A two-decade analysis of more than a quarter-million pediatric cancer cases shows that overall survival continues to improve, but the gains have not been shared equally across diagnoses, demographic groups, or regions of the United States. Rhabdomyosarcoma, an aggressive childhood soft-tissue tumor known for its propensity for local invasion and distant metastasis, clearly illustrates the problem. Children with localized disease now have substantially better outcomes, while survival for high-risk and metastatic disease has changed little over the past several years. That disparity has pushed researchers to examine not only the tumor cells themselves but also the surrounding tissue.
Key Takeaways
- A national analysis of 272,279 pediatric cancer cases diagnosed from 2001 to 2021 found that 5-year relative survival increased from 83.0% to 86.8% over the study period. Survival remained lower among infants, non-Hispanic Black patients, and patients living in lower-income or non-Northeastern counties.[1]
- Rhabdomyosarcoma remains an uneven disease. Five-year survival for intermediate-risk patients is now 50%-70%, while the approximately one in five patients classified as high-risk continues to face 5-year survival of only 20%-30%.[2][3]
- Raya Saab, MD, a pediatric oncologist at Stanford Cancer Institute, and colleagues are studying how rhabdomyosarcoma spreads, including the role of tumor-secreted small extracellular vesicles and the surface protein CD147, which appears to help recruit surrounding tissue into metastasis.[4][5]
Progress, Unevenly Distributed
A new analysis published in Cancer provides a broad view of how children and adolescents with cancer in the United States have fared since the beginning of this century. Jason M. Stevenson, MD, MSCR, a pediatric hematologist-oncologist, led the study at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta and Emory University, with colleagues from Emory, the Centers for Disease Control and Prevention (CDC), and Cyberdata Technologies.[1] Using data from the National Program of Cancer Registries, which covers an estimated 87.4% of the U.S. population, the investigators examined 272,279 cancers diagnosed in patients younger than 20 years between 2001 and 2021. They calculated 5- and 10-year relative survival and analyzed the results by age, sex, race and ethnicity, U.S. Census region, county-level economic status, cancer type, stage, and year of diagnosis.[1]
Across the entire study period, 5-year relative survival was 84.7%, while 10-year relative survival was 82.3%. All-cause 10-year survival, calculated separately using the Kaplan-Meier method, was 81.7%.[1] Survival also improved over time. Five-year relative survival increased from 83.0% among children diagnosed during 2001-2011 to 86.8% among those diagnosed during 2012-2021, an absolute increase of 3.8 percentage points.[1] Approximately 15,000 children and adolescents in the United States are diagnosed with cancer each year. Although cancer remains the second leading cause of death in this age group, overall survival has now moved well above 80%.[1]
The national numbers, however, hide important differences.
Ten-year survival was higher among female patients than male patients. Adolescents aged 15 to 19 had the highest relative survival among the age groups studied, while infants younger than 1 year had the lowest.[1] Race and ethnicity showed the largest differences. Non-Hispanic Black patients had the lowest 5- and 10-year relative survival, at 79.2% and 76.3%, respectively, compared with 86.3% and 84.0% among non-Hispanic White patients.[1]
Geography and economic status were also associated with survival. Relative survival was highest among patients living in counties in the top economic-status quartile and among patients in the Northeast. The registry data do not establish why these differences exist, but access to specialized pediatric cancer centers, timely diagnosis, and the ability to complete intensive treatment are among the factors relevant to pediatric cancer care.[1]
The authors’ conclusion is straightforward: pediatric cancer survival has improved, but differences by age, sex, race and ethnicity, economic status, geography, and cancer type remain.[1] A national survival estimate describes outcomes across a population; it cannot predict the outcome for an individual child, whose prognosis depends heavily on the specific cancer and clinical characteristics.
Rhabdomyosarcoma as a Case Study
Rhabdomyosarcoma is one of the clearest examples of this uneven progress. In this disease, the major differences in outcome are closely tied to risk group and stage at diagnosis. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and adolescents. It arises from immature precursor cells that would normally develop into skeletal muscle and can occur almost anywhere in the body. The head and neck, genitourinary tract, and extremities are among the most common sites.[2]
Approximately 350 new cases are diagnosed each year in the United States. Clinicians classify patients by the tumor’s TNM stage, the clinical group assigned after initial surgery, and the presence or absence of a PAX3/FOXO1 or PAX7/FOXO1 fusion gene. Together, these factors place patients into low-, intermediate-, or high-risk groups with substantially different prognoses.[2] The prognostic differences between these groups remain striking. About half of pediatric patients with rhabdomyosarcoma are classified as intermediate-risk, with 5-year survival now ranging from 50% to 70%.[2][3] These outcomes reflect decades of refinement in chemotherapy, surgery, and radiation therapy. Overall, 5-year survival for localized disease has risen above 70%-80%. The longer-term improvement is also substantial. Among children younger than 15 years, 5-year relative survival for rhabdomyosarcoma increased from 53% in the mid-1970s to 71% in contemporary estimates.[3]
That progress has not extended equally to patients with the highest-risk disease. Approximately 20% of patients are classified as high-risk at diagnosis. Patients with metastatic disease at presentation and those whose disease recurs after initial treatment also continue to have poor outcomes. Five-year survival in these groups remains approximately 20%-30%, with relatively little change across successive treatment eras.[3] Adolescents and young adults with rhabdomyosarcoma also continue to have poorer outcomes than younger children, even within the same risk category.[3] Treatment for these patients remains based on the familiar combination of multi-agent chemotherapy, surgery, and radiation therapy directed at residual disease. These approaches have been refined over time, but no fundamentally different treatment strategy has replaced them for patients with high-risk or metastatic disease.[3]
The Biology of How Rhabdomyosarcoma Spreads
The limited progress in high-risk disease is one reason researchers are looking more closely at the biology of metastasis. Raya Saab, MD, the Lindhard Family Professor of Pediatric Cancer Biology at Stanford, leads a research program focused on why rhabdomyosarcoma invades and metastasizes. Her laboratory is studying the signaling pathways involved in tumor invasion and spread, with the longer-term goal of identifying potential therapeutic targets.[4]
Saab has identified metastasis and recurrence as major reasons treatment fails in intermediate- and high-risk rhabdomyosarcoma. Her group’s work therefore focuses on understanding the biological mechanisms that allow tumor cells to invade surrounding tissue and spread to distant sites.[4] One area of investigation involves tumor-cell differentiation. Rhabdomyosarcoma cells resemble immature muscle precursor cells. Mature skeletal muscle cells normally stop dividing once they have completed differentiation. Saab’s laboratory has therefore examined whether pushing rhabdomyosarcoma cells further along the differentiation pathway could stop them from proliferating.
Her laboratory has identified retinoic acid, a vitamin A-related compound with established roles in cellular differentiation, as one agent capable of promoting this process. The research has also examined whether differentiation-promoting strategies can be combined with existing treatment to improve responses.[4] Retinoic acid alone, however, does not appear to be sufficient to complete tumor-cell maturation, and identifying complementary agents remains an area of investigation.[4] A second line of research takes a different approach: examining what happens outside the tumor cell.
Rhabdomyosarcoma cells can release small extracellular vesicles, including exosomes, that carry molecular cargo into the surrounding environment. A peer-reviewed study involving Saab and colleagues, published in Cells in 2022, examined CD147, also known as Basigin or EMMPRIN, a transmembrane surface protein found in rhabdomyosarcoma-derived exosomes.[5] In human tumor tissue examined in that study, CD147 expression was observed exclusively in metastatic rather than localized tumors.[5] Laboratory experiments showed that exosomes released by rhabdomyosarcoma cells increased the proliferation, migration, and invasive capacity of normal fibroblasts, the connective-tissue cells that make up much of the tumor microenvironment.
When CD147 was downregulated in the tumor cells producing the exosomes, both the tumor cells’ invasive capacity and the ability of their exosomes to activate surrounding fibroblasts were substantially reduced.[5] CD147 spans the cell membrane, with domains exposed on both the inner and outer surfaces. Its structure makes it a potential target for antibody-based or small-molecule approaches. Researchers have investigated such strategies in other cancers, but CD147-targeted therapy has not yet entered clinical testing for rhabdomyosarcoma.[5]
Saab’s group has also reported molecular differences among rhabdomyosarcomas. Researchers have identified four molecular subtypes, each associated with different signaling pathways. Work from Saab’s laboratory indicates that these subtypes can also release extracellular vesicles containing different molecular cargo.[4] These findings suggest that the mechanisms driving metastasis may differ between molecular subtypes. However, current rhabdomyosarcoma treatment is not yet tailored to these subtypes. Saab has identified this lack of molecularly directed treatment, together with the limited options for recurrent and metastatic disease, as important unmet needs.[4]
To study these differences, Saab’s laboratory is working with the Stanford Bass Center Tissue Biorepository to develop laboratory models from patient-donated tumor samples.[4] The goal is to better represent the histologic diversity of sarcomas and to study how tumors with different cellular characteristics grow and respond to treatment. The laboratory is combining these models with single-cell and tissue-level technologies to examine the tumor and the surrounding tissue together.[4]
CD147: A Signal That Recurs Across Pediatric Tumor Types
The findings in rhabdomyosarcoma are part of a larger body of research on CD147 in cancer. A 2019 review in Cancers described CD147 as a glycoprotein involved in the regulation of the tumor microenvironment through several mechanisms, including induction of matrix-degrading proteinases and regulation of tumor-cell glycolysis. The review concluded that CD147 overexpression has prognostic significance across a range of solid and hematologic malignancies.[6]
A 2023 review examined CD147 expression in cancers of the central nervous system, head and neck, breast, lung, gastrointestinal tract, and skin.[7] The review described CD147 as an upstream inducer of matrix metalloproteinases, including MMP-2 and MMP-9. These enzymes degrade extracellular matrix components and can facilitate tumor invasion.[7] The same review also described CD147’s role as a chaperone for monocarboxylate transporters 1 and 4. These transporters help tumor cells export lactate generated through glycolysis. CD147 is required for efficient trafficking of these transporters to the cell surface.[7]
A separate 2024 review examined CD147 as a potential therapeutic target in hematologic malignancies, including leukemia, lymphoma, and myeloma.[8]
Research in other pediatric cancers provides additional examples of CD147 biology. In childhood posterior fossa type A ependymoma, the most common malignant pediatric brain tumor arising in the posterior fossa, a 2025 spatial-phenotyping study published in Laboratory Investigation examined CD147-expressing cells directly within tumor tissue.[9] Donatella Lucchetti and colleagues used multiplex imaging to map these cells and found that CD147-positive microglial cells were located closer to proliferating tumor cells and CD8-positive T cells in higher-grade tumors than in lower-grade tumors.[9] The investigators proposed that CD147-positive microglia may contribute to exclusion of cytotoxic T cells from the tumor microenvironment.
That proposed mechanism differs from the fibroblast-related findings in rhabdomyosarcoma, but both studies point to CD147 as a molecule associated with interactions between tumor cells and surrounding cells.[5][9] Another pediatric study examined CD147 in T-cell acute lymphoblastic leukemia (T-ALL). In a 2022 study published in Cancer Letters, researchers engineered T cells to express a CD147-directed chimeric antigen receptor. In laboratory experiments, the engineered cells killed human T-ALL cell lines and patient-derived leukemia cells, controlled leukemia progression, and extended survival in a mouse model of human T-ALL.[10] The study remains preclinical. No CD147-directed cellular therapy has been tested in children with T-ALL or rhabdomyosarcoma.[10] Nevertheless, the findings show that engineered immune cells can target CD147 and recognize CD147-expressing tumor cells under laboratory conditions.
The most clinically advanced example of CD147-directed treatment comes from an adult cancer. Metuximab (Licartin®; Chengdu Huasun Biotechnology Co)*, an antibody against CD147 developed in China and linked to radioactive iodine-131, was evaluated in a randomized phase 2 trial involving 156 patients with hepatocellular carcinoma after curative resection. In that study, 5-year relapse-free survival was 43.4% in the treated group compared with 21.7% in the control group. The 2023 review by Nyalali and colleagues reported a hazard ratio of 0.49, with only a small proportion of treated patients experiencing grade 3 or 4 adverse events.[7]
This provides clinical evidence that CD147 can be targeted therapeutically in at least one cancer type. It does not, however, establish that the same approach will work in rhabdomyosarcoma. In rhabdomyosarcoma, evidence for CD147 remains based on laboratory experiments and human tissue specimens rather than patient treatment.[5]
What Remains Unresolved
Neither research strategy discussed here has entered a clinical trial in rhabdomyosarcoma. Researchers have studied the differentiation-based approach in laboratory models. Although retinoic acid has a well-established role in normal cellular differentiation, no combination of differentiation-inducing agents has been shown to drive rhabdomyosarcoma cells to full maturation, and the strategy has not been tested for safety or efficacy in patients with rhabdomyosarcoma.[4]
The CD147 findings likewise remain preliminary. The rhabdomyosarcoma study was a peer-reviewed laboratory investigation involving cell lines and human tissue samples.[5] The association between CD147 expression and metastatic disease was clear in that dataset, but no CD147-targeted therapy has been evaluated in rhabdomyosarcoma in patients or in animal models.[5]
The significance of the four molecular subtypes also remains unclear. It is unclear whether the subtypes correspond to distinct, actionable therapeutic targets or whether pathways overlap.[4] The national survival analysis raises different questions. The Stevenson study was descriptive. It documented differences in survival by race and ethnicity, economic status, and geography, but the registry data cannot establish which factors account for those differences.[1] Potential contributors could include access to pediatric specialty centers, clinical trial participation, time to diagnosis, treatment adherence, or differences in tumor biology and subtype distribution. Determining the contribution of these factors will require additional research.[1]
Defined by Progress—and a Remaining Gap
National survival data and rhabdomyosarcoma research offer two views of the same problem. Pediatric cancer survival has improved substantially over the past two decades. Those gains reflect years of work refining chemotherapy, surgery, and radiation therapy across many different cancers. But the national numbers also show that improvement has not reached every patient equally. Rhabdomyosarcoma provides a particularly clear example. Most children with localized or intermediate-risk disease now have substantially better survival than patients treated in earlier treatment eras. For the approximately 20% with high-risk disease, however, survival remains poor, particularly when the disease is metastatic at diagnosis or returns after treatment.[3]
Research led by Saab and others addresses a central question behind that treatment gap: why do some rhabdomyosarcomas invade and spread while others do not? The answer is not yet known. Studies of tumor differentiation, extracellular vesicles, CD147, and the tumor microenvironment offer potential explanations and identify biological processes that could eventually be targeted. For now, however, these approaches remain experimental. For patients with high-risk or metastatic rhabdomyosarcoma, the need is clear: treatments that can prevent or control metastatic disease are still lacking. The next advances will depend on translating a better understanding of rhabdomyosarcoma biology into therapies that can be tested in patients.
Note: * The Chinese National Medical Products Administration (NMPA) approved Iodine-131 (¹³¹I) metuximab injection under the trade name Licartin®. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have not approved metuximab.
References
[1] Stevenson JM, Lupo PJ, Miller TP, Dai S, Henley SJ, Tai E, Boring MA, Siegel DA. Pediatric cancer survival in the United States from 2001 to 2021. Cancer. 2026 Jul 1;132(13):e70505. doi: 10.1002/cncr.70505. PMID: 42360091; PMCID: PMC13411459.
[2] American Cancer Society. Rhabdomyosarcoma Stages and Risk Groups. Online. Last accessed on September 6, 2026
[3] National Cancer Institute. Childhood Rhabdomyosarcoma Treatment (PDQ®)–Health Professional Version. Online. Last accessed on September 6, 2026
[4] Stanford Cancer Institute. Unraveling how a deadly childhood cancer spreads could keep it in its place [feature on Raya Saab, MD]. September 8, 2026.
[5] Fahs A, Hussein N, Zalzali H, Ramadan F, Ghamloush F, Tamim H, El Homsi M, Badran B, Boulos F, Tawil A, Ghayad SE, Saab R. CD147 Promotes Tumorigenesis via Exosome-Mediated Signaling in Rhabdomyosarcoma. Cells. 2022 Jul 22;11(15):2267. doi: 10.3390/cells11152267. PMID: 35892564; PMCID: PMC9331498.
[6] Landras A, Reger de Moura C, Jouenne F, Lebbe C, Menashi S, Mourah S. CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker. Cancers (Basel). 2019 Nov 16;11(11):1803. doi: 10.3390/cancers11111803. PMID: 31744072; PMCID: PMC6896083.
[7] Nyalali AMK, Leonard AU, Xu Y, Li H, Zhou J, Zhang X, Rugambwa TK, Shi X, Li F. CD147: an integral and potential molecule to abrogate hallmarks of cancer. Front Oncol. 2023 Nov 7;13:1238051. doi: 10.3389/fonc.2023.1238051. PMID: 38023152; PMCID: PMC10662318.
[8] Spinello I, Labbaye C, Saulle E. Metabolic Function and Therapeutic Potential of CD147 for Hematological Malignancies: An Overview. Int J Mol Sci. 2024 Aug 23;25(17):9178. doi: 10.3390/ijms25179178. PMID: 39273126; PMCID: PMC11395103.
[9] Lucchetti D, Colella F, d’Amati A, Servidei T, Gessi M, Chiara P, Cellini B, Toma F, Giacò L, Persiani F, Perelli L, Mantini G, Genovese G, Masetto I, Ruggiero A, Sgambato A. Spatial Analysis Identifies CD147 as a Novel Marker of High-Grade Childhood Posterior Fossa Ependymoma. Lab Invest. 2025 Jul;105(7):104175. doi: 10.1016/j.labinv.2025.104175. Epub 2025 Apr 16. PMID: 40250710.
[10] Lucchetti D, Colella F, d’Amati A, Servidei T, Gessi M, Chiara P, Cellini B, Toma F, Giacò L, Persiani F, Perelli L, Mantini G, Genovese G, Masetto I, Ruggiero A, Sgambato A. Spatial Analysis Identifies CD147 as a Novel Marker of High-Grade Childhood Posterior Fossa Ependymoma. Lab Invest. 2025 Jul;105(7):104175. doi: 10.1016/j.labinv.2025.104175. Epub 2025 Apr 16. PMID: 40250710.
[11] St. Jude Children’s Research Hospital. Rhabdomyosarcoma Treatment and Clinical Trials. Available at: https://www.stjude.org/care-treatment/treatment/childhood-cancer/solid-tumors/rhabdomyosarcoma.html
This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. The molecular findings and investigational strategies described here, specific to rhabdomyosarcoma, including differentiation-based approaches and CD147-targeted concepts, remain in preclinical laboratory research and have not been evaluated in clinical trials. CD147-directed radioimmunotherapy has reached a phase 2 clinical trial in hepatocellular carcinoma, an adult indication discussed here for context; no CD147-targeted therapy has been tested clinically in any pediatric cancer.
Featured image: © 2024 – 2026. Licensed under the Unsplash+ License. Used with permission.
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