Pediatric Soft Tissue Tumors Research Articles

Chapter 13: What is new in fibroblastic/myofibroblastic tumors in children.

Fibroblastic and myofibroblastic neoplasms represent about 12% of pediatric soft tissue tumors. Most of these neoplasms in children are either benign or locally aggressive with rare metastasis, while malignant cases are uncommon. Diagnosing these tumors is challenging due to overlapping morphologies and the limited utility of immunohistochemistry. Advances in molecular techniques, especially RNA sequencing, have improved our understanding of the molecular drivers of these tumors, leading to better classification. Key molecular alterations, such as RTK and MAPK activation, are central in the development of tumors like infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumors (IMT). The identification of alternative fusions in IFS and IMT underscores the importance of an integrated diagnostic approach. Furthermore, new RTK-driven lesions, now included in the WHO's "NTRK-rearranged mesenchymal neoplasms", have been identified. This review provides an update on recent findings in RTK-driven myofibroblastic tumors and highlights novel entities still in need of classification.

Pediatric soft tissue tumors : Tumors of uncertain origin

Soft tissue tumors of childhood are an extremely heterogeneous group of tumors that require precise diagnosis for therapy. In this article, selected tumors of uncertain origin that exhibit characteristic histological, immunophenotypical, and molecular features are addressed. Angiomatoid fibrous histiocytoma, alveolar soft part sarcoma, extrarenal rhabdoid tumor, synovial sarcoma, and desmoplastic small round cell tumor differ in their pathology, their clinical behavior, and prognosis.

Pediatric Fibromatosis Lacks the Internal Tandem Duplication of EGFR Seen in Congenital Mesoblastic Nephroma.

Classical and mixed congenital mesoblastic nephroma (CMN) are characterized by an internal tandem duplication (ITD) of the EGFR gene, in contrast to cellular CMN that usually harbors an ETV6::NTRK3 gene fusion. This same fusion occurs in infantile fibrosarcoma, and this tumor can be considered as the soft tissue equivalent of cellular CMN. A soft tissue equivalent of classic/mixed CMN remains undefined at the genetic level. Since classical CMN resembles fibromatosis of soft tissue histologically, we asked whether fibromatosis in children might show EGFR ITD. ITD was investigated using the polymerase chain reaction and primers for exons 18 and 25 of the EGFR gene. Seven of the eight cases of classical or mixed CMN were positive by this approach, but none of the five cellular CMNs. Of 11 cases of fibromatosis (six plantar, two digital, and three desmoid), none were positive for EGFR ITD. Within the limits of this small study, we conclude that pediatric fibromatosis is likely not characterized by EGFR ITD. There are isolated reports of pediatric soft tissue tumors that harbor EGFR ITD, but these have the appearance of infantile fibrosarcoma or mixed CMN rather than fibromatosis. We did not find any such cases, since all 14 cases of infantile fibrosarcoma in our study had an ETV6::NTRK3 fusion. The soft tissue tumors with EGFR ITD are not a morphologic match for the low-grade histology of classical CMN. Whether they have a similar favorable biology or behave more like fibrosarcoma with an ETV6::NTRK3 fusion or an alternative fusion involving other kinases remains to be determined.

Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.

Pediatric Hemangiomas in the Female Genital Tract: A Literature Review.

Hemangiomas are aberrant proliferations of blood vessels and the most frequent benign pediatric soft tissue tumors. Although they are common, genital localization is rare. This study aimed to assist doctors in the diagnosis, management, and treatment of pediatric vulvovaginal hemangiomas by conducting a review of the literature. We conducted a literature review including papers published between August 2009 and May 2023. While most hemangiomas are usually indolent and resolve with time, in some cases, especially cervicovaginal and uterine ones, they might present with severe symptoms like heavy bleeding and need further instrumental investigation for diagnosis, like CT or MRI. As for the treatment, many options are available, with medical therapy or expectant management being the first choice. Vulvovaginal pediatric hemangiomas are rare and require more research on how to detect and manage these lesions, especially the symptomatic and the psychologically impacting ones. For the time being, treatment should be personalized based on the patient's situation and clinician's expertise.

Solitary myofibroma in children: a report of two cases

Myofibromas are rare benign tumors of myofibroblasts, seen more commonly in children. These tumors typically involve soft tissues with a predilection for the head and neck. Malignant neoplasia is often suspected for these rapidly growing tumors in early childhood. Clinical and radiological findings are not typical, and histopathological examination makes the definitive diagnosis. This pathology requires the intervention of a multidisciplinary team and regular follow-up. We report our experience with two children with myofibromas, one in the right arm of a 5-year-old girl and the other in the right axilla of a 9-year-old boy. Tumors were totally resected in both children, who are under follow-up with no adjuvant treatment free of disease after surgery. Myofibroma should be considered in the differential diagnosis of pediatric soft tissue tumors. Surgical resection is sufficient for treatment and patients should be followed regularly for possible recurrences.

The Incidence of Multiple Fusions in a Series of Pediatric Soft Tissue and Bone Tumors.

Next generation sequencing (NGS) has increased the detection of fusion genes in cancer. NGS has found multiple fusions in single tumor samples; however, the incidence of this in pediatric soft tissue and bone tumors (PSTBTs) is not well documented. The aim of this study is to catalogue the incidence of multiple fusions in a series of PSTBTs, and apply a modified gene fusion classification system to determine clinical relevance. RNA from 78 bone and soft tissue tumors and 7 external quality assessment samples were sequenced and analyzed using recently-described Metafusion (MF) software and classified using a modification of previously-published schema for fusion classification into 3 tiers: 1, strong clinical significance; 2, potential clinical significance; and 3, unknown clinical significance. One-hundred forty-five fusions were detected in 85 samples. Fifty-five samples (65%) had a single fusion and 30 (35%) had more than 1 fusion. No samples contained more than 1 tier 1 fusion. There were 40 tier 1 (28%), 36 tier 2 (24%), and 69 (48%) tier 3 fusions. A significant percentage of PSTBTs harbor more than 1 fusion, and by applying a modified fusion classification scheme, the potential clinical relevance of such fusions can be determined.

A dysfunctional miR-1-TRPS1-MYOG axis drives ERMS by suppressing terminal myogenic differentiation

Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the transcriptional repressor TRPS1 are specifically enhanced in the embryonal subtype, resulting in impaired terminal myogenic differentiation and tumor growth. During normal myogenesis, expression levels of TRPS1 have to decrease to allow myogenic progression, as demonstrated by overexpression of TRPS1 in myoblasts impairing myotube formation. Consequentially, myogenic differentiation in embryonal rhabdomyosarcoma invitro as well as invivo can be achieved by reducing TRPS1 levels. Furthermore, we show that TRPS1 levels in RD cells, the bona fide model cell line for embryonal rhabdomyosarcoma, are regulated by miR-1 and that TRPS1 and MYOD1 share common genomic binding sites. The myogenin (MYOG) promoter is one of the critical targets of TRPS1 and MYOD1; we demonstrate that TRPS1 restricts MYOG expression and thereby inhibits terminal myogenic differentiation. Therefore, reduction of TRPS1 levels in embryonal rhabdomyosarcoma might be a therapeutic approach to drive embryonal rhabdomyosarcoma cells into myogenic differentiation, thereby generating postmitotic myotubes.

Infantile fibrosarcoma of the perineum with dorsal metastasis in a neonate: a case report original

BackgroundInfantile fibrosarcoma is a rare pediatric soft tissue tumor and usually appears in children before one year of age. Distal extremities constitute the most frequently affected locations, and other tissues such as the trunk, head and neck, gut, sacrococcygeal region, and viscera are uncommon sites.Case presentationWe describe a rare case of infantile fibrosarcoma arising from the perineum. First, a cystic mass was detected using prenatal ultrasonography, and then an echo was changed in serial ultrasound examinations. A solid cystic lesion was found at term; a hypoechoic lesion occurred in the back. The tumor became so large that massive bleeding occurred, which then underwent surgical resection. Pathological examination confirmed infantile fibrosarcoma.ConclusionOur report demonstrates not all ultrasonographic findings in cases of infantile fibrosarcoma exhibit a solid mass during the initial examination — an early-stage lesion may reveal a cystic echo. Infantile fibrosarcoma has a good prognosis and surgery constitute the main treatment, with adjuvant chemotherapy being received if necessary.

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

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

Imaging of pediatric abdominal soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

This paper provides imaging recommendations for pediatric abdominal tumors that arise outside of the solid viscera. These tumors are rare in children and have been categorized in two groups: abdominal wall and peritoneal tumors (desmoid tumor and desmoplastic small round cell tumor) and tumors that arise from the gastrointestinal tract (gastrointestinal stromal tumor and gastrointestinal neuroendocrine tumor). Authors offer consensus recommendations for imaging assessment of these tumors at diagnosis, during follow-up, and when off-therapy.

Primary leiomyosarcoma of the inferior vena cava in a pediatric case: a case report and literature review

BackgroundLeiomyosarcoma is classified as a soft tissue sarcoma. In adults, leiomyosarcoma is the most common malignancy affecting the vascular system; however, vascular leiomyosarcoma in children is extremely rare as most pediatric soft tissue tumors are rhabdomyosarcomas. The survival rate is very low, and incomplete resection is a poor prognostic factor. There is also a high rate of distant recurrence, with the lungs and liver being the most common sites of metastasis. There is no established effective chemotherapy, and complete surgical resection is the only potentially curative treatment for leiomyosarcoma.Case presentationA 15-year-old female patient with no significant medical history presented with severe upper abdominal pain and was admitted. Abdominal contrast-enhanced computed tomography and magnetic resonance imaging showed a large retroperitoneal tumor protruding into the lumen of the inferior vena cava behind the liver and multiple small nodules, and metastasis to the liver was suspected. The tumor was 6 × 4 × 5 cm in diameter, located just behind the hepatic hilar structures, and was suspected to infiltrate into the right portal vein. The tumor was diagnosed as a leiomyosarcoma through an open tumor biopsy. As the multiple liver metastases were located only in the right lobe of the liver on imaging, we performed tumor resection with right hepatectomy and replacement of the inferior vena cava (IVC). The postoperative course was uneventful; however, on postoperative day 51, distant metastatic recurrences were found in the remaining liver and right lung. The patient was immediately started on chemotherapy and trabectedin proved to be the most effective drug in the treatment regimen; however, severe side effects, such as hepatotoxicity, prevented timely administration, and the patient passed away 19 months after surgery.ConclusionsIVC resection and reconstruction combined with right hepatectomy were able to be safely performed even in a pediatric case. To improve the prognosis of leiomyosarcoma with multiple metastases, an effective treatment strategy combining surgical treatment and chemotherapy, including molecularly targeted drugs, should be established as early as possible.

Prof Norman Jaffe, DSc, MD (1933-2022): The Osteosarcoma Giant.

This brief note is written to laud the memory of Dr Norman Jaffe, DSc, MD, a professor of pediatrics, who was a pioneer in the treatment of osteosarcoma and other pediatric bone and soft tissue tumors.

Imaging of pediatric extragonadal pelvic soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

The most common pediatric extragonadal pelvic cancers include germ cell tumors, sacrococcygeal teratomas, and rhabdomyosarcomas (arising from the urinary bladder, prostate, paratesticular tissues, vagina, uterus, and perineum). This paper describes the radiological and nuclear medicine features of these entities and provides consensus-based recommendations for the assessment at diagnosis, during, and after treatment.

Imaging of pediatric extremity soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Pediatric soft tissue tumors of the extremity include rhabdomyosarcoma and nonrhabdomyosarcoma neoplasms. This manuscript provides consensus-based imaging recommendations for imaging evaluation at diagnosis, during treatment, and following completion of therapy for patients with a soft tissue tumor of the extremity.

CRISPR activation screen identifies TGFβ-associated PEG10 as a crucial tumor suppressor in Ewing sarcoma

As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an “undruggable” fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFβ pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFβ pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFβ signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy.

Abstract 702: Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis

Abstract Ewing Sarcoma (ES) is a rare but deadly pediatric bone and soft tissue tumor, with little improvement in survival for decades despite knowing the driving fusion oncoprotein EWS-FLI1. EWS-FLI1 is notably toxic, acting as an aberrant transcription factor and leading to growth arrest and apoptosis in all but a few cell types. ES incidence in populations of European ancestry is nearly ten times that found in children with primarily African ancestry. To better understand how EWS-FLI1 transforms the transcriptome and the protective effect of the African genome, we leveraged this disparate genomic context to study ES tumorigenesis by introduction of EWS-FLI1 into cells derived from donors with a range of African ancestry followed by RNA sequencing (RNA-seq). Induced pluripotent stem cell (iPSC) lines with genome wide SNP genotyping data were obtained and local ancestry was assessed using RFMix to establish genetic ancestry. Two lines each of ~100% European and African ancestry and four lines with intermediate European/African admixture (45% to 90% African) were differentiated into neural crest cells (iNCC, a proposed cell-of-origin for ES) and transduced with a lentivirus expressing either a GFP reporter or a GFP-2A-EWS/FLI1 cassette. Interestingly, iNCC derived from European lines maintained a higher frequency of cells expressing GFP/EWS-FLI1 than the pure African lines, with admixed lines showing an intermediate frequency. RNA was extracted at 48- and 96-hour time points and sequenced for gene expression analysis. As expected, we identified pronounced changes to the transcriptional landscape in EWS-FLI1-induced cells compared to control with 13,578 differentially expressed genes (adjusted p-value < 0.05). More interestingly we identified 3,128 genes with ancestry-associated gene expression differences in response to EWS-FLI1 expression. Gene Set Enrichment Analysis (GSEA) using MSigDB 50 hallmark gene sets (v7.4) detected 24 significantly enriched gene sets with an inverse correlation with percent African ancestry, including those sets involved with oxidative phosphorylation, MYC v1 and v2, and MTORC1 signaling. To identify those expression changes that are key to ES tumorigenesis we are comparing the transcriptional profiles of our EWS-FLI1 expressing iNCC to ES tumors and ES cell lines as well as other models of ES derived from mesenchymal stem cells. Ongoing studies will include profiling of chromatin accessibility and EWS-FLI1 occupation for each ancestral iNCC line following EWS-FLI1 transduction to determine the early, ancestry-linked transitions that are permissive to oncogenic transformation. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES. Citation Format: Rachel M. Moss, Kelsie L. Becklin, Lauren J. Mills, Branden S. Moriarity, Beau R. Webber, Logan G. Spector. Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 702.

Malignant Ectomesenchymoma of Pelvis in an Infant

Malignant ectomesenchymoma is a rare pediatric soft tissue tumor that contains both neuroectodermal and mesenchymal components. It is frequently found in the pelvis, paratesticular soft tissue, external genitalia and the head-neck region. We present a 12-month-old boy with a recurrent pelvic tumor excised 5 months ago and diagnosed as neuroblastoma. Histological consultation of the initial tumor tissue revealed a biphasic pattern with rhabdomyosarcomatous and neural components. The mesenchymal component was embryonal rhabdomyosarcoma showing desmin, myogenin, and Myo-D1 positivity. The neuroectodermal component was mainly Schwannian stroma stained with S100 antibody and scattered synaptophysin and chromogranin positive ganglion cells were also present. The patient was diagnosed with malignant ectomesenchymoma. A chemotherapy regime was started and surgical approach to the recurrent tumor was planned. We present here a pediatric case of malignant ectomesenchymoma because of its rarity and it is important that this entity should be considered in the differential diagnosis for appropriate clinical management.

Update of pediatric soft tissue tumors with review of conventional MRI appearance-part 2: vascular lesions, fibrohistiocytic tumors, muscle tumors, peripheral nerve sheath tumors, tumors of uncertain differentiation, and undifferentiated small round cell sarcomas.

There are numerous soft tissue tumors and tumor-like conditions in the pediatric population. Magnetic resonance imaging is the most useful modality for imaging these lesions. Although certain soft tissue lesions exhibit magnetic resonance features characteristic of a specific diagnosis, most lesions are indeterminate, and a biopsy is necessary for diagnosis. We provide a detailed update of soft tissue tumors and tumor-like conditions that occur in the pediatric population, emphasizing each lesion's conventional magnetic resonance imaging appearance, using the recently released 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumors as a guide. In part one of this review, pediatric tumor-like lesions, adipocytic tumors, fibroblastic and myofibroblastic tumors, and perivascular tumors are discussed. In part two, vascular lesions, fibrohistiocytic tumors, muscle tumors, peripheral nerve sheath tumors, tumors of uncertain differentiation, and undifferentiated small round cell sarcomas are reviewed. Per the convention of the WHO, these lesions involve the connective, subcutaneous, and other non-parenchymatous organ soft tissues, as well as the peripheral and autonomic nervous system.

Abstract 312: Targeted NanoSpheres (TNS)

Abstract The tumor-targeted, nanoparticle delivery technology has shown the possibility of increasing the delivered dose of virtually any small therapeutics to tumor cells while limiting the drug uptake by normal tissues, thereby greatly increasing the effective MTD. By refining the early formulations and after extensive testing, we developed a novel targeted liposomal nanoparticle, Targeted NanoSpheres (TNS). We showed this novel nano-formulated platform can overcome many deficiencies of conventional nanoparticles and therefore has enhanced potential as an effective delivery vehicle for virtually any type of cancer for which a suitable tumor cell surface antigen is present. We have developedNV103, a first-in-class anti-CD99 TNS (CD99-TNS/Irinotecan), for the treatment of Ewing Sarcoma (EWS), a highly lethal pediatric and young adult bone and soft tissue tumor driven by a fusion protein, typically EWS/FLI1 in over 85% of cases. Cancer cells have the ability to develop resistance to the chemotherapy. Our present salvage/rescue study with NV103 showed that NV103 can overcome irinotecan resistance of Ewing tumor with simple change of dose schedule (dose intensification), not increasing the dose. The results from our salvage/rescue studies with NV103 suggested that successful dose intensification schedules with NV103 could be used to treat relapsed or resistant patients in future clinical trials. Furthermore, Targeted Nanosphere (TNS) can be used to overcome drug resistance of various cancers.This platform is also being investigated for other types of cancer that either express CD99, or other tumor antigens like GD2 and B7-H3. Citation Format: HyungGyoo Kang, Jon Nagy, Bryon Upton, Racheal Upton, Timothy Triche, Timothy Triche. Targeted NanoSpheres (TNS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 312.