What’s new in pediatric bone sarcomas and benign bone tumors

Abstract

Significant progress has been made in the diagnosis and treatment of pediatric bone tumors in recent years. For malignant bone tumors, a better understanding of the molecular pathogenesis has been achieved, providing new directions for targeted approaches and immunotherapy. Advances in imaging techniques, such as whole-body magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography/computed tomography, have improved the accuracy of staging, treatment response evaluation, and recurrence monitoring. In surgical treatment, 3D printing technology, computer navigation, and minimally invasive techniques have shifted the paradigm from resection to functional reconstruction. Technologies, including modular and expandable implants, along with bio-integrated prostheses, support long-term functional recovery in pediatric patients. For benign bone tumors, the use of targeted drugs like denosumab and the refinement of minimally invasive techniques such as cryotherapy and radiofrequency ablation have achieved a better balance between disease control and functional preservation. The ongoing development of multidisciplinary collaboration further optimizes personalized treatment strategies. Looking ahead, continuous progress in precision medicine will steer the diagnosis and treatment of pediatric bone tumors toward minimally invasive, individualized, and innovative approaches.

Keywords

Pediatric bone tumors precision medicine molecular diagnosis targeted therapy immunotherapy

Historical perspective and shift in treatment paradigms

Malignant sarcomas: From chemotherapy milestones to the era of precision medicine

The treatment history of childhood malignant bone tumors reflects a long journey from despair to hope, followed by a plateau and then new breakthroughs. Osteosarcoma and Ewing sarcoma, as the most common malignant bone tumors in children, exemplify this evolution.¹ Before the 1970s, amputation was the primary treatment for osteosarcoma. However, even with radical amputation, long-term survival rates remained below 20%,² as most patients developed distant metastases and ultimately died. The first breakthrough came in the 1970s with the introduction of adjuvant and neoadjuvant chemotherapy. The application of high-dose methotrexate, doxorubicin, and cisplatin significantly increased survival to approximately 70% for patients with non-metastatic osteosarcoma, marking the first major milestone in pediatric bone tumor therapy.³

Similarly, Ewing sarcoma treatment benefited from optimized chemotherapy regimens. Intensive combination chemotherapy introduced in the 1970s–1980s, particularly vincristine, actinomycin D, cyclophosphamide, and ifosfamide, etoposide (IE), improved survival to 70%, especially in localized disease.⁴ Unlike osteosarcoma, Ewing sarcoma is radiosensitive, making radiotherapy beneficial for local control, particularly in challenging sites like the pelvis, and for treating pulmonary metastatic disease.⁴ Another key discovery in the 1990s was the identification of characteristic chromosomal translocations in Ewing sarcoma, most commonly the EWS-FLI1 or EWS-ERG fusion genes.⁴ This finding provided a specific and disease-defining marker and laid the foundation for a better understanding of its pathogenesis.

Despite these advances, the treatment of malignant bone tumors entered a decades-long plateau. Standard first-line regimens remained largely unchanged, and cure rates struggled to improve further. Prognosis for metastatic and relapsed patients remained particularly poor, with survival rates stagnating between 10% and 30%.^3,5 This stagnation highlighted the urgent need for new strategies, catalyzing a paradigm shift from traditional chemotherapy toward precision medicine (Table 1).

Table 1.

Comparison of the evolution in treatment of pediatric malignant and benign bone tumors.

Period	Malignant bone tumors (mainly osteosarcoma & Ewing sarcoma)	Benign bone tumors
Before 1970s	Mainly amputation; before the advent of chemotherapy, the 5-year survival rate was only 10%–20%.⁶	Conventional surgical management based on observation or simple excision/curettage.⁷
1970–1990s	Introduction of multi-agent chemotherapy (e.g., high-dose methotrexate, doxorubicin, cisplatin); 5-year survival for localized disease improved to 60%–70%. Neoadjuvant chemotherapy plus surgery became standard.⁶	Continued use of curettage/excision, with increasing focus on balancing functional preservation and recurrence risk.⁸
1990–2000s	Limb-salvage surgery and reconstruction techniques became mature; overall survival plateaued with limited improvement.²	Image-guided percutaneous techniques entered clinical use: CT-guided RFA was established for osteoid osteoma.⁹
2000s–present	Exploration of targeted therapy, immunotherapy, and risk-stratified chemotherapy. Overall survival improved slightly in selected subgroups.¹⁰	A combination of pharmacologic and interventional approaches formed an “individualized, function-preserving” pathway—represented by RANKL inhibitor (Denosumab) reducing surgical invasiveness in giant cell tumor; bisphosphonates after curettage may lower recurrence; RFA, microwave/cryoablation, sclerotherapy, and cementoplasty have become mature options.¹¹

RFA: radiofrequency ablation; RANKL: receptor activator of NF-κB ligand.

Benign tumors: Evolution from surgical resection to multimodal intervention

The treatment philosophy for benign bone tumors has followed a distinct evolutionary path. Traditionally, surgical resection or curettage was the mainstay. While effective for local control, these procedures risked functional impairment, growth plate damage, and recurrence, especially in children at critical developmental stages.^12,13 Such interventions can lead to long-term sequelae like limb length discrepancy, joint dysfunction, and impaired bone quality and mineral density.

Recent years have seen a strategic shift toward exploring pharmacological interventions and minimally invasive techniques, aiming to balance efficacy with functional preservation. As understanding of the molecular mechanisms of benign bone tumors deepens, individualized and minimally invasive approaches have become new standards. For example, in giant cell tumor of bone (GCTB), traditional wide resection carries a 5%–15% recurrence rate.^14–16 The use of denosumab, a targeted drug blocking the Receptor activator of NF-κB/Receptor activator of NF-κB ligand (RANK/RANKL) signaling pathway, has significantly reduced the need for more radical surgery. Clinical studies show that denosumab can allow some patients to avoid surgery altogether or undergo only limited resection while maintaining treatment safety.¹⁷

Similarly, adjuvant techniques, such as cryotherapy, have been increasingly adopted as part of extended intralesional procedures for selected benign aggressive tumors (e.g., aneurysmal bone cyst and chondroblastoma), with some reports suggesting potential improvement in local control; however, outcomes remain technique- and selection-dependent.⁸

These advances collectively drive the transformation of benign bone tumor treatment from a purely surgical approach to a more diversified, function-preserving strategy (Table 1).

Innovations in diagnosis and assessment

Malignant sarcomas: Entering the era of molecular and functional imaging

Rapid advances in molecular diagnostics have fundamentally changed the diagnosis and classification of pediatric malignant bone tumors. Over the past decade, an increasingly widespread use of next-generation sequencing approaches has provided deeper insights into the molecular biology of osteosarcoma and Ewing sarcoma.²

Osteosarcoma is characterized by a highly complex and unstable genome. Chromothripsis—the cataclysmic shattering and reassembly of single or multiple chromosomes—is present in nearly two-thirds of osteosarcomas.¹⁸ Inactivation of key tumor suppressor pathways, genes like TP53 and RB1, and dysregulation of signaling pathways, such as mTOR and Wnt, are confirmed drivers of tumorigenesis.^19,20 Importantly, a subset of osteosarcomas seems to develop homologous recombination deficiency (HRD), similar to breast cancer susceptibility gene-mutant tumors, providing a rationale for therapeutically exploring Poly (Adenosine Diphosphate Ribose) polymerase (PARP) inhibitors,²¹ though studies have shown variable sensitivity potentially linked to molecular subgroups.²⁰

The core driver of Ewing sarcoma is a gene fusion between members of the FET and ETS gene families, most commonly EWSR1-FLI1.²² This fusion transcription factor acts as a “pioneer factor,” massively remodeling the chromatin landscape and epigenetic state through specific histone modifications, DNA methylation changes at promoters/enhancers and acetylation, thereby activating specific oncogenic transcription programs.²³ This profound epigenetic reprogramming is key to oncogenesis,²⁴ making targeting involved epigenetic regulators an attractive new strategy.²⁵

Liquid biopsy is an emerging monitoring tool that can detect specific variants or even gene fusions in circulating tumor DNA.²⁶ This noninvasive method holds promise for real-time therapy response monitoring, highly sensitive detection of minimal residual disease during remission for early relapse warning, and assessment of occult or metastatic disease.²⁷ While not yet routine clinical practice for Ewing sarcoma, liquid biopsy is a hot research topic due to the disease’s known molecular driver.

In imaging, functional metabolic imaging has become a core standard. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), as a representative whole-body functional imaging technique, provides a maximum standardized uptake value (SUVmax) that serves as a key parameter. In addition, hybrid FDG-PET/MRI is increasingly used, enabling combined whole-body metabolic assessment and high-contrast soft-tissue evaluation in a single session while reducing radiation exposure by avoiding the CT component.²⁸ It is used not only for precise staging but also as an important indicator of treatment response (quantitative SUVmax changes predict progression) and a prognostic biomarker.²⁹ Studies suggest that dynamic SUVmax changes in FDG uptake parameters (including SUVmax) are associated with treatment response and prognosis in high-grade bone sarcomas.³⁰

Simultaneously, whole-body magnetic resonance imaging (WB-MRI) with diffusion-weighted imaging (DWI) offers a radiation-free whole-body assessment, avoiding ionizing radiation risks. This technique excels at detecting bone marrow metastases and shows superior sensitivity to traditional bone scans in assessing CNS and abdominal organ involvement.^31,32 Its lack of radiation makes it ideal for patients requiring long-term, multi-phase follow-up, especially radiation-sensitive children²⁸ (Table 2).

Table 2.

Innovations in diagnostic and evaluation technologies.

Classification	Technical focus	Key advances	Clinical application/value	Evidence sources
Malignant bone tumors	Molecular diagnosis	Osteosarcoma shows high genomic complexity with chromothripsis; inactivation of TP53/RB1; aberrant PI3K/mTOR/AKT and Wnt signaling; a subset exhibits HRD.	Provides rationale for PARP inhibitors and supports molecular subtyping and precision therapy.	(2,18,21)
Malignant bone tumors	Molecular diagnosis (Ewing sarcoma)	Core drivers are EWS-FLI1 or EWS-ERG fusions; fusion proteins induce epigenetic reprogramming (chromatin/DNA methylation changes).	Specific diagnostic biomarkers, chromatin-regulating complexes (e.g., BAF) are promising therapeutic targets.	(4,22–25)
Malignant bone tumors	Liquid biopsy	Detection of ctDNA and specific fusion fragments.	Noninvasive dynamic response monitoring, early MRD detection, and relapse-risk prediction.	(26,27)
Malignant bone tumors	Functional & metabolic imaging (FDG-PET/CT)	Changes in SUV-derived parameters have been investigated as response and prognostic biomarkers.	SUV-derived parameters have been explored as potential prognostic biomarkers in some series.	(28,30)
Malignant bone tumors	Functional imaging (WB-MRI + DWI)	Radiation-free whole-body assessment; superior to bone scan for marrow involvement.	Suitable for long-term pediatric follow-up; low radiation risk.	(28,31,32)
Benign bone tumors	High-resolution imaging	MRI/CT delineate anatomy and soft-tissue relations; DCE-MRI & DWI help distinguish hypervascular ABC from hypovascular SBC.	Improves diagnostic accuracy and surgical planning.	(33,34)
Benign bone tumors	Molecular pathology	Chondroblastoma: H3F3B/H3F3A K36M; GCTB: H3F3A G34W; HME: EXT1/2 loss; NOF: RAS/MAPK pathway mutations.	Establishes molecular subtypes; increases diagnostic specificity, and guides individualized care.	(35–40)
Benign bone tumors	Molecular imaging probes & radiomics	CAIX-targeted nanobubbles and structure–function fusion MRI probes.	Molecular-level benign–malignant discrimination; personalized risk-prediction models.	(41,42)

TP53: tumor protein p53; RB1: Retinoblastoma 1; mTOR: mechanistic target of rapamycin; HRD: homologous recombination deficiency; EWS-FLI1: Ewing sarcoma breakpoint region 1–Friend leukemia integration 1 fusion; EWS-ERG: Ewing sarcoma breakpoint region 1–ETS-related gene fusion; DNA: deoxyribonucleic acid; ctDNA: circulating tumor DNA; MRD: minimal residual disease; MRI: magnetic resonance imaging; CAIX: carbonic anhydrase IX; ABC: aneurysmal bone cyst; SBC: simple bone cyst; GCTB: giant cell tumor of bone; HME: hereditary multiple exostoses; NOF: non-ossifying fibroma; RAS/MAPK: Rat Sarcoma virus oncoprotein/Mitogen-Activated Protein Kinase; FDG-PET/CT: fluorodeoxyglucose positron emission tomography/computed tomography; SUV: standardized uptake value; WB-MRI: whole-body magnetic resonance imaging; DWI: diffusion-weighted imaging; DCE: dynamic contrast-enhanced; PARP: poly (ADP-ribose) polymerase.

Benign tumors: Precision in imaging and pathology

The diagnostics of benign bone tumors is also evolving from a purely morphologic to a molecularly enhanced approach, aiming to increase specificity and reduce unnecessary invasive procedures through multimodal techniques.

Advances in imaging

High-resolution MRI and CT significantly improve the assessment of tumor extent, proximity to growth plates, and soft tissue infiltration, providing precise spatial guidance for surgical planning. Advanced sequences like dynamic contrast-enhanced MRI (DCE-MRI) and DWI further enhance the assessment of tumor biology. For instance, highly vascular aneurysmal bone cysts (ABC) show high perfusion and rapid enhancement on DCE-MRI, while less vascular simple bone cysts exhibit low perfusion and slow enhancement, aiding differentiation.^33,34 Molecular imaging probes, like nano-bubbles targeting Carbonic anhydrase IX, enable specific tracing of the tumor microenvironment (TME).⁴¹ The development of structure–function dual-modal MRI probes further facilitates molecular-level discrimination between benign and malignant tumors.⁴²

Integrated PET-MRI has emerged as a powerful hybrid modality, combining the metabolic quantification of PET with the superior soft-tissue resolution and functional imaging capabilities (e.g., DWI) of MRI in a single session. This synergy not only enhances diagnostic accuracy for primary staging and the detection of bone marrow metastases but also significantly reduces overall radiation exposure compared with standalone PET-CT or sequential PET-CT and MRI examinations. The reduced radiation dose is particularly advantageous for pediatric patients who require long-term follow-up.²⁸

Contributions of molecular pathology

In chondroblastoma, H3-3B p.K36M variants demonstrate high sensitivity and specificity in routine histology, significantly improving diagnostic accuracy for challenging cases.³⁵ GCTB typically harbors H3-3A p.G34W mutations, and the G34W-specific immunohistochemical antibody can help to distinguish morphological mimics.³⁶ For osteochondroma/multiple hereditary exostoses (HME), EXT1/EXT2 variants have been shown to represent the genetic drivers,³⁷ with HME patients having a significantly higher risk of developing secondary chondrosarcoma, warranting closer follow-up based on imaging, including evaluation of cartilage cap thickness as a key imaging feature. Non-ossifying fibroma and brown tumors in hyperparathyroidism have been reported to be RAS/MAPK(Rat Sarcoma virus oncoprotein/Mitogen-Activated Protein Kinase) pathway-driven and to harbor KRAS and FGFR1 mutations.^38–40 ABCs show USP6 rearrangements, and solitary bone cysts harbor underlying EWSR1::NFATC2 fusions.⁴³ Taken together, in the past 10–15 years, recurrent genetic drivers have been identified for the majority of benign bone tumors that can facilitate and objectify the diagnosis (Table 2).

Clinical translation

Integrating these technologies builds better prognostic models. Combining radiomic features with molecular subtyping allows clinicians to accurately predict the tumor’s natural course and plan individualized intervention strategies.

Evolution of treatment strategies and new options

Systemic therapy for malignant sarcomas: Beyond conventional chemotherapy

Chemotherapy optimization and toxicity management

Chemotherapy remains the cornerstone and first-line standard for osteosarcoma. The MAP regimen (high-dose Methotrexate, Adriamycin(doxorubicin), Platinol(cisplatin)) administered perioperatively, combined with radical resection, significantly improves outcomes compared to surgery alone.⁴⁴ For patients with a poor histological response to preoperative MAP (<90% tumor necrosis), postoperative intensification with ifosfamide or IE failed to improve survival and significantly increased toxicity in both the international European and American Osteosarcoma Study Group trial-1 and Japanese JCOG0905 randomized trials.^45,46 Therefore, completing standard MAP postoperatively, even after a poor response, is the evidence-based recommendation, avoiding ineffective intensification and added toxicity.

Breakthroughs in targeted therapy

Overall, the molecular heterogeneity and “low drug ability” of the highly unstable genome of osteosarcomas are one reason why targeted therapies mostly offer only an “incremental benefit,” particularly without a uniform standard beyond second-line. In relapsed/metastatic settings, regorafenib significantly prolonged progression-free survival (3.6 vs. 1.7 months; HR≈0.42) in a randomized, double-blind, placebo-controlled phase II study, confirming its activity in refractory osteosarcoma.⁴⁷ Cabozantinib showed anti-tumor activity signals in osteosarcoma and Ewing sarcoma cohorts in the French multicenter CABONE single-arm phase II trial,⁴⁸ but evidence remains limited due to the non-controlled design.

Repositioning and innovative exploration of immunotherapy

Overall, modern immunotherapy provides limited single-agent benefit in osteosarcoma. Key obstacles include an immunologically “cold” TME and limited T-cell infiltration, shifting research focus toward modifying the TME and cell therapies. Adding muramyl tripeptide to chemotherapy reportedly increased 6-year survival from 70% to 78% in osteosarcoma patients.⁴⁹ This drug is European Medicines Agency (EMA)-approved for combination with chemotherapy in non-metastatic high-risk osteosarcoma but not FDA-approved, possibly due to differing regulatory assessments of evidence levels. Early Chimeric antigen receptor T cells studies directed against different targets (HER2⁵⁰ or GD2⁵¹) in relapsed/refractory osteosarcoma showed feasibility and acceptable safety but limited objective responses, suggesting a need for combination/sequential strategies and microenvironment remodeling to amplify efficacy. Tumor-associated macrophages play a crucial role in the immunosuppressive properties of the TME. Drugs like pexidartinib can reprogram these cells and promote T-cell infiltration in sarcoma models,⁵² but clinical translation remains in its early stages. The feasibility of combining it with immune checkpoint inhibitors and the optimal combination regimen still requires prospective validation (Table 3).

Table 3.

Systemic therapy for malignant bone tumors: Key evidence and clinical positioning.

Therapeutic direction/drug	Evidence/key study	Main findings	Clinical setting/population	Level of evidence
Perioperative chemotherapy (MAP)	(2,3,10)	Remains cornerstone for localized osteosarcoma; outcomes depend on surgical quality.	Newly diagnosed, localized osteosarcoma.	Guidelines/historical RCTs
Post-op Intensification: MAP + IE (EURAMOS-1)	(46)	No EFS benefit in poor responders; increased toxicity.	Poor responders to neoadjuvant chemo.	RCT
Post-op Intensification: MAP + IF (JCOG0905)	(45)	No survival benefit; more toxicity.	Poor responders.	RCT
Regorafenib	(47)	PFS 3.6 vs. 1.7 months; HR ≈ 0.42.	Relapsed/metastatic osteosarcoma.	Randomized Phase II
Cabozantinib (CABONE)	(48)	6-month PFS ≈ 33%, ORR ≈ 12% (single arm).	Refractory osteosarcoma/Ewing sarcoma.	Phase II, single arm
Mifamurtide (with chemo)	(49)	OS benefit signal; approved in EU (not FDA).	Non-metastatic high-risk osteosarcoma.	Regulatory/re-analysis
HER2/GD2 CAR-T	(50,51)	Safe and feasible; limited objective responses.	Refractory/relapsed osteosarcoma/Ewing.	Phase I/Reviews
CSF-1R Inhibitors (pexidartinib)	(52)	Reprograms TAMs and enhances T-cell infiltration; early-stage evidence.	Combination/exploratory therapy.	Translational/early data

EURAMOS: European and American Osteosarcoma Study Group Trial 1; EFS: event-free survival; MAP: Methotrexate, Adriamycin(doxorubicin), Platinol(cisplatin); PFS: progression-free survival; OS: overall survival; ORR: objective response rate; HR: hazard ratio; CAR-T: chimeric antigen receptor T cells; HER2: human epidermal growth factor receptor 2; CSF-1R: colony-stimulating factor 1 receptor; TAMs: tumor-associated macrophages; RCT: randomized controlled trial.

Updates in radiotherapy strategies and techniques

For lung metastases in Ewing sarcoma, multidisciplinary consensus favors adding whole lung irradiation (WLI) to systemic therapy. The recommended dose is typically 15 Gy in 10 fractions (12 Gy/8 fractions for children <5 years), using heart-sparing IMRT or proton techniques to reduce late toxicity.⁵³ Proton therapy in pediatric sarcomas maintains local control while reducing dose to normal tissues and long-term adverse effects, with multiple cohorts and prospective studies consistently showing improved quality of life and low rates of severe late toxicity.^54,55 The exact contribution of WLI to overall survival remains debated, so indications and doses must be individualized based on metastatic burden, age, and concurrent medications.⁵⁶

Innovations in benign bone tumor treatment

Driven by growing molecular and microenvironment understanding, benign bone tumor treatment has shifted from “surgery alone” to a “drugs—minimally invasive—functional preservation” framework, aligning with the “de-escalation + individual stratification” concept in malignant tumors.

Denosumab (Anti-RANKL)

Denosumab, by inhibiting the RANKL-osteoclast axis, is FDA- and EMA-approved for unresectable or resection-morbid adult and skeletally mature adolescent GCTB, establishing “anti-osteoclast therapy” for benign/low-grade bone tumors.⁵⁷ In respectable GCTB, short-course preoperative denosumab can shrink the tumor and induce reactive ossification, facilitating joint and critical structure preservation. However, debates continue regarding recurrence risk, optimal dose, treatment duration, dosing intervals, and even malignant transformation, requiring individualized approaches.⁵⁸ For ABCs, systematic reviews suggest symptomatic relief and imaging improvement in refractory/recurrent cases,⁵⁹ but randomized controlled evidence is lacking, recommending use in selected cases or research settings with multidisciplinary and ethical oversight. Regarding osteosarcoma, current evidence is mostly mechanistic and preclinical⁶⁰ (Table 4).

Table 4.

Therapies for benign bone tumors: Pharmacologic and minimally invasive approaches.

Intervention/drug	Key evidence	Main conclusion	Applicable population/scenario	Level of evidence
Denosumab (GCTB)	(57,58)	Reduces tumor size and promotes ossification; established role in unresectable or function-threatening cases; duration and discontinuation timing under debate.	Giant cell tumor (adults/skeletally mature adolescents).	Phase II/real-world evidence
Denosumab for ABC	(59)	Provides symptom relief and radiologic improvement in refractory/recurrent ABC (non-RCT).	Selected or research cases.	Retrospective/small series
Bisphosphonates (ABC/LCH)	(61,62)	Relieves pain, promotes bone healing; higher-quality data needed.	Recurrent or surgically difficult cases.	Retrospective/small cohort
Bisphosphonate in pediatric growth	(63)	Risk of delayed tooth eruption/root development; requires monitoring.	Pediatric/adolescent management.	Experimental/observational
Cryotherapy (intracavitary adjuvant)	(8,64)	Reduces recurrence after curettage; caution for fracture/skin necrosis.	Locally aggressive benign lesions.	Retrospective/cohort
UBC cavity treatment + bone substitute	(65)	Low recurrence, good function in long-term follow-up.	UBC	Cohort
Osteoid Osteoma: CT-guided RFA	(66–68)	Technical success >90%, durable remission; repeatable for recurrence.	Spinal/non-spinal osteoid osteoma.	Systematic review/comparative studies

GCTB: giant cell tumor of bone; ABC: aneurysmal bone cyst; LCH: Langerhans cell histiocytosis; UBC: unicameral bone cyst; CT: computed tomography; RFA: radiofrequency ablation; RCT: randomized controlled trial.

Bisphosphonates

Bisphosphonates (zoledronic acid, pamidronate), also inhibiting osteoclasts, can serve as an adjunct or alternative strategy in recurrent or surgically challenging ABC cases. Prospective small cohorts report safety, feasibility, and structural improvement.⁶¹ The lesion will ossify within 6–12 months. In Langerhans cell histiocytosis of bone, a retrospective cohort study suggested bisphosphonates to provide pain relief and bone remodeling,⁶² but prospective validation is needed to define suitable populations and timing. An animal study indicated zoledronic acid could cause growth-related adverse effects like delayed tooth eruption and affected root development,⁶³ necessitating careful risk-benefit assessment and oral monitoring in children/adolescents. By contrast, evidence for anti-RANKL effects on dentition is scarcer but still warrants caution.

Technological iterations in surgery and local therapy

Driven by precision medicine, surgical and local therapy techniques for pediatric bone tumors are undergoing profound changes. Building on advanced diagnostic assessment and molecular biological knowledge, surgical goals have evolved from simple excision to eradicate tumors while maximizing functional preservation and long-term quality of life.

Surgical reconstruction strategies: From limb salvage to functional outcomes

Building on precise preoperative planning with 3D imaging and navigation, the surgical management of pediatric bone tumors spans a spectrum of reconstructive strategies. The choice depends on tumor location and extent, patient age and skeletal maturity, expected functional needs, and patient preferences, guided by a multidisciplinary team. Decisions are ideally made within a multidisciplinary team, balancing durable local control with long-term function and growth-related considerations.

Limb-salvage reconstruction modalities

Limb-salvage reconstruction can be categorized into anatomical restoration (biological reconstruction or endoprosthesis) and functional conversion procedures (such as rotationplasty).

Biological reconstruction utilizing the host’s integration and remodeling potential. Allografting of large bone blocks enables immediate structural repair and allows for anatomical reconstruction, but carries risks of nonunion, fracture, infection, and late-stage structural degeneration.⁶⁹ It often requires long-term protection and close monitoring. Vascularized fibular autografts (including single or double-barrel configurations) offer living bone with superior biological potential for union; when combined with an allograft, they may improve revascularization and durability in large intercalary defects.⁷⁰ These techniques, however, remain technically demanding and may incur donor-site morbidity. Distraction osteogenesis (bone transport) is another option for selected segmental defects, avoiding allograft-related complications, but it typically requires prolonged external fixation and intensive follow-up with potential issues such as pin-tract infection, joint stiffness, and patient burden.⁷¹

Contemporary expandable systems allow staged or less invasive lengthening in selected cases and may facilitate earlier mobilization and predictable alignment restoration. Endoprosthetic reconstruction using modular or expandable implants addresses large skeletal defects and the challenge of limb-length discrepancy in growing children, though challenges such as high infection rates persist.⁷² Patient-specific and 3D-printed porous metal components can be used to better match anatomy and promote osseointegration, particularly in complex defects; nevertheless, long-term durability data in children remain limited.⁷³ While endoprostheses often provide excellent early function, but recognized complications include aseptic loosening, mechanical failure, periprosthetic fracture, and infection, which may necessitate revision surgery over time.

Rotationplasty remains an established, function-preserving option for selected young patients with tumors around the knee. By preserving the neurovascular bundle and reorienting the ankle to function as a knee joint, rotationplasty can offer durable biomechanics, high activity potential, and energy-efficient gait compared with transfemoral amputation.⁷⁴ Given its aesthetic and psychosocial implications, careful patient selection and structured preoperative counseling are essential.

Amputation and palliative surgery

When limb salvage is not possible—such as with extensive tumor involvement, unreconstructable soft-tissue compromise, critical neurovascular encasement, or uncontrolled infection—amputation remains a definitive oncologic option to achieve local control and relieve symptoms. With modern prosthetic design and coordinated rehabilitation, meaningful functional recovery can be achieved in many patients. In advanced disease settings, surgical goals may shift toward palliation, prioritizing pain control, stability, and quality of life, with procedures tailored accordingly.

The role of advanced planning and emerging technologies

Advanced planning tools, including computer-assisted navigation, patient-specific 3D-printed cutting guides, and anatomical models, are now routinely integrated across various reconstruction approaches.⁷⁵ These technologies enhance the accuracy of osteotomy and help achieve margin-targeted resection, thereby improving surgical reproducibility (Figure 1).

Figure 1.

(a) 5-year-old patient with Ewing’s sarcoma of the distal femur underwent limb-sparing surgery following neoadjuvant chemotherapy (90% tumor necrosis). The tumor did not break through the distal physis, so we could save the knee joint and plan the resection on the computer with the patient-specific cutting guides and the corresponding allograft box after receiving the CT data of the elected allograft. Also, due to the limited amount of space, we planned a custom-made titanium plate. (b) The final 3D products (3D model, allograft box, and custom-made plate). (c) Resection guides with soft tissue and resected specimen. (d) Allograft resection in the box and inserted with the vascularized fibula. (e) Implanted allograft with vascularized fibula and implanted custom-made plate. (f) Postoperative X-rays of the left femur. (g) 5-year follow-up examination with femoral neck screws removed due to growth—patient has excellent function. (h) Full-length supine X-ray at 8-year follow-up.

In parallel, tissue-engineering approaches, including bioactive and biodegradable scaffolds combined with growth factors and cellular strategies, are being explored to enhance biological integration and may provide future growth-adaptive solutions in selected pediatric reconstructions.

Integration of minimally invasive techniques and biotherapy

The combination of minimally invasive interventions and biotherapy has significantly altered the treatment paradigm for benign and aggressive bone tumors. Cryotherapy, as an adjuvant to curettage, uses liquid nitrogen deep freezing of the cavity to effectively reduce recurrence risk in ABC and some chondroblastomas and GCTBs, though attention to complications like fracture and skin necrosis is necessary, requiring standardized temperature control and protection techniques.⁶⁴ After curettage combined with intraoperative cryotherapy, lesions can be adequately treated while preserving bone structure, enabling early functional rehabilitation (Figure 2). Percutaneous or mini-open cavity decompression with calcium phosphate cement or calcium sulfate filling achieves low recurrence rates and good function in long-term follow-up and may be particularly suitable for weight-bearing sites (especially the proximal femur) and other locations at high risk of pathological fracture.⁶⁵ CT-guided radiofrequency ablation (RFA) has become a preferred minimally invasive standard for osteoid osteoma, with near-100% technical success, ~90% long-term clinical remission, and low complication rates; recurrent cases can undergo repeated ablation.⁶⁶ Multiple systematic reviews and cohort studies show RFA to be equivalent to or even show superior effectiveness and safety compared to surgery for osteoid osteoma, with advantages also in hospitalization costs.^67,68 Simultaneously, drug therapy creates new possibilities for other surgical strategies: preoperative denosumab can shrink GCTB and ossify the margins, creating conditions for limb-salvage surgery; bisphosphonates show promotion of bone repair in ABC and other neoplasms.

Figure 2.

(a) A 9-year-old patient has an aneurysmal bone cyst (3D CT). (b) MRI following biopsy and cryotherapy (first, a sample is taken from the adjacent bone using a 15G bone punch biopsy system and sent for histological analysis. (c) Then, the 17G cryoablation needle (White Plus Sign) is inserted through the same channel—white arrow). To protect the adjacent soft tissues (vagina, including urethra and pudendal nerve), perform NaCl hydrodissection—this results in a clear separation of these structures. Then perform cryoablation (white arrow) for benign findings using a conservative protocol (10 minutes of freezing, 10 minutes of thawing, 7 minutes of freezing at 60%), with early functional recovery (d) 2 months postoperative (e): 4 months postoperative.

Future prospects and challenges

The advent of the precision medicine era brings new opportunities and challenges to the treatment of pediatric bone tumors. Based on current technological developments and clinical practice, future research will explore molecular stratification, immune microenvironment regulation, surgical innovation, and long-term quality of life.

Deepening molecular stratification and individualized therapy

Future treatment strategies will rely more heavily on in-depth molecular subtyping. New technologies like single-cell sequencing and spatial transcriptomics promise to better understand the complex mechanisms of tumor heterogeneity and microenvironment interactions, providing a theoretical basis for developing new therapeutic targets. For example, confirming a HRD signature in osteosarcoma may justify the use of PARP inhibitors. Optimizing and standardizing liquid biopsy technology will become a vital component of a disease-monitoring system, enabling truly dynamic individualized therapy approaches.

Breakthroughs in immunotherapy and targeted drugs

Although immune checkpoint inhibitors have shown limited single-agent efficacy in malignant bone tumors so far, combination strategies targeting the tumor immune microenvironment represent an important option. Future research will focus on combining colony-stimulating-factor 1 inhibitors with immune-checkpoint inhibitors or adoptive cell therapy to overcome current immunotherapy resistance. Meanwhile, novel antibody–drug conjugates targeting B7 homolog 3 show promise in early clinical trials. Developing new drugs for rare mutations and innovating drug delivery systems will also be key to enhancing efficacy and reducing toxicity.

Innovation in surgical techniques and rehabilitation systems

Surgical technology will continue to evolve toward precision and minimally invasive directions. Robot-assisted surgery and augmented reality navigation are expected to further improve tumor resection accuracy. Progress in biomaterials will drive the development of bioactive, biodegradable implants that better suit the growth and development needs of pediatric patients. Integrating intelligent rehabilitation systems with exoskeleton robots will achieve individualized and data-driven postoperative rehabilitation, significantly improving functional recovery. Furthermore, prognostic prediction models based on big data and artificial intelligence will help clinicians optimize surgical timing and surgical program selection.

Emphasis on quality of survival and long-term follow-up

As cure rates improve, survivors’ long-term quality of life receives increasing attention. Future efforts need to establish more systematic long-term follow-up systems, focusing on monitoring and managing late effects of treatment, such as cardiomyopathy, secondary cancers, and infertility. Developing function-preserving treatment strategies to reduce sequelae like limb dysfunction and affected growth will become a crucial treatment goal. Simultaneously, the individual needs for psychological support of patients and their families must be integrated into the standard treatment process.

Conclusion

Over the past two decades, the field of pediatric bone tumors has successfully moved beyond a long therapeutic plateau and entered a new era of precision medicine. This progress stems from the synergistic development and integration of molecular diagnostics, imaging methods, and surgical treatment strategies. For malignant bone tumors, molecular stratification has deepened our understanding of disease biology and opened new avenues for targeted and immunotherapy, while innovations like 3D printing, navigation, and minimally invasive techniques have driven a profound shift from radical resection to functional reconstruction. In benign tumors, applying targeted drugs like denosumab and refining minimally invasive techniques like cryotherapy have helped improve the balance between disease control and functional preservation. Importantly, for benign—particularly benign-aggressive—tumors, reducing local recurrence while preserving function remains a central challenge and should be a key focus of future optimization. The ongoing refinement of the multidisciplinary collaboration model ensures the precise implementation and optimization of individualized treatment plans. Looking ahead, despite persistent challenges in research on rare tumor subtypes, immunotherapy breakthroughs, long-term quality of life improvement, integration of artificial intelligence, and interdisciplinary cooperation will undoubtedly steer pediatric bone tumor diagnosis and treatment toward greater precision, minimal invasiveness, and individualization, ultimately achieving the dual goals of improving survival rates and quality of life for all affected children.

Supplemental Material

sj-pdf-1-cho-10.1177_18632521261444250 – Supplemental material for What’s new in pediatric bone sarcomas and benign bone tumors

Supplemental material, sj-pdf-1-cho-10.1177_18632521261444250 for What’s new in pediatric bone sarcomas and benign bone tumors by Nicolas von der Weid, Daniel Baumhoer and Andreas H Krieg in Journal of Children's Orthopaedics

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Nicolas von der Weid

Andreas H Krieg

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