The Relationship Between Circulating Tumor Cells in Peripheral Blood and Clinical Characteristics of Pediatric Neuroblastoma and Prognostic Evaluation

doi:10.21203/rs.3.rs-4864974/v1

Objective

This study aims to evaluate the relationship between the detection of circulating tumor cells (CTCs) in peripheral blood and the clinical characteristics and prognostic value of advanced (III-IV) pediatric neuroblastoma (NB).

Methods

This retrospective analysis included 144 children with advanced NB who received comprehensive treatment at our hospital from September 2020 to October 2022. Detailed clinical data of the patients were collected, and CTCs in samples were detected using a negative enrichment method based on immunomagnetic beads adsorption combined with immunofluorescence technology. The prognostic evaluation criteria and cut-off values for CTCs were determined using the receiver operating characteristic (ROC) curve method. Furthermore, univariate and Cox multivariate regression analyses were used to identify independent risk factors affecting the prognosis of children with NB.

Results

According to the optimal cut-off values obtained from the X-tile software, the patients were divided into high and low expression groups. The number of children with Progress (P < 0.001), Maximum tumor diameter ≥ 10cm (P = 0.004), low differentiation (P = 0.034), and stage IV (P = 0.007) in the high expression group was significantly higher than in the low expression group. The CTCs in children with Progress were higher than those in children with Mitigation (P < 0.001); children with Maximum tumor diameter < 10cm had lower CTCs than those with ≥ 10cm (P < 0.001); stage IV children had higher CTCs than stage III children (P = 0.036). The AUC for Maximum tumor diameter, Degree of differentiation, and Tumor stage were 0.703, 0.669, 0.574, and 0.598, respectively. Multivariate Cox regression analysis showed that CTCs (P < 0.001, OR = 2.958), Efficacy (P = 0.005, OR = 1.814), and Maximum tumor diameter (P < 0.001, OR = 2.586) were independent prognostic factors affecting OS in children with NB. Time-dependent ROC curve analysis showed that the model's AUC for predicting 1-year and 2-year survival was 0.747 and 0.802, respectively.

Conclusion

CTCs detection can significantly assess the clinical characteristics and prognosis of advanced pediatric NB, and CTCs, Efficacy, and Maximum tumor diameter are independent prognostic factors.

Neuroblastoma

Circulating Tumor Cells

Immunomagnetic Bead Adsorption

Prognostic Evaluation

Comprehensive Treatment

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and young children, ranking as the third most common pediatric malignancy, accounting for 8%-10% of childhood malignant tumors [1]. NB originates from primitive neural crest cells and can occur anywhere along the sympathetic nerve chain, with nearly half occurring in the adrenal glands [2]. The tumor can metastasize through the lymphatic or hematogenous systems, and approximately 50% of children have local or distant metastases at the time of diagnosis [3]. NB exhibits significant heterogeneity, capable of spontaneous regression, transformation into benign ganglioneuroma, or continued progression leading to death, depending on various clinical and biological risk factors [4].

Currently, clinical treatment regimens generally include surgery, chemotherapy, radiotherapy, immunotherapy, or stem cell transplantation as part of comprehensive treatment [5]. With continuous improvements in diagnostic and therapeutic methods, the overall survival rate (OS) of children has significantly improved. However, the prognosis for children with metastatic NB remains poor [6]. Studies have shown that among children with NB who are older than 18 months and have metastases, only about 50% can be cured despite multiple treatments [7]. Therefore, selecting a reliable and precise tumor staging and prognostic evaluation system, and based on this, choosing appropriate treatment plans is crucial for improving the survival rate and quality of life of these children.

In recent years, the detection of circulating tumor cells (CTCs) in peripheral blood, as an emerging molecular biological "liquid biopsy" technology, has received widespread attention [8]. CTCs are tumor cells shed from primary or secondary tumors into the bloodstream, easy to obtain, and provide comprehensive biological information, including RNA, genomic epigenetic markers, lipids, and proteins [9]. This information can reflect the tumor status and burden level in real-time, making it significant for tumor diagnosis, screening, long-term monitoring, and personalized treatment guidance [10]. Compared to traditional tissue biopsies, lymph node biopsies, and bone marrow punctures, CTCs detection is less invasive, simpler to operate, can be collected multiple times, and has high clinical application value [11]. Currently, CTCs detection is mainly used in adult tumors such as prostate cancer [12], rectal cancer [13], small cell lung cancer [14], and breast cancer [15], but its application in pediatric solid tumors has not yet reached the level of adults. As a common pediatric solid tumor with abundant clinical samples, NB has great research prospects and value.

The innovation of this study lies in introducing the emerging "liquid biopsy" technology of CTCs detection, providing more comprehensive and real-time tumor information through the detection of tumor cells in the blood. This method is simpler and less invasive compared to traditional tissue biopsies, lymph node biopsies, and bone marrow punctures, and can be collected multiple times to achieve dynamic monitoring. By analyzing the relationship between CTCs expression levels and the survival rate of children with NB, this study provides potential observation indicators for clinical treatment and prognosis.

Sample Source

This retrospective analysis included children with NB who received comprehensive treatment at our hospital from September 2020 to October 2022.

Inclusion and Exclusion Criteria

Inclusion Criteria: Children who met the criteria for stage III and IV according to the INSS staging system [16]; confirmed diagnosis of NB by pathological examination; no prior treatment before this study; complete clinical data.

Exclusion Criteria: Children with an expected survival time of less than 6 months; children with other malignant tumors; children with severe congenital diseases; children lost to follow-up or with incomplete follow-up data.

Sample Collection

A total of 224 samples meeting the inclusion criteria were collected, and 80 samples were excluded according to the exclusion criteria, resulting in 144 samples that met the requirements for this study.

Clinical Data Collection

Clinical data were obtained from the children's electronic medical records and outpatient follow-up records. Baseline data included age, sex, Efficacy, Maximum tumor diameter, Degree of differentiation, Tumor stage, and risk level. Laboratory data included CTCs, with laboratory indicators obtained preoperatively.

CTCs Detection

In the morning on an empty stomach, 5 mL of peripheral venous blood was drawn from the children and placed in anticoagulant-containing blood collection tubes to ensure thorough mixing with the anticoagulant to prevent coagulation. These anticoagulant blood samples were stored in a 4°C environment and tested within 12 hours. Red blood cell lysis buffer was added to lyse the red blood cells, and the released matrix was removed by centrifugation (10 cm, 800 rpm, 5 min). The collected white blood cells and tumor cells were subjected to immunomagnetic bead technology to adsorb the white blood cells, thereby enriching the tumor cells. Finally, CTCs were identified and counted using an automated circulating tumor live cell capture system and immunofluorescence in situ hybridization technology.

Treatment Plan

All patients followed the standard treatment guidelines of the "Expert Consensus on the Diagnosis and Treatment of Pediatric Neuroblastoma" [17]. The treatment process included preoperative reduction induction chemotherapy, followed by surgical resection and postoperative chemotherapy after four cycles. Based on the efficacy evaluation results, subsequent consolidation treatment or continued radiotherapy, chemotherapy, autologous stem cell transplantation, or immunotargeted therapy was selected.

Follow-up

Patients were followed up postoperatively, and the condition of NB patients was assessed according to the efficacy evaluation criteria of the national expert consensus, with complete response and partial response classified as Mitigation. Cases that did not meet the above criteria were classified as Progress. Follow-up continued until June 2024, with follow-ups every 3 months in the first year post-treatment, and every 6 months thereafter.

Outcome Measurement

1.Analyze the relationship between CTCs expression levels and survival in children with NB using X-tile software to determine the optimal cut-off value. 2.Divide children into high and low expression groups based on the optimal cut-off value from X-tile software and compare the differences in baseline data between the two groups. 3.Analyze the expression levels of CTCs in Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage, and evaluate their diagnostic value. 4.Use Cox regression analysis to identify independent prognostic factors affecting overall survival (OS) in children with NB. 5.Construct a Nomogram model based on independent prognostic factors from Cox regression, and use time-dependent ROC curve analysis to evaluate the model's value in predicting 1-year and 2-year survival.

Statistical Analysis

Statistical analysis was performed using SPSS 26.0 software. Measurement data are expressed as mean±standard deviation (mean±sd), and comparisons between groups were made using an independent samples t-test. Count data are expressed as percentages or rates (%), and the chi-square test was used for comparisons. The ROC curve was used to analyze the diagnostic value of CTCs in Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage. Cox regression analysis was used to identify independent prognostic factors affecting overall survival (OS) in children with NB. The Nomogram was constructed using the rms package in R software (version 4.3.2), ROC curve analysis was performed using the pROC package, time-dependent ROC curve analysis was conducted using the timeROC package, and Kaplan-Meier (K-M) curve analysis was carried out using the survival and survminer packages. All visualizations were done using ggplot2. A p-value of <0.05 was considered statistically significant.

The Relationship Between CTCs Expression Levels and Survival in Children with NB

By the follow-up deadline in June 2024, 43 children were still alive, with a survival rate of 29.86%. The average survival time of the children was 21.72 months (95% CI: 20.23~23.20). The prognostic value of CTCs in NB was analyzed using X-tile software. The results showed that when the optimal cut-off value was <14.48, the prognosis of the children significantly improved (Figure 1A-B).

Comparison of Baseline Data Based on CTCs Expression Levels

According to the optimal cut-off values obtained from X-tile software, the children were divided into high and low expression groups. Further comparison of the baseline data between the two groups revealed that the number of children with Progress (P<0.001), Maximum tumor diameter ≥10cm (P=0.004), low differentiation (P=0.034), and stage IV (P=0.007) in the high expression group was significantly higher than in the low expression group, indicating statistical significance (Table 1). There was no statistical significance in age, sex, and risk level between the groups (P>0.05).

Table 1 Relationship Between CTCs Expression Levels and Baseline Data

Factors		CTCs Expression Levels		χ2 Value	P Value
Factors		High Expression (n=69)	Low Expression (n=75)	χ2 Value	P Value
Age
	≥18 months	31	43	2.214	0.137
	<18 months	38	32
Sex
	Male	43	53	1.127	0.288
	Female	26	22
Efficacy
	Progress	40	17	18.73	<0.001
	Mitigation	29	58
Maximum tumor diameter
	≥10cm	51	38	8.227	0.004
	<10cm	18	37
Degree of differentiation
	Low differentiation	29	19	4.508	0.034
	Medium + high differentiation	40	56
Tumor stage
	Stage IV	43	30	7.162	0.007
	Stage III	26	45
Risk level
	High risk	52	53	0.401	0.526
	Medium risk	17	22

Note: Circulating Tumor Cells (CTCs).

CTCs Expression in Efficacy, Maximum Tumor Diameter, Degree of Differentiation, and Tumor Stage

Baseline data analysis revealed that CTCs were associated with Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage. Therefore, further comparison of CTCs expression levels in different baseline data was conducted. The results showed that CTCs in children with Progress were higher than those in children with Mitigation, with statistical significance (P<0.001, Figure 2A); children with Maximum tumor diameter <10cm had lower CTCs than those with ≥10cm, with statistical significance (P<0.001, Figure 2B); there was no difference in CTCs among children with different degrees of differentiation (P=0.148, Figure 2C); children with stage IV had higher CTCs than those with stage III, with statistical significance (P=0.036, Figure 2D).

Diagnostic Value of CTCs in Efficacy, Maximum Tumor Diameter, Degree of Differentiation, and Tumor Stage

The above study determined that CTCs expression was related to Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage. Therefore, separate ROC curves for CTCs in Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage were plotted. The results showed that the area under the curve (AUC) for Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage were 0.703, 0.669, 0.574, and 0.598, respectively (Figure 3, Table 2). Among them, CTCs had the highest AUC in distinguishing clinical efficacy, while the AUC for distinguishing tumor stage and degree of differentiation was the lowest.

Table 2 ROC Parameters

Metric	Efficacy	Maximum tumor diameter	Degree of differentiation	Tumor stage
AUC	0.703	0.669	0.574	0.598
95%CI	0.614 - 0.703	0.577 - 0.669	0.476 - 0.574	0.504 - 0.598
specificity	0.724	0.491	0.385	0.718
sensitivity	0.684	0.809	0.833	0.521
Youden index	0.408	0.3	0.219	0.239
Cut off	14.845	11.655	11.755	15.06
Accuracy	0.708	0.688	0.535	0.618
Precision	0.619	0.72	0.404	0.655
F1 Score	0.65	0.762	0.544	0.58

Note: Circulating Tumor Cells (CTCs) and Area Under Curve (AUC).

Prognostic Factors Affecting OS in Children with NB

In this study, Cox regression analysis was used to screen prognostic factors affecting OS in children with NB. Univariate analysis showed that CTCs (P<0.001, OR=4.221), Efficacy (P<0.001, OR=2.395), Maximum tumor diameter (P<0.001, OR=3.43), and Degree of differentiation (P=0.01, OR=1.69) were prognostic factors affecting the prognosis of children (Table 3). Multivariate Cox regression analysis showed that CTCs (P<0.001, OR=2.958), Efficacy (P=0.005, OR=1.814), and Maximum tumor diameter (P<0.001, OR=2.586) were independent prognostic factors affecting OS in children with NB (Table 4, Figure 4).

Table 3 Univariate Cox Regression

Factor	Beta	StdErr	PValue	HR	95% CI Lower Limit	95% CI Upper Limit
CTCs	1.440	0.213	<0.001	4.221	2.782	6.404
Age	0.060	0.199	0.763	1.062	0.718	1.570
Sex	-0.041	0.211	0.847	0.960	0.635	1.451
Efficacy	0.873	0.200	<0.001	2.395	1.617	3.548
Maximum tumor diameter	1.232	0.237	<0.001	3.430	2.154	5.461
Degree of differentiation	0.525	0.205	0.010	1.690	1.131	2.525
Tumor stage	0.296	0.200	0.138	1.345	0.909	1.990
Risk level	-0.008	0.222	0.973	0.992	0.642	1.534

Note: Circulating Tumor Cells (CTCs).

Table 4 Multivariate Cox Regression

Factor	Beta	StdErr	PValue	HR	95% CI Lower Limit	95% CI Upper Limit
CTCs	1.084	0.230	<0.001	2.958	1.884	4.643
Efficacy	0.595	0.211	0.005	1.814	1.199	2.744
Maximum tumor diameter	0.950	0.250	<0.001	2.586	1.584	4.222
Degree of differentiation	0.166	0.210	0.428	1.181	0.783	1.781

Note: Circulating Tumor Cells (CTCs).

Construction of a Nomogram Model Based on Independent Prognostic Factors

At the end of the study, a visual Nomogram model was constructed based on independent prognostic factors. The model included Efficacy, Maximum tumor diameter, and CTCs. Among them, CTCs were strongly correlated with patients' OS, while Efficacy and Maximum tumor diameter were related to tumor OS (Figure 5A). Furthermore, time-dependent ROC curve analysis showed that the model's AUC for predicting 1-year and 2-year survival was 0.747 and 0.802, respectively, indicating that the model has certain clinical value in predicting patients' survival (Figure 5B).

Understanding the molecular mechanisms of NB tumor progression helps evaluate tumor growth, invasion, and metastasis, guiding early treatment and improving the therapeutic outcomes of malignant tumors [18]. CTCs are tumor cells that enter the circulatory system after shedding from primary or secondary tumors. Under appropriate microenvironmental conditions, a small portion of CTCs can evolve into metastatic tumors [19]. Therefore, CTCs detection can be used for early tumor diagnosis. Additionally, measuring the concentration of CTCs in a patient's blood can reflect the tumor burden, aiding in tumor diagnosis, chemotherapy efficacy, and prognostic evaluation [20]. In this study, we examined the relationship between CTCs levels in children with NB and their prognosis. The results showed that when CTCs were < 14.48, the prognosis of the children significantly improved. Further analysis revealed that children with high CTCs expression had significantly higher numbers of Progress cases, Maximum tumor diameter ≥ 10cm, low differentiation cases, and stage IV cases compared to those with low CTCs expression. These results suggest that high CTCs levels may indicate a higher rate of tumor cell shedding and greater metastatic potential. Shed tumor cells entering the circulatory system may form new metastatic sites in other parts of the body, leading to disease progression and deterioration [21]. Therefore, CTCs detection has important clinical application value, allowing physicians to assess tumor aggressiveness and metastatic risk and develop more targeted treatment plans.

Previous studies by Zhu et al. [22] have shown that CTC-leukocyte aggregates appearing before and after two cycles of chemotherapy and the total count of CTCs at the end of chemotherapy are strong predictors of prognosis in patients with small cell lung cancer receiving first-line treatment. Additionally, Yan et al. [23] reported that positive CTCs are an independent predictor of poor prognosis in patients with gallbladder adenocarcinoma after resection. Preoperative CTC detection may play an important role in guiding treatment strategies for these patients. Furthermore, Li et al. [24] found that CTCs have a guiding effect on adjuvant therapy for patients with early-stage endometrial cancer post-surgery. These findings are consistent with the conclusions of this study, suggesting that CTCs detection has significant value in prognostic evaluation and treatment strategy formulation across various tumor types.

To further determine the relationship between CTCs and baseline data, we compared the expression of CTCs in different baseline data categories, such as Efficacy, Maximum tumor diameter, Degree of differentiation, and Tumor stage. The results showed that CTCs levels were higher in children with Progress than those with Mitigation, higher in children with Maximum tumor diameter ≥ 10cm than those with < 10cm, and higher in stage IV children than stage III children, but there was no difference in CTCs levels among children with different degrees of differentiation. The consistency of Efficacy, Maximum tumor diameter, and Tumor stage with previous results was observed, while the lack of difference in CTCs levels among different degrees of differentiation might be due to the small sample size and the varying frequency distribution of CTCs levels among patients with different degrees of differentiation. We hope to collect more samples in future studies to improve these results. Interestingly, further ROC curve analysis revealed that pre-treatment CTCs have high clinical value in assessing efficacy, with an AUC of 0.703. We speculate that this is because high CTCs levels may indicate a higher tumor burden and invasiveness, which in turn affects treatment outcomes [25]. Additionally, high CTCs levels may reflect a higher rate of tumor cell shedding, associated with tumor biological behavior [26]. Furthermore, high-shedding tumors are less sensitive to treatment, affecting efficacy evaluation. For instance, the study by Gradilone et al. [27] found that patients with positive CTCs and those with CTCs expressing two or more multidrug resistance-related proteins had shorter progression-free survival (PFS).

Finally, we used Cox regression analysis to identify independent prognostic factors affecting OS in children with NB. The results showed that CTCs, Efficacy, and Maximum tumor diameter were independent prognostic factors affecting OS in children with NB. Efficacy reflects the patient's direct response to treatment, indicating whether the treatment successfully controls the tumor. Effective treatment can significantly reduce tumor burden, delay disease progression, and prolong survival [28]. Efficacy also indicates whether the disease is stable, mitigated, or progressing, which is crucial for long-term survival. Maximum tumor diameter is a direct indicator of tumor burden; larger tumors usually indicate a higher tumor burden and more complex treatment challenges [29]. Larger tumors are more likely to metastasize and invade, leading to poor prognosis. Larger tumors generally represent a later stage and higher severity of the disease, indicating greater treatment challenges and lower chances of cure [30]. CTCs reflect the presence and quantity of tumor cells shed from primary or secondary sites into the circulatory system, directly indicating metastatic potential [31]. High CTCs levels suggest that tumor cells are prone to shedding and metastasis, indicating higher metastatic risk and poorer prognosis [32]. These indicators not only reflect tumor burden and biological behavior but also provide important information on treatment response and prognosis, helping physicians develop more precise treatment strategies to improve long-term survival rates in children.

Based on these independent prognostic factors, we constructed a visual Nomogram model and found that the model's AUC for predicting 1-year and 2-year survival was 0.747 and 0.802, respectively. This suggests that CTCs, Efficacy, and Maximum tumor diameter are not only important prognostic indicators but can also provide reliable survival prediction tools through the Nomogram model, offering strong support for clinicians in developing individualized treatment plans and prognostic evaluations.

However, this study has certain limitations. First, the sample size was relatively small, including only 144 children, which may affect the stability and generalizability of the statistical results. Second, the study was conducted at a single center, potentially introducing regional and selection biases. Additionally, as a retrospective study, there is a risk of selection and information biases, potentially affecting the accuracy of the results. Lastly, the follow-up period was relatively short, possibly insufficient for a comprehensive evaluation of long-term prognosis. We hope that future studies can address these limitations by expanding the sample size, collaborating with multiple centers, designing prospective studies, and extending the follow-up period to provide more comprehensive and reliable prognostic evaluations, ultimately improving clinical treatment outcomes.

This study demonstrates that CTCs, Efficacy, and Maximum tumor diameter are independent prognostic factors affecting overall survival (OS) in children with advanced NB. These findings suggest that CTCs, Efficacy, and Maximum tumor diameter are not only important prognostic indicators but can also provide reliable survival prediction tools through the Nomogram model, offering strong support for clinicians in developing individualized treatment plans and prognostic evaluations.

Author Contributions

Junhua Tuo, Zhi Zhao, and Xuan He have significantly contributed to the conception and design of the manuscript, while Xiaoning Ma and Zhengsheng Liu have made valuable contributions in the acquisition, analysis, and interpretation of the data. The entire authorship team actively participated in drafting the manuscript, with Baogang Yang and Meng Zhang providing critical revisions. Finally, all authors carefully reviewed and approved the final version of the manuscript.

Ethics Approval and Consent to Participate

This study has been approved by the Ethics Committee of Shaanxi Provincial People’s Hospital and obtained informed consent from the subjects. This study is a retrospective observational study and has been granted a clinical trial registration exemption application.

Consent for publication

This study has been reviewed and approved by all authors and agrees to be published.

Funding

Shaanxi Provincial People's Hospital Science and Technology Talent Support Program Top Talent Project (No. 2022BJ-10).

Availability of Data and Materials

All data is included in the manuscript. In order to protect the privacy of patients, our policy does not allow the disclosure of detailed information related to patients to the outside world, Can contact the corresponding author to obtain it.

Competing interests

All authors in this study have no conflict of interest.

Acknowledgements

None.

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No competing interests reported.

The Relationship Between Circulating Tumor Cells in Peripheral Blood and Clinical Characteristics of Pediatric Neuroblastoma and Prognostic Evaluation

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