered together with a recently reported PES in which methylation analysis was also performed. He remained disease-free for 18 months after surgery, followed by chemoradiation. As more cases are examined, our findings suggest that PES may have a unique methylation profiling signature., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Bone tumours are relatively rare and, as a consequence, treatment in a centre with expertise is required. Current treatment guidelines also recommend review by a specialised pathologist. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of bone sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations., Methods and Results: According to the ICCR's process for dataset development, an international expert panel consisting of pathologists, an oncologic orthopaedic surgeon, a medical oncologist, and a radiologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were bone tumour experts affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, including a synoptic reporting guide, were published on the ICCR website., Conclusion: These first international datasets for bone sarcomas are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve management of bone sarcoma patients., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Angiomyofibroblastoma (AMF), a rare benign vulvovaginal mesenchymal tumour, poses a diagnostic challenge due to histologic and immunohistochemical overlap with other vulvar mesenchymal tumours. Recently, MTG1-CYP2E1 fusion transcripts were reported in 5/5 AMFs; no other genetic alterations have been described to date. Herein, we sought to investigate the frequency of the MTG1-CYP2E1 fusion and the presence of other potential genetic alterations in a cohort of AMFs (n = 7, patient age range: 28-49 years). Tumours demonstrated classic morphologic features including alternating hypo/hypercellular areas, capillary channels surrounded by epithelioid/spindled tumour cells, and variable amounts of mature adipose tissue. reverse transcription-polymerase chain reaction (RT-PCR) for MTG1-CYP2E1 fusion, performed in all seven cases, showed the fusion transcript in five of six cases (one case with technical failure). Two tumours, including the one lacking the fusion, were subjected to targeted next-generation sequencing (104 genes) and a sarcoma fusion assay (28 genes); the fusion negative AMF also underwent RNA sequencing. No additional mutations, copy number alterations, or fusion genes were identified with the assays employed. We conclude that the majority of AMFs harbour recurrent MTG1-CYP2E1 fusion transcripts and identification of this fusion may aid in the diagnosis., (© 2022 John Wiley & Sons Ltd.)

Background: Local recurrence of microinvasive sarcoma or benign aggressive pathologies can be limb- and life-threatening. Although frozen pathology is reliable, tumor microinvasion can be subtle or missed, having an impact on surgical margins and postoperative radiation planning. The authors' service has begun to temporize the tumor bed after primary tumor excision with a wound vacuum-assisted closure (VAC) pending formal margin analysis, with coverage performed in the setting of final negative margins., Methods: This retrospective analysis included all patients managed at a tertiary referral cancer center with VAC temporization after soft tissue sarcoma or benign aggressive tumor excision from 1 January 2000 to 1 January 2019 and at least 2 years of oncologic follow-up evaluation. The primary outcome was local recurrence. The secondary outcomes were distant recurrence, unplanned return to the operating room for wound/infectious indications, thromboembolic events, and tumor-related deaths., Results: For 62 patients, VAC temporization was performed. The mean age of the patients was 62.2 ± 22.3 years (median 66.5 years; 95% confidence interval [CI] 61.7-72.5 years), and the mean age-adjusted Charlson Comorbidity Index was 5.3 ± 1.9. The most common tumor histology was myxofibrosarcoma (51.6%, 32/62). The mean volume was 124.8 ± 324.1 cm 3 , and 35.5% (22/62) of the cases were subfascial. Local recurrences occurred for 8.1% (5/62) of the patients. Three of these five patients had planned positive margins, and 17.7% (11/62) of the patients had an unplanned return to the operating room. No demographic or tumor factors were associated with unplanned surgery., Conclusions: The findings showed that VAC-temporized management of microinvasive sarcoma and benign aggressive pathologies yields favorable local recurrence and unplanned operating room rates suggestive of oncologic and technical safety. These findings will need validation in a future randomized controlled trial., (© 2021. Society of Surgical Oncology.)

Background: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking., Methods: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes., Results: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance., Conclusion: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors., Implications for Practice: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Introduction: The aim of this study was to describe patient characteristics, treatment, and oncologic outcomes of soft-tissue sarcomas (STSs) of the hand., Methods: Sixty-nine STSs of the hand in adult patients treated at a tertiary referral center were retrospectively included. We describe patient and tumor characteristics along with oncologic outcomes., Results: Epithelioid sarcoma (23%) was the most common histologic subtype, followed by synovial sarcoma (15%). Of all tumors, 17 (25%) were grade I, 22 (32%) were grade II, and 30 (44%) were grade III. The 5-year disease-free survival for epithelioid sarcomas was 75% with a disease survival of 100%, along with a metastatic rate of 15%. Of the patients with a synovial sarcoma, 40% developed metastases, and the 5-year disease-free survival was 68% and the 5-year disease survival was 73%., Conclusion: Hand STSs are aggressive tumors with a high metastatic potential. Even with adequate oncologic treatment, long-term clinical follow-up (10 years) in these tumors is advised. The treating surgical oncologist should not be deceived by their smaller size., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.

The entity "pericytoma with t(7;12)" was described as a rare, distinct perivascular myoid neoplasm provisionally classified within the family of myopericytic tumors that demonstrates t(7;12)(p22;q13) translocation with resultant ACTB-GLI1 fusion and biologically was felt to behave in an indolent fashion. However, a recent study showed that tumors with this and similar translocations may have variable morphology and immunohistochemical phenotype with inconsistent myopericytic characteristics and a propensity for metastasis, raising questions regarding the most appropriate classification of these neoplasms. Herein, we report 3 additional patients with tumors harboring t(7;12) and ACTB-GLI1 fusion. The tumors arose in adults and involved the proximal tibia and adjacent soft tissues, scapula and adjacent soft tissues, and ovary. All tumors were composed of round-to-ovoid cells with a richly vascularized stroma with many small, delicate, branching blood vessels, where the neoplastic cells were frequently arranged in a perivascular distribution. Both tumors involving bone showed histologic features of malignancy. By immunohistochemistry, all tested tumors were at least focally positive for smooth muscle actin (3/3) and CD99 (patchy) (2/2), with variable staining for muscle-specific actin (2/3), S100 protein (1/3), epithelial membrane antigen (2/3), and pan-keratin (1/3); all were negative for desmin and WT1 (0/3). The 2 patients with bone tumors developed metastases (27 and 84 mo after diagnosis). Whether these tumors are best classified as malignant myopericytoma variants or an emerging translocation-associated sarcoma of uncertain differentiation remains to be fully clarified; however, our study further documents the potential for these tumors to behave in an aggressive fashion, sometimes over a prolonged clinical course.

Conventional well-differentiated, dedifferentiated, and myxoid liposarcomas have long been known to harbor numerous typical genetic alterations that allow for diagnosis of these tumors. These include MDM2 and CDK4 amplification in well-differentiated and dedifferentiated liposarcomas as well as FUS-DDIT3 rearrangements in myxoid liposarcoma. More recently, in-frame TRIO-TERT fusion genes have been described in a subset of non-translocation-related sarcomas including myxofibrosarcoma, dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, pleomorphic rhabdomyosarcoma, and leiomyosarcoma. These genetic rearrangements lead to TERT mRNA expression levels hundreds of times higher than normal, causing increased telomerase activation in these tumors. Herein, we describe an unusual case of a liposarcoma with spindle cell features and a TRIO-TERT fusion transcript identified through next-generation sequencing.

The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and response to therapy. We present herein 4 new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these 4 patients. We also reviewed the literature describing similar cases. All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in 3 cases, and FUS-NFATc2 fusion in one case. Two patients were treated with neoadjuvant chemotherapy using Ewing sarcoma regimens, and surgical excision was performed on 3 patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months, one patient developed local recurrence and metastases to the lungs. Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The evolving classification of round cell sarcomas is driven by molecular alterations. EWSR1-PATZ1 fusion positive spindle and round cell sarcoma is one such new tumor entity. Herein, we report 2 EWSR1-PATZ1 fusion positive spindle and round cell sarcomas with overlapping histologic features and polyphenotypic differentiation. The intra-abdominal tumors affected female patients, 31-and 53-year old. Both tumors showed sheets and nests of round to spindle cells, fine chromatin, tiny conspicuous nucleoli, moderate cytoplasm, and thick bands of intratumoral fibrosis. On immunohistochemistry, both tumors showed positivity for CD99, desmin, myogenin, MyoD1, S100, Sox10, CD34, and GFAP and were negative for keratin. Fluorescence in situ hybridization revealed rearrangement at EWSR1 locus. Next-generation sequencing-based RNA fusion assay revealed EWSR1-PATZ1 fusion in both cases. EWSR1-PATZ1 fusion positive spindle and round cell sarcomas show abundant intratumoral fibrosis and polyphenotypic differentiation, thus mimicking a range of tumors including desmoplastic small round cell tumor. The precise classification of this spindle and round cell sarcoma and its relationship to the Ewing sarcoma family of tumors remains to be determined.

Background and Objectives: It is unclear whether the quantitative width of the surgical margin influences outcomes in patients with extremity and truncal soft tissue sarcoma (STS) treated with radiotherapy (RT)., Methods: We performed a retrospective review of 382 patients with localized extremity or truncal STS who underwent limb-sparing surgery and RT from 1983 to 2010, and we analyzed the significance of resection margin status and quantitative margin width on outcomes., Results: Surgical margins were positive in 68 (18%) patients and negative in 314 (82%) patients. For those patients with a reported quantitative margin width (n = 235), the width of the negative margin was ≤1 mm (n = 128), >1 mm and ≤5 mm (n = 79), and >5 mm (n = 28). At a median follow-up of 82 months, the local recurrence rates were 5.4% and 11.8% for margin-negative and margin-positive patients, respectively. There were no differences in the rates of local or distant recurrence nor of any survival outcome based on the quantitative width of the surgical margin, provided that it was negative., Conclusions: In patients undergoing RT and limb-sparing surgery for STS, achieving a negative margin is essential for optimizing both local control and survival. However, the absolute quantitative width of the negative margin does not significantly influence outcome, and so attempts at wide margins of resection appear to be unnecessary. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their STS, in which case wider margins of resection may be necessary., Implications for Practice: In patients undergoing radiation therapy and limb-sparing surgery for soft tissue sarcoma, the quantitative width of the negative margin does not influence outcome, and so attempts at wide margins of resection appear to be unnecessary, especially when such attempts compromise the functional outcome. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their soft tissue sarcoma, in which case wider margins of resection may be necessary., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Aims: To assess the clinical and histopathological spectrum of primary intra-articular sarcomas., Methods and Results: Fifteen patients were identified as having primary intra-articular sarcomas and the clinical and pathological features were evaluated. There were nine males and six females who ranged in age from 16 to 84 (mean 44) years. All tumours originated in the knee joint. The pathological diagnoses included: five synovial sarcoma, three extraskeletal myxoid chondrosarcomas, two high-grade myxofibrosarcoma (one conventional, one epithelioid), two undifferentiated pleomorphic sarcoma (one with giant cells) and one each myxoinflammatory fibroblastic sarcoma, conventional hyaline chondrosarcoma, and high-grade myofibroblastic sarcoma. All tumours were treated by segmental resection or amputation. Adjuvant therapy was given in selected cases. Follow-up ranged from 11 to 150 months. Of patients with follow-up, two died of disease; one developed pulmonary metastases after 6 years and was then lost to follow-up. Nine patients were alive and free of disease 12-150 months after diagnosis., Conclusions: Primary sarcomas of the joints are very rare and most frequently affect the knee. Our experience indicates that synovial sarcoma and extraskeletal myxoid chondrosarcoma are the most common intra-articular sarcomas., (© 2016 John Wiley & Sons Ltd.)

Loss of expression of the SMARCB1 (INI1/BAF47/SNF5) tumor-suppressor protein, originally identified in pediatric malignant rhabdoid tumors, has been noted in significant percentages of epithelioid sarcomas of classical and proximal-type and in myoepithelial carcinomas. Epithelioid sarcoma and myoepithelial carcinoma are very rare in the vulvar region, and few of these cases have been evaluated for SMARCB1 protein loss by immunohistochemistry (IHC) or for SMARCB1 gene alterations by molecular genetic techniques. We studied the clinicopathologic, IHC, and molecular genetic features of 14 SMARCB1-deficient vulvar neoplasms. All available routinely stained sections were reexamined, and IHC analysis for wide-spectrum cytokeratins, high-molecular weight cytokeratins, epithelial membrane antigen, S100 protein, CD34, smooth muscle actin, desmin, and SMARCB1 was performed. Multiplex ligation-dependent probe amplification and DNA sequencing of the SMARCB1 gene was performed on 12 cases with sufficient available tissue. The 14 vulvar tumors occurred in adult women (mean age 46 y, range 22 to 62 y) and measured 1.1 to 8.8 cm in size (mean 4.7 cm). Tumors were classified as classical-type epithelioid sarcoma (N=1), proximal-type epithelioid sarcoma (N=6), myoepithelial carcinoma (N=4), and "SMARCB1-deficient vulvar sarcoma, not otherwise specified" (N=3) on the basis of combined histopathologic and IHC findings. One myoepithelial carcinoma showed divergent rhabdomyoblastic differentiation. All tested cases showed partial or complete SMARCB1 deletions (homozygous: 9 cases; heterozygous: 3 cases). One case with a heterozygous deletion also showed a c.528delC mutation in exon 5. Fluorescence in situ hybridization for EWSR1 rearrangement was performed for 3 cases classified as myoepithelial carcinoma and was negative. Follow-up (13 patients, range 5 to 72 mo, mean 31 mo) data showed 3 patients dead of disease, 1 alive with unresectable metastatic disease, 1 alive with radiographic evidence of extensive lymph nodal disease, and 8 alive without disease. We conclude that SMARCB1-deficient vulvar neoplasms chiefly comprise epithelioid sarcoma and myoepithelial carcinoma, although some defy easy classification. No association was seen between clinical behavior and the type of SMARCB1 alteration.

Sclerosing epithelioid fibrosarcoma is a rare soft tissue tumor that is composed of epithelioid fibroblasts embedded in an abundant extracellular collagenous matrix. They have been shown to be weakly epithelial membrane antigen (EMA) positive by immunohistochemistry and may contain intercellular junctions ultrastructurally. We present a case of a 52-year-old female who presented with a sclerosing Muc-4-positive sarcoma with glandular differentiation of the sciatic nerve, resembling sclerosing epithelioid fibrosarcoma. The glandular component showed strong expression of keratin and EMA and ultrastructurally showed numerous intercellular junctions and intraluminal microvilli, supportive of true glandular differentiation. The patient received preoperative radiotherapy (50 Gray) and subsequent resection of the mass with negative margins. She is currently disease free at 20-month follow-up. This case report describes an unusual sclerosing Muc-4-positive sarcoma with glandular differentiation, distinctive expression of epithelial immunohistochemical markers, and glandular differentiation by electron microscopy., (© The Author(s) 2014.)

Background: Fine-needle aspiration biopsy of spindled mesenchymal lesions, including schwannomas, are challenging because of overlapping cytomorphological features. The objective of the current study was to identify key diagnostic cytological criteria for the diagnosis of schwannoma and to distinguish it from its common mimics., Methods: A total of 58 schwannomas were evaluated and compared with 98 benign and low-grade spindle cell lesions, including 17 gastrointestinal stromal tumors and 20 fibromatosis cases. Biopsy confirmation was available for all cases. The authors semiquantitatively evaluated cellularity, quality of stroma (fibrous and fibrillar), the presence of single cells with bipolar cytoplasmic processes, and marked nuclear pleomorphism (in the absence of other features of malignancy). Nuclear features evaluated included fishhook-type nuclei, intranuclear inclusions, chromatin pattern, and nucleoli., Results: Schwannomas demonstrated cohesive tissue fragments with fibrillary and occasionally fibrous stroma. The presence of intranuclear inclusions and marked nuclear pleomorphism and the absence of single cells with bipolar cytoplasmic processes emerged as statistically significant differences between the schwannoma and the nonschwannoma groups. When 5 criteria were present (high numbers of clusters, few to no single cells, fibrillary stroma, nuclei with pointed tips, and anisonucleosis) the sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of schwannoma were 22%, 97%, 81%, and 68%, respectively., Conclusions: Cohesive tissue fragments with fibrillary/fibrous stroma, intranuclear inclusions, marked nuclear pleomorphism, and the absence of spindled cells with bipolar cytoplasmic processes are strongly suggestive of schwannoma and assist in excluding potential mimics., (© 2015 American Cancer Society.)

Background: Histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS., Methods: Between 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome., Results: The median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving ≥95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [P = .002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with ≥95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology., Conclusions: In a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome., (© 2014 American Cancer Society.)

Background: Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance., Methods: Prospective Phase II clinical trial incorporating high dose RT. Eligible patients had primary or locally recurrent thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas. Treatment included pre- and/or post-operative photon/proton RT ± radical resection., Results: Fifty patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). RT dose was ≤72.0 GyRBE in 25 patients and 76.6-77.4 GyRBE in 25 patients. With 7.3-year median follow-up, the 5 and 8-year actuarial local control (LC) rates were 94% and 85% for primary tumors and 81% and 74% for the entire group. Local recurrence was less common for primary tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, P = 0.002. The 8-year actuarial risk of grade 3-4 late RT morbidity was 13%. No myelopathies were seen. No late neurologic toxicities noted with radiation doses ≤72.0 GyRBE while three sacral neuropathies appeared after doses of 76.6-77.4 GyRBE., Conclusions: LC with this treatment is high in patients with primary tumors. Late morbidity appears to be acceptable., (© 2014 Wiley Periodicals, Inc.)

Patients with pleomorphic soft tissue sarcomas with myogenic differentiation (MD) are thought to have a worse prognosis than those without MD. In this study, we sought to determine the prognostic significance of MD in a restricted cohort of patients with high-grade undifferentiated pleomorphic sarcoma (UPS) of the extremities or trunk that were uniformly treated at a single institution. Thirty-eight patients met the inclusion criteria: (1) extremity or truncal soft tissue UPS, (2) histologic high grade, (3) size of 8 cm or more, (4) received protocol treatment. Immunohistochemical stains were performed on each tumor for 3 muscle markers: muscle-specific actin, smooth muscle actin, and desmin. A tumor was classified as having MD if it showed positive staining for at least 1 muscle marker. We correlated the line of differentiation with outcome using χ(2) and Kaplan-Meier analysis. MD was identified in 15 tumors and non-MD in 23 tumors. There were no significant differences between the myogenic and nonmyogenic groups in terms of age, sex, tumor size, tumor grade, or follow-up. The overall survival (OS) and disease-specific survival (DSS) were both 86.7% for patients with myogenic sarcomas. The OS and DSS were both 91.3% for those with nonmyogenic sarcomas. There was no significant difference between groups for OS or DSS in χ(2) testing (P = .649) or on Kaplan-Meier curve/log-rank testing (P = .541). In this homogenous group of patients with large, high-grade, extremity or truncal UPS who received neoadjuvant chemoradiotherapy, MD did not predict a worse survival than non-MD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen., Methods: We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed., Results: Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS., Conclusions: For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response., Methods and Materials: Patients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans., Results: The 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence., Conclusions: The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Despite their shared predilection for superficial soft tissue of distal extremities and frequent local recurrences, myxoinflammatory fibroblastic sarcoma (MIFS) and hemosiderotic fibrolipomatous tumor (HFLT) have distinct morphologic appearances. Recent studies have identified an identical t(1;10)(p22;q24) in five cases of MIFS and two of HFLT, as well as common amplifications on 3p11-12. To investigate further their potential relationship and to determine the incidence of t(1;10) in a larger cohort, we subjected seven MIFS, 14 HFLT, and three cases with mixed morphology, to molecular and cytogenetic analysis. Fluorescence in situ hybridization (FISH) analysis for rearrangements of TGFBR3 on 1p22 and of MGEA5 on 10q24 was performed in all cases, whereas the status of VGLL3 gene amplification on 3p12.1 was investigated in 12 cases. Conventional karyotyping was performed in one HFLT and two cases with mixed MIFS/HFLT histology. Overall 83% of cases showed rearrangements in both TGFBR3 and MGEA5. All three cases with mixed features of MIFS and HFLT were positive. Cytogenetic analysis performed in three cases confirmed an unbalanced der(10)t(1;10)(p22;q24). VGLL3 gene amplification was noted in 10/12 cases of both histologies. The high incidence of t(1;10) in MIFS and HFLT reinforces a shared pathogenetic relationship. Furthermore, the co-existence of both components either synchronously or metachronously in a primary or subsequent recurrence, suggest either different morphologic variants or different levels of tumor progression of a single biologic entity. FISH analysis for TGFBR3 and MGEA5 rearrangements can be applied as a reliable diagnostic molecular test when confronted with limited material or a challenging diagnosis., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design., Methods and Materials: We analyzed the 56 patients who underwent computed tomography-planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post-gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, and >or=95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 50.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins)., Results: Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LF) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin<1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients., Conclusions: These target volume definitions appear to be appropriate for most patients. No local recurrences were observed with surgical margins >or=1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy., ((c) 2010 Elsevier Inc. All rights reserved.)

Epithelioid sarcoma is an uncommon malignancy that usually arises in the superficial soft tissues of the extremities. Classically, epithelioid sarcoma grows as nodules of mild to moderately atypical epithelioid cells, frequently with central necrosis. The stroma is variably fibrous and may rarely contain heterotopic bone. The presence of bone within epithelioid sarcoma raises a variety of lesions in the differential diagnosis, including reactive processes as well as benign and malignant neoplasms.This morphological variant of epithelioid sarcoma and its associated diagnostic pitfalls has received little attention in the literature. The authors report herein 4 cases of epithelioid sarcoma with heterotopic bone and highlight the morphological characteristics of the bone and how such variants can be distinguished from other bone-forming lesions of the soft tissues.

Background: We sought to reduce local recurrence for retroperitoneal sarcomas by using a coordinated strategy of advanced radiation techniques and aggressive en-bloc surgical resection., Methods: Proton-beam radiation therapy (PBRT) and/or intensity-modulated radiation therapy (IMRT) were delivered to improve tumor target coverage and spare selected adjacent organs. Surgical resection of tumor and adjacent organs was performed to obtain a disease-free anterior margin. Intraoperative electron radiation therapy (IOERT) was delivered to any close posterior margin., Results: Twenty patients had primary tumors and eight had recurrent tumors. Tumors were large (median size 9.75 cm), primarily liposarcomas and leiomyosarcomas (71%), and were mostly of intermediate or high grade (81%). PBRT and/or IMRT were delivered to all patients, preferably preoperatively (75%), to a median dose of 50 Gy. Surgical resection included up to five adjacent organs, most commonly the colon (n = 7) and kidney (n = 7). Margins were positive for disease, usually posteriorly, in 15 patients (54%). IOERT was delivered to the posterior margin in 12 patients (43%) to a median dose of 11 Gy. Surgical complications occurred in eight patients (28.6%), and radiation-related complications occurred in four patients (14%). After a median follow-up of 33 months, only two patients (10%) with primary disease experienced local recurrence, while three patients (37.5%) with recurrent disease experienced local recurrence., Conclusions: Aggressive resection of retroperitoneal sarcomas can achieve a disease-negative anterior margin. PBRT and/or IMRT with IOERT may possibly deliver sufficient radiation dose to the posterior margin to control microscopic residual disease. This strategy may minimize radiation-related morbidity and reduce local recurrence, especially in patients with primary disease.

Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS)., Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed., Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis., Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >or=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas., Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque., Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE., Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

Background: Soft tissue sarcomas generally have a

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

Purpose: Positive margins (PM) remain after surgery in some soft-tissue sarcoma (STS) patients. We investigated the efficacy of radiation therapy (RT) in STS patients with PM., Methods and Materials: A retrospective chart review was performed on 154 patients with STS at various anatomic sites with PM, defined as tumor on ink, who underwent RT with curative intent between 1970 and 2001. Local control (LC), disease-free survival (DFS), and overall survival (OS) rates were evaluated by univariate (log-rank) and multivariate analysis of prognostic and treatment factors., Results: At 5 years, actuarial LC, DFS, and OS rates were: 76%, 46.7%, and 65.2%, respectively. LC was highest with extremity lesions (p < 0.01), radiation dose >64 Gy (p < 0.05), microscopically (vs. grossly visible) positive margin (p = 0.03), and superficial lesions (p = 0.05). Patients receiving >64 Gy had higher 5-year LC, DFS, and OS rates of 85%, 52.1%, and 67.8% vs. 66.1%, 41.8%, and 62.9% if < or =64 Gy, p < 0.04. OS was worse in patients with G2/G3 tumors with local failure (LF), p < 0.001. Other known prognostic factors, including grade, stage, size, and age (>50), also significantly influenced OS. By multivariate analysis, the best predictors of LC were site (extremity vs. other), p < 0.01 and dose (>64 vs. < or =64 Gy), p < 0.05; the best predictors for OS were size, p < 0.001, gross vs. microscopic PM, p < 0.05, and LF, p < 0.01., Conclusion: Local control is achieved in most PM STS patients undergoing RT. Doses >64 Gy, superficial location, and extremity site are associated with improved LC. OS is worse in patients with tumors with lesions >5 cm, grossly positive margins, and after local failure.

A case study of a 62-year-old female with swelling of the left knee and pain, is presented. It mentions the case demonstrated the presence of primary extra-axial, para-articular chordoma of the knee. it also mentions extraskeletal myxoid chondrosarcoma in the patient demonstrated a cord-like growth pattern and is embedded in abundant extracellular myxoid matrix.

Cites a study conducted by researchers in the U.S. which found that Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET) is an aggressive neoplasm of bone and soft tissue. Characterization of the tissue by the presence of small round blue cells; Feature for diagnosis is molecular evidence of variants; Analysis of the ultrastructural features of well-documented EWS/PNETS that stained for pankeratin by immunohistochemistry.