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Cancer Innovation Apr 2024Rhabdomyosarcoma (RMS) originates from primitive mesenchymal cells and is the most common soft tissue tumor in childhood. F-fluoro-deoxyglucose (F-FDG) positron emission...
Rhabdomyosarcoma (RMS) originates from primitive mesenchymal cells and is the most common soft tissue tumor in childhood. F-fluoro-deoxyglucose (F-FDG) positron emission tomography (PET)/computed tomography (CT) has been reported to be valuable in RMS staging and risk stratification. Paratesticular RMS is a relatively uncommon form of RMS, most of which are of the embryonal histologic type. Paratesticular alveolar RMS is associated with aggressive behavior, high metastatic potential, and poor outcomes. To the best of our knowledge, F-FDG PET/CT imaging findings of paratesticular alveolar RMS have never been described. Here, we report on a 16-year-old boy's rare paratesticular alveolar RMS with multiple metastases and its findings on F-FDG PET/CT. This case also demonstrates the potential value of F-FDG PET/CT in RMS staging and treatment decisions, and may aid in the differential diagnosis.
PubMed: 38946934
DOI: 10.1002/cai2.121 -
Frontiers in Cell and Developmental... 2024We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and...
We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and describe the central mechanisms that determine sarcomagenesis. Further, we discuss seminal studies in translational genomics, which enabled epigenetic characterization of fusion-driven sarcomas. Important context for epigenetic mechanisms include, but are not limited to, cell cycle and metabolism, core regulatory circuitry, 3-dimensional chromatin architectural dysregulation, integration with ATP-dependent chromatin remodeling, and translational animal modeling. Paradoxically, while the genetic requirements for oncogenic transformation are highly specific for the fusion partners, the epigenetic mechanisms we as a community have uncovered are categorically very broad. This dichotomy prompts the question of whether the investigation of rare disease epigenomics should prioritize studying individual cell populations, thereby examining whether the mechanisms of chromatin dysregulation are specific to a particular tumor. We review recent advances focusing on rhabdomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, undifferentiated round cell sarcoma, Ewing sarcoma, myxoid/round liposarcoma, epithelioid hemangioendothelioma and desmoplastic round cell tumor. The growing number of groundbreaking discoveries in the field, motivated us to anticipate further exciting advances in the area of mechanistic epigenomics and direct targeting of fusion transcription factors in the years ahead.
PubMed: 38946804
DOI: 10.3389/fcell.2024.1416946 -
Disease Models & Mechanisms Jun 2024Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general... (Review)
Review
Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general therapies are sometimes curative, the cancer often recurs, resulting in poor outcomes for patients. Fusion-driven pediatric soft tissue sarcomas are genetically defined by chromosomal translocations that create a chimeric oncogene. This distinctive, almost 'monogenic', genetic feature supports the generation of animal models to study the respective diseases in vivo. This Review focuses on a subset of fusion-driven pediatric soft tissue sarcomas that have transgenic animal tumor models, which includes fusion-positive and infantile rhabdomyosarcoma, synovial sarcoma, undifferentiated small round cell sarcoma, alveolar soft part sarcoma and clear cell sarcoma. Studies using the animal models of these sarcomas have highlighted that pediatric cancers require a specific cellular state or developmental stage to drive tumorigenesis, as the fusion oncogenes cause different outcomes depending on their lineage and timing of expression. Therefore, understanding these context-specific activities could identify targetable activities and mechanisms critical for tumorigenesis. Broadly, these cancers show dependencies on chromatin regulators to support oncogenic gene expression and co-opting of developmental pathways. Comparative analyses across lineages and tumor models will further provide biological and therapeutic insights to improve outcomes for these children.
Topics: Animals; Humans; Sarcoma; Disease Models, Animal; Oncogene Proteins, Fusion; Child
PubMed: 38916046
DOI: 10.1242/dmm.050704 -
Medicinal Research Reviews Jun 2024Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%-70%) and alveolar RMS (aRMS;... (Review)
Review
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%-70%) and alveolar RMS (aRMS; 20%-30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion-positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion-negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long-term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.
PubMed: 38885148
DOI: 10.1002/med.22059 -
Human Pathology Jun 2024Neoplasms of the tongue are relatively common, and the vast majority are epithelial in phenotype. Although uncommon, a diverse and distinctive array of mesenchymal...
Neoplasms of the tongue are relatively common, and the vast majority are epithelial in phenotype. Although uncommon, a diverse and distinctive array of mesenchymal neoplasms arises in this anatomic site. To increase our understanding of these lesions, we reviewed our experience of MNs of the tongue and described their clinicopathologic features. The pathology archives from 2005-2021 and the consultation files of one of the authors were queried for all MNs of the tongue. We reviewed the histologic slides and ancillary studies and obtained clinical data from the available medical records. Ninety-three cases were identified, and they form the study cohort - to our knowledge, this is the largest series of mesenchymal neoplasms of the tongue. Forty-eight patients were female, and forty-five were male, with a mean age of 51 years (range: 1-94 years). The tumors included 43 (46.2%) hemangiomas, 14 (15%) granular cell tumors, 8 (9%) lipomas, 4 (4.3%) schwannomas, 4 (4.3%) solitary fibrous tumors - all with low risk of progression based on risk stratification criteria, 2 (2.2%) lymphangiomas, 3 (3.2%) Kaposi sarcomas, 2 (2.2%) chondromas, 2 (2.2%) myofibromas, 1 (1.1%) solitary circumscribed neuroma, 1 (1.1%) perineurioma, 1 (1.1%) neurofibroma, 1 (1.1%) ectomesenchymal chondromyxoid tumor, 1 (1.1%) atypical glomus tumor with a NOTCH2 rearrangement and TLL2 mutation, 1 (1.1%) spindle cell rhabdomyosarcoma, 1 (1.1%) pleomorphic fibroblastic sarcoma, 1 (1.1%) malignant rhabdoid tumor, 1 (1.1%) leiomyosarcoma, 1 (1.1%) angiosarcoma, and 1 (1.1%) alveolar soft part sarcoma. Most of the patients underwent surgical excision, and 1 patient (with hemangioma) underwent embolization. On follow-up, the patient with spindle cell rhabdomyosarcoma developed postoperative numbness at the surgical site and was disease-free through 17 months of follow-up. The patient with leiomyosarcoma declined adjuvant radiation and developed metastasis to the lung at 22 months. The patient with alveolar soft part sarcoma had metastases to the lung at the time of diagnosis and received adjuvant chemotherapy. The remaining patients had no local or distant recurrence. MNs of the tongue are usually benign and characterized by either endothelial, adipocytic, or schwannian differentiation. The mainstay of treatment is surgical excision with the extent of excision determined by tumor type. Adjuvant therapy is reserved for high-grade sarcomas.
PubMed: 38876200
DOI: 10.1016/j.humpath.2024.06.005 -
Transgenic Research Jun 2024Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal...
Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.
PubMed: 38851650
DOI: 10.1007/s11248-024-00390-0 -
European Journal of Cancer Prevention :... May 2024This systematic review aims to synthesize the available literature to determine the association between birthweight and the risk of nonneurological childhood cancers.
OBJECTIVES
This systematic review aims to synthesize the available literature to determine the association between birthweight and the risk of nonneurological childhood cancers.
METHODS
We conducted a systematic search of PubMed, Web of Science, and Scopus databases up to May 2023 to identify observational studies. Heterogeneity between studies was evaluated using the I2 statistics. Publication bias was assessed using Begg and Egger tests. We calculated the odds ratio (OR) or risk ratio (RR) with a 95% confidence interval (CI) using a random-effects model.
RESULTS
Of 11 034 studies retrieved from the search, 56 studies (including 10 568 091 participants) were eligible. The ORs (95% CI) of low (<2500 g) versus normal birthweight (2500-4000 g) and childhood cancers were as follows: leukemia, 0.92 (0.77-1.11); acute lymphoblastic leukemia, 0.82 (0.72-0.94); acute myeloid leukemia, 0.98 (0.77-1.24); lymphoma, 0.99 (0.47-2.10); Hodgkin, 0.79 (0.61-1.03); non-Hodgkin, 0.85 (0.60-1.20); neuroblastoma, 1.34 (1.14-1.58); retinoblastoma, 0.95 (0.68-1.32); rhabdomyosarcoma, 0.86 (0.61-1.20); embryonal, 0.97 (0.66-1.43); alveolar, 1.92 (0.43-8.51); and Wilms tumor, 1.01 (0.83-1.24). The ORs (95% CI) of high (>4000 g) versus normal birthweight and childhood cancers were as follows: leukemia, 1.30 (1.18-1.42); acute lymphoblastic leukemia, 1.27 (1.16-1.39); acute myeloid leukemia, 1.13 (0.98-1.30); lymphoma, 1.69 (0.72-3.94); Hodgkin, 1.22 (1.02-1.46); non-Hodgkin, 1.22 (0.80-1.86); neuroblastoma, 1.20 (1.02-1.41); retinoblastoma, 1.17 (0.93-1.48); rhabdomyosarcoma, 1.07 (0.90-1.27); embryonal, 1.22 (1.00-1.49); alveolar, 1.02 (0.46-2.27); and Wilms tumor, 1.49 (1.34-1.67).
CONCLUSION
This meta-analysis identified high birth weight as a potential risk factor for some childhood cancers, while low birth weight might be protective against a few.
PubMed: 38837193
DOI: 10.1097/CEJ.0000000000000894 -
Frontiers in Oncology 2024Rhabdomyosarcoma (RMS) is a common soft tissue malignant tumor, especially in young patients. Alveolar rhabdomyosarcoma (ARMS) is a subtype of RMS that is prevalent in...
Rhabdomyosarcoma (RMS) is a common soft tissue malignant tumor, especially in young patients. Alveolar rhabdomyosarcoma (ARMS) is a subtype of RMS that is prevalent in adolescents. This malignant tumor usually develops in the extremities and can also involve the trunk, perineum, and pelvis. Now, we report a rare case of pelvic lymph node metastatic alveolar RMS in a young patient, which was determined by fine needle aspiration cytology (FNAC). To the best of our knowledge, this is the first case in which the definite diagnosis of ARMS was initially made by FNAC.
PubMed: 38835374
DOI: 10.3389/fonc.2024.1340865 -
BMJ Case Reports Jun 2024Rhabdomyosarcomas are the most common soft-tissue sarcomas, found usually in the younger age group. Histologically, they are subdivided into embryonal, alveolar,...
Rhabdomyosarcomas are the most common soft-tissue sarcomas, found usually in the younger age group. Histologically, they are subdivided into embryonal, alveolar, pleomorphic and not otherwise specified. They have a heterogenous appearance on imaging with few additional characteristic features based on the subtype. Botryoid variant of embryonal rhabdomyosarcoma commonly involves the genitourinary and the biliary system. They can be multifocal. Most of these lesions have a heterogenous appearance on imaging with areas of necrosis and haemorrhage. On ultrasound, they are polypoidal with cystic areas and are vascular. The lesions are hyperintense on T2 sequences, isointense to the skeletal muscle on T1 sequences and show heterogenous enhancement. Surgery is the mainstay of treatment along with radiotherapy or chemotherapy depending on the site and the stage of the tumour. We report a case of botryoid variant of rhabdomyosarcoma involving the vagina and the urinary bladder.
Topics: Female; Humans; Magnetic Resonance Imaging; Rhabdomyosarcoma, Embryonal; Ultrasonography; Urinary Bladder Neoplasms; Vaginal Neoplasms; Child, Preschool
PubMed: 38834309
DOI: 10.1136/bcr-2023-259549 -
Virchows Archiv : An International... Jun 2024Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small...
Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.
PubMed: 38833173
DOI: 10.1007/s00428-024-03835-3