Soft Tissue Sarcoma In Children Research Articles

Secondary malignant neoplasms after bone and soft tissue sarcomas in children, adolescents, and young adults.

Increased survival in young sarcoma patients comes along with a higher incidence of second malignant neoplasms (SMNs). The incidence, latency, histiotype, and outcome of these patients were analyzed because this information is essential to design evidence-based long-term follow-up care programs for young sarcoma survivors. Patients entered on clinical trials or registered in registries with a primary sarcoma in 1 of the cooperative sarcoma study groups in the framework of the Society for Pediatric Oncology and Hematology (GPOH) were screened for SMNs. Descriptive analysis, the Kaplan-Meier method, the Gray model, the Fine-Gray model, and the Cox regression model were used for the statistical analyses. A total of 159 out of 7079 (2.2%) patients were registered with a SMN. Among them, 104 solid SMNs (65%) and 56 hematologic SMNs (35%) occurred. Median latency from first diagnosis of sarcoma to the diagnosis of SMN was 6.8 years (range, 0-26.7 years). Cumulative incidence of SMN was 8.8% after 30 years. Five-year-survival was 67.1% (95% confidence interval [CI], 66.0-68.2) for the 7079 patients and it was 45.1% (95% CI, 36.2-53.6) after the diagnosis of a SMN (subcohort of n = 159 patients). There is a remarkable high cumulative incidence of SMNs after bone and soft tissue sarcomas in children, adolescents, and young adults. Therefore, effective transition as well as risk adapted long-term follow-up care programs should be developed and offered to young sarcoma survivors. Bone sarcomas and soft tissue tumors are rare tumors in children, adolescents, and young adults. The treatment varies, but may comprise chemotherapy, surgery, and/or radiotherapy. Developing a subsequent malignant tumor is a long-term risk for the patients. To better characterize this risk, we analyzed the data of 7079 patients (up to 21 years old) with bone sarcomas or soft tissue tumors. Our findings provide a basis to counsel young sarcoma survivors on their individual risk of subsequent malignant tumors. Moreover, these data can help to establish recommendations for aftercare in young sarcoma survivors.

Down-Regulated miR-130a/b Attenuates Rhabdomyosarcoma Proliferation via PPARG.

Background: Rhabdomyosarcoma (RMS) is one of the most common types of soft-tissue sarcomas in children, and it exhibits a low 5-years survival rate. The survival outcome has shown no significant improvements in the past 30 years miRNA profiling of RMS might therefore provide a novel insight into uncovering new molecular targets for therapy. Methods: We analyzed miRNA and RNA sequencing data from patients and the TARGET database to reveal the potential miRNA-mRNA axes and validated them in patients’ samples. After the miRNA antagomirs were used to silence the target miRNAs in the cell model, qRT-PCR, western immunoblotting analysis, and proliferation assays were performed to explore the interaction between miR-130a/b and peroxisome proliferator-activated receptor gamma (PPARG) and their effects. Results: In RMS patients, the expression of miR-130a/b was augmented, and its related PPARG gene was suppressed. Bioinformatics analysis showed that miR-130a/b targeted the PPARG gene and inhibited the proliferation of human RMS cell lines. In addition, rosiglitazone maleate activated the expression of PPARG in human RMS cell lines to suppress proliferation. Conclusion: miR-130a/b regulates the malignant process in RMS by targeting PPARG. Furthermore, the PPARG agonist rosiglitazone maleate attenuated the proliferation of RD cells and might therefore be of benefit to RMS patients.

K-Ras and p53 mouse model with molecular characteristics of human rhabdomyosarcoma and translational applications.

ABSTRACTRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS. The anatomic sites of primary RMS development recapitulated human disease, including tumors in the head, neck, extremities and abdomen. We confirmed RMS histology and diagnosis through Hematoxylin and Eosin staining, and positive immunohistochemical staining for desmin, myogenin, and phosphotungstic acid–Hematoxylin. Cell lines from GEMM tumors were established with the ability to engraft in immunocompetent mice with comparable histological and staining features as the primary tumors. Tail vein injection of cell lines had high metastatic potential to the lungs. Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Finally, pre-clinical use of these murine RMS lines showed similar therapeutic responsiveness to chemotherapy and targeted therapies as human RMS cell lines.

Anaplasia in childhood rhabdomyosarcoma: An under reported entity.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Anaplasia is a rare phenomenon seen in childhood RMS. The most common histologic subtype was Embryonal followed by Alveolar and spindle subtype. A total of 11 cases of pediatric RMS were selected from January 2017 to June 2019 presenting at various sites. Out of 11 cases, 2 were further diagnosed as Embryonal, 2 as Alveolar, 2 as Pleomorphic, 1 as Spindle subtype and rest 4 as RMS-NOS based on morphology. All cases were positive for Desmin. The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the tumor cell (anaplastic cells) was selected as the main criterion to diagnose Anaplasia. Out of the total 11 cases, anaplasia was seen in 7 cases. Out of these seven, five cases showed Focal Anaplasia (FA) (71.4%) and 2 cases showed Diffuse Anaplasia (DA) (28.6%). Out of 2 cases of Embryonal RMS one exhibited focal anaplasia (50%). One case of Spindle RMS showed diffuse anaplasia, 2 cases of pleomorphic RMS showed focal anaplasia. Out of 3 cases of RMS- NOS, 2 exhibited focal anaplaisa and one displayed Diffuse anaplasia. Both Alveolar RMS had no features of anaplasia. Presence of Anaplasia is a frequent observation in pediatric RMS. Anaplasia is often under reported in pediatric RMS. Pathologist should be more aware of this rare phenomenon.

Five-Year Follow-up After Multimodal Treatment Incorporating HDR Brachytherapy for Bladder Prostate Rhabdomyosarcoma in Children

Five-Year Follow-up After Multimodal Treatment Incorporating HDR Brachytherapy for Bladder Prostate Rhabdomyosarcoma in Children

An Integrative Morphologic and Molecular Approach for Diagnosis and Subclassification of Rhabdomyosarcoma.

Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features. To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma. Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience. Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice.

Giant Orbital Rhabdomyosarcoma in a Newborn: Case Report

Rhabdomyosarcoma is the single most common type of soft tissue sarcoma in childhood and teenage, it has been reported from birth to the seventh decade, with the majority of cases presenting in early childhood but it is very rare in neonates. The orbit including the eyelids is the usual primary site in the head and neck, and it is a highly malignant tumor. There have been only a few cases of congenital orbital rhabdomyosarcoma previously reported in the literature. We report a case of a newborn girl that was admitted in our structure 2 days after her birth with giant right orbital mass inducing proptosis that was discovered at birth. MRI showed a poorly defined mass but biopsy of the tumor confirmed the diagnosis of Rhabdomyosarcoma. Chemotherapy was started accordingly with VAC regimen with a good evolution under treatment infortunatly the patient died at four month old from an infectious disease because she doen’t receive any vaccination. Congenital RMS has a poor prognosis and must benefit from a multidisciplinary approach. Children with cancer need to be immunized against the common vaccine-preventable diseases sometimes during ongoing chemotherapy to increase their chance of survival. Prenatal diagnosis may also improve the prognosis of these patients.

Temporal Bone Rhabdomyosarcoma Mimicking Chronic Suppurative Otitis Media

Rhabdomyosarcoma (RMS) is one of the most commonly encountered soft-tissue sarcomas in childhood. The most common location is in the head-and-neck region, followed by the urogenital system, extremities, and torso. Head and neck is a common site though the temporal bone is an extremely rare site with only a few reported cases in the literature till now. Herein, we report a case of a sclerosing type of temporal bone RMS in an 8-year-old young girl. We discuss clinical, pathological, radiological findings and management of temporal bone RMS. Misdiagnosis is common because of this aggressive temporal bone lesion's similarity to more common benign diseases. Clinicians should maintain suspicion for RMS in patients with chronic otitis media not responsive to medical therapy and should refer a specialist multidisciplinary team in a timely manner as an early diagnosis will optimize the chance of survival. Clinical features, radiologic findings, and histopathological examination using immunohistochemistry are all important for the correct diagnosis of temporal bone RMS. It is important to be aware of and to know how to deal with such rare cases.

Evolving classification of rhabdomyosarcoma.

Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million people aged below 20 years. Based on the clinicopathological features and genetic abnormalities identified, rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. This review discusses the evolution of the classification of rhabdomyosarcoma to the present day, together with a discussion of key histomorphological and genetic features of each subtype and the diagnostic approach to these tumours.

Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo.

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

Primary Salivary Rhabdomyosarcoma in Childhood: A Rare Presentation

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. It is originated from embryonic mesenchyma and can arise anywhere in the body. Head and neck location accounts for 35% of all RMC locations. The parotid gland is very rarely affected. Because of this infrequent occurrence and the multiplicity of therapeutic means of management, we report a case a 5-year-old child which was diagnosed as parotid RMS.

DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours.

Updates and Diagnostic Challenges in Surgical Pathology and Cytopathology.

Updates and Diagnostic Challenges in Surgical Pathology and Cytopathology.

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.

S1899 A Rare Case of a Primary Colonic Undifferentiated Pleomorphic Sarcoma in a Pediatric Patient

Introduction: Soft tissue sarcomas are a group of malignant tumors originating from primitive mesenchymal tissue. Rhabdomyosarcomas account for 4% of these tumors while the remaining types account for 3% of these tumors in children. Undifferentiated pleomorphic sarcoma is one of the many types of non-rhabdomyosarcoma malignancies and accounts for 2-6% of all childhood soft tissue sarcomas. They most commonly arise in the extremities. We present a pediatric patient with an undifferentiated pleomorphic sarcoma arising from the cecum. Case description/methods: A 12-year-old girl with a past medical history of obesity presented with intermittent abdominal pain, diarrhea, weight loss, and vomiting over a 4–5 month period. She was taking naproxen daily for the abdominal pain. She was also found to have iron deficiency anemia and anemia with a hemoglobin of 5.3 gm/dl. EGD was unremarkable but colonoscopy revealed a 7 cm fungating non-obstructing large mass in the cecum as well as 2 five mm pedunculated polyps in the rectum. Imaging revealed peri-colonic, mesenteric, and mediastinal lymph nodes as well as a 1.2 cm solid nodule in the left lower lobe. Then she underwent surgery revealing a colo-colonic intussusception and a right hemicolectomy for the malignancy. Later on, the patient had a video assisted thoracoscopic surgery with wedge resection of the pulmonary nodule. Colonic pathology revealed an undifferentiated pleomorphic sarcoma while lung pathology revealed histoplasmosis. Discussion: While rare pediatric malignancies such as this have a scarcity of literature presented, this appears to be the first reported case of an undifferentiated pleomorphic sarcoma arising from the cecum in a pediatric patient. Patients commonly present in the second decade of life with a painless mass but since this patient’s mass is in the intestines, it went undetected until it grew quite large ( > 7 cm). She did have typical symptoms of gastrointestinal malignancy such as vague abdominal pain, weight loss, bowel habit changes, and iron deficiency anemia but a malignancy is oftentimes lower on the differential for the pediatric age group. At the time of diagnosis, it is important perform staging via imaging including CT/MRI and PET. In our patient, when found, it had already metastasized to distant lymph nodes. Surgical resection of local disease can possibly lead to a relapse free life and possibly a cure but oftentimes adjuvant chemotherapy is also needed if there is metastasis.Figure 1.: A and B: Colonoscopy revealed a fungating non-obstructing, non-circumferential large mass in the cecum. The mass measured seven cm in length and 5 mm in diameter.

The Role of BiP and the IRE1α-XBP1 Axis in Rhabdomyosarcoma Pathology.

Simple SummaryThe expression of BiP (GRP78), spliced XBP1 (sXBP1, nuclear XBP1), and IRE1α, were significantly associated with Rhabdomyosarcoma (RMS) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS; (n = 192) compared to normal skeletal muscle tissues (n = 16). There was a significant correlation between BiP expression and the lymph node score, and between IRE1α, cytosolic XBP1 and sXBP1 expression and the stage score in all of the types of RMS. BiP and sXBP1 expression were significantly associated with all of the subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. There were correlations between BiP expression and the lymph node score in ARMS, and sXBP1 expression and the tumor score in PRMS.Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. Methods: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. Results: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). Conclusions: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.

Genetic Characterization, Current Model Systems and Prognostic Stratification in PAX Fusion-Negative vs. PAX Fusion-Positive Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (PAX-FOXO1/VGLL2/NCOA2). Despite advances in our understanding of the pathobiological and molecular landscape of RMS, the prognosis of these tumors has not significantly improved in recent years. Developing a better understanding of genetic abnormalities and risk stratification beyond the fusion status are crucial to developing better therapeutic strategies. Herein, we aim to highlight the genetic pathways/abnormalities involved, specifically in fusion-negative RMS, assess the currently available model systems to study RMS pathogenesis, and discuss available prognostic factors as well as their importance for risk stratification to achieve optimal therapeutic management.

Pediatric liposarcoma: A case series and literature review.

Liposarcoma is arare soft tissue sarcoma in children. While prognosis, clinical behavior, and response to therapy among the various histologic subtypes are well described in adults, data in children are limited. Here, we describe our experience treating 14 children with liposarcoma at a large, academic pediatric center and review the available pediatric literature. This comprehensive report adds treatment, survival, and genomic data to pediatric liposarcoma literature.

Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion.

Simple SummaryRhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and there is a critical need to develop efficacious and tolerable anticancer therapies against this aggressive disease. To uncover druggable RMS-associated tumor antigens, we analyzed the cell surface protein repertoire in RMS tumor cells and normal tissue. We identified several surface proteins highly enriched in RMS, including the immune checkpoint molecule B7-H3. A further analysis using patient specimens showed that B7-H3 is overexpressed in most of RMS tumors and weakly or not detected in normal organs. Interestingly, we found that B7-H3 depletion was associated with higher immune cell killing activity against tumor cells. In line with this, high B7-H3 tumor expression was associated with lower CD8 T-cell density. Our study reveals novel RMS-associated proteins for the development of targeted therapies. In addition, we demonstrate that targeting B7-H3 function can pave the way for the design of new immunotherapies in the treatment of RMS.Novel therapeutic strategies are needed for the treatment of rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. By using a combination of cell surface proteomics and transcriptomic profiling of RMS and normal muscle, we generated a catalog of targetable cell surface proteins enriched in RMS tumors. Among the top candidates, we identified B7-H3 as the major immunoregulatory molecule expressed by RMS tumors. By using a large cohort of tissue specimens, we demonstrated that B7-H3 is expressed in a majority of RMS tumors while not detected in normal human tissues. Through a deconvolution analysis of the RMS tumor RNA-seq data, we showed that B7-H3-rich tumors are enriched in macrophages M1, NK cells, and depleted in CD8+-T cells. Furthermore, in vitro functional assays showed that B7-H3 knockout in RMS tumor cells increases T-cell mediated cytotoxicity. Altogether, our study uncovers new potential targets for the treatment of RMS and provides the first biological insights into the role of B7-H3 in RMS biology, paving the way for the development of next-generation immunotherapies.

Periorbital Mass in a 2-month-old Girl.

Periorbital Mass in a 2-month-old Girl.