Table 3.
Overview of major primary childhood sarcomas, risk factors for their development, current treatments, non-cancerous late effects, most common second primary malignancies, and risk factors for their evolvement.
| Primary Sarcoma | Late Effects | ||||
|---|---|---|---|---|---|
| Entity | Predisposition and Risk Factors | Treatment | Non-Carcinogenic | SPM | Risk Factors |
| Rhabdo-myosarcoma | first-degree relatives of pediatric RMS patients, LFS, germline DICER1 mutations, Beckwith Weidemann syndrome, Costello syndrome, Noonan syndrome, and genetic aberrations in FGFR4, IGF1R, PDGFRA, ERBB2/4, MET, MDM2, CDK4, PIK3CA and BCOR expression of PAX-FOXO chimeric proteins [341,342,343,344,345,346] |
surgery and/or EBRT [347,348] CT by VAC (vincristine, actinomycin D, and cyclophosphamide) or IVA (ifosfamide, vincristine, and actinomycin D) [349,350] |
visual, endocrine, cardiopulmonary, neurosensory, neuromotor, neuroendocrine, dental, thyroid, cognitive [351,352] | sarcomas, bone tumors, breast or thyroid cancer, or skin cancer without melanoma [177] | EBRT [353] cyclophosphamide [354,355] |
| Nonrhabdo-myosarcoma | NF, LFS and Maffucci syndrome translocations causing SYT-SSX, ASPL-TFE3, and TLS-CHOP fusion previous exposure to IR [333,356] |
CT with doxorubicin, vincristine, cyclophosphamide, and dactinomycin [357] EBRT [358] targeting of IGF-1R (cixutumumab), PDGFR (pazopanib, sorafenib), VEGF (pazopanib, bevacizumab, sorafenib), ALK (crizotinib), MET (crizotinib), mTOR (temsirolimus), PD-L1 (nivolumab), or CAR-T cells targeting NY-ESO-1 or HER2 [348,359] |
subcutaneous fibrosis, lymphedema, joint stiffness, cardiac, skeletal, renal, infertility [358,359,360,361] | EBRT [353] cyclophosphamide [354,355] |
|
| Osteosarcoma | RB, Rothmund-Thomson syndrome, LFS, and WRN [362] amplifications in CDC5L, MAPK7, MET, PIM1, PMP22, PRIM1, RUNX2, and VEGFA [363] |
neoadjuvant CT comprising cisplatin, doxorubicin followed by high-dose methotrexate, and surgical removal of the tumor often followed by adjuvant CT conventional high dose EBRT rarely applied, ion-beam EBRT for inoperable osteosarcoma [364] |
cardiac toxicity nephrotoxicity, neurotoxicity, hearing loss, infertility [365] | hematopoietic, soft tissue, thyroid respiratory system, breast [366] | EBRT and high dose CT [366] |
| Ewing Sarcoma | translocations causing EWS-FLI-1 or EWS-ERG gene fusions [367] | EBRT and radical surgery SBRT [368] multiagent CT with VACD (vincristine, cyclophosphamide, Actinomycin D, and doxorubicin) CT plus ifosfamide and etoposide [369] targeting EWSR1/FLI1 or EZH2 (tazemetostat), BET proteins (BRD2, BRD3, BRD4), LSD1, NKX2.2 (vorinostat), CDK4/6, EWSR1/FLI1 (trabectedin, lurbinectedin), the IGF1/IGF1R-axis (cituximab, figitumumab) combined with a mTor1-inhibitor (temsirolimus), ERK or HSP90, PARP (olaparib, talazoparib, niraparib), VEGFR (cediranib, egorafenib), or c-KIT and PDGFR (imatinib, regorafenib) [370] immunological signaling pathways compromising CXCR4-CXCL12 (AMD3100), intracellular antigens including WT1, XAGE-1, the EWS–FLI1 chimeric transcription factor, cancer vaccines based on PAX3- and EWS–FLI1, vigil immunotherapy, oncolytic viruses, T cell receptor therapy with anti-CD3/4-1BBL cells or CD8+ T cells targeting antigens like PAPPA, EZH2 or CHM1, CAR-T cells targeting LINGO, ROR1 or IGF-1R [371,372,373,374,375] |
cardiac, pulmonary, bone growth, musculoskeletal, infertility [376] | acute myeloid leukemia, myelodysplastic syndromes, breast and thyroid cancer [377,378,379] | EBRT VACD plus etoposide and ifosfamide [377,378] |
Abbreviations: SPM, second primary malignancy; NF, neurofibromatosis; LFS, Li-Fraumeni syndrome; FA, Fanconi anemia; RB, retinoblastoma; WRN, Werner syndrome; SBRT, stereotactic body radiotherapy; CT, chemotherapy; EBRT, external beam radiotherapy; IR, ionizing radiation.