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Neuroblastoma with high ASPM reveals pronounced heterogeneity and poor prognosis

BMC Cancer volume 24, Article number: 1151 (2024) Cite this article

A Correction to this article was published on 01 October 2024

This article has been updated

Abstract

Objective

We explored the preliminary value of abnormal spindle-like microcephaly- associated (ASPM) protein in aiding precise risk sub-stratification, prediction of metabolic heterogeneity, and prognosis of neuroblastoma (NB).

Methods

This retrospective study enrolled newly diagnosed patients with NB who underwent positron emission tomography/computed tomography (PET/CT) before therapy, and tumor tissue was collected after surgery. Regression analysis was used to evaluate ASPM expression and risk stratification in patients with NB. The expression levels of ASPM, clinical information, and PET/CT text features were analyzed using univariate and multivariate survival analyses. Finally, a correlation analysis was used to explore the relationship between ASPM and tumor metabolic heterogeneity.

Results

There were 48 patients with NB in this study (35 boys and 13 girls); 22 patients progressed and 16 died. We found that the level of ASPM was highly associated with risk stratification (OR = 5.295, 95%IC: 1.348–41.722, p = 0.021). Patients with NB and high-risk stratification with high ASPM level had a lower 3-year progression-free survival (PFS) rate (14.28%) and 1-year PFS rate (57.14%) than those with low ASPM level (57.14% and 93.75%, respectively). Using univariate and multivariate survival analyses, this study revealed that ASPM and LDH were independent risk factors for both PFS and overall survival (OS), whales GLZLM_ZLNU was only a risk factor for PFS.

Conclusion

ASPM holds promise as a novel biomarker for refining current risk stratification and predicting prognosis in neuroblastoma. Elevated levels of ASPM, LDH, and GLZLM_ZLNU may be associated with poorer survival outcomes in neuroblastoma patients.

Peer Review reports

Introduction

Neuroblastoma (NB) is the most common pediatric solid tumor, accounting for approximately 15% of childhood cancer-related deaths. NB is highly heterogeneous, with clinical outcomes ranging from spontaneous remission to lethal progression, and 60% of the patients have high-risk NB [14]. Indeed, the cure rate of NB patients in the high-risk group has declined to less than 50% owing to limits on the efficacy of existing treatment [20, 25]. Age, International Neuroblastoma Risk Group Staging System (INRGSS), histologic category, tumor grade, DNA ploidy, MYCN amplification, and copy number status at 11q at diagnosis determine the current risk stratifications of NB patients. However, the survival of patients with high-risk neuroblastoma remains poor. The exploration and integration of new prognostic markers into NB classification systems may allow for more precise risk stratification and refined treatment protocols.

Abnormal spindle-like microcephaly-associated () (ASPM) protein, a centrosomal protein, is upregulated and widely expressed in many malignant tissues [2, 3, 12]. ASPM expression is associated with the pathological grade and poor survival in a variety of tumors, such as prostate cancer, pancreatic ductal adenocarcinoma, ovarian cancer, and hepatocellular carcinoma [24, 32,33,34]. Data accumulated over recent years indicate that ASPM as a regulatory hub of development- and stemness-associated signaling pathways to regulate cancer stem cells (CSCs) in cancer and provide a plausible explanation for its cell-to-cell expressional heterogeneity [31]. However, the relationship between ASPM and neuroblastomas has not yet been reported.

18F-FDG positron emission tomography/computed tomography (PET/CT) has been widely used for staging and predicting the prognosis of neuroblastoma, especially in countries with no availability of metaiodobenzylguanidine, including China [16]. Considering the heterogeneity of neuroblastomas, the standardized uptake value does not always accurately reflect the glucose metabolism of the tumor [5]. Radiomics extracted from PET/CT imaging enables the evaluation of intra-tumoral heterogeneity based on glucose metabolism [15]. Recent studies have shown that radiomics not only noninvasively visualizes the characteristics of the whole tumor but also improves risk stratification and predicts prognosis in neuroblastoma [4, 8].

Base on the findings that ASPM and FDG-PET metabolic parameters are highly related to tumor heterogeneity and prognosis, we aimed to evaluate the value of ASPM in risk stratification and prognosis prediction of neuroblastoma, and to further explore the relationship between ASPM and tumor metabolic heterogeneity.

Materials and methods

Patients

This retrospective study reviewed 158 patients newly diagnosed with NB who underwent PET/CT at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine from December 2012 to April 2021. The following inclusion criteria were used: (a) pathologically proven NB; (b) no therapy before surgery; (c) baseline PET/CT available before any therapeutic or interventional procedures; (d) complete clinical characteristic, laboratory, and genetic data; and (e) postoperative sample available for immunofluorescence. Eventually, a total of 48 NB patients was involved in this study (girls, 13 and boys, 35) (Fig. 1). Clinical information was collected, including age; stage; risk stratification; MYCN amplification status; and lactate dehydrogenase (LDH), 4-hydroxy-3 -methoxy-mandelic acid, homovanillic acid (HVA), and ferritin levels. The postoperative tumor tissues of all patients with NB were collected, the expression of ASPM in tumor tissues was stained by immunofluorescence (IF), and the degree of expression was analyzed using Image J software (National Institutes of Health, USA; version 1.53a). Progression-free survival (PFS) was defined as the time from the diagnosis of NB to the date of progression. Overall survival (OS) was calculated as the time from the start date of cancer treatment to the date of death from any cause or the last follow up. If the deaths from any cause happened before progression are coded as an event for PFS. This study was approved by the Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. All patients’ data and images were anonymized, and informed consent was waived.

Fig. 1
figure 1

Flowchart shows study population with inclusion and exclusion criteria

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PET/CT imaging acquisition

All patients underwent PET/CT (Siemens, Biograph mCT) according to the European Association of Nuclear Medicine guidelines for tumor imaging [30]. 18F-FDG was intravenously injected at a dose of 3.7 MBq/kg after at least 6 h of fasting and the blood glucose level was < 200 mg/dl. PET/CT imaging from the skull to the proximal thigh was acquired approximately 1 h after the injection. Sedation would be considered before scanning children who were unable to follow the instructions. The PET images were reconstructed using 3D ordered subsets expectation maximization (3 iterations, 24 subsets). Low-dose CT scans were acquired with a tube voltage of 100 kV, slice thickness of 3 mm, automated tube current modulation, and pitch of 1.5 min.

Radiomics features segmentation and selection

The original PET/CT images were imported into LIFEx software (Version 6.31) to segment and extract the features [35]. The volumes of interest (VOI) of the entire primary tumor were delineated manually by two nuclear medicine physicians with 8 and more than 15 years of PET/CT experience, respectively. The final region of interest was confirmed after consensus was reached, and each VOI contained at least 64 contiguous voxels. Eventually, 69 radiomics features of each patient were extracted from the 3D VOI, including 37 first-order and 32 s-order features, which are defined and explained at http://www.lifexsoft.org.

IF semi-quantitative analysis

Immunofluorescent staining of the whole neuroblastoma tissue was performed using standard protocols [17]. The antibody against ASPM was purchased from Abcam (cat no. ab238106; dilution 1:100). Photomicrographs were taken with a DMI3000B camera (Leica). The relative intensity of ASPM expression was analyzed using Image J software [13]. The staining was assessed by setting a threshold using the thresholding tool. The auto setting can be selected or the sliders can be manually moved until all the stained areas that need analysis are selected. Finally, selecting the button of “Analyze-Set-Measurements” and the intensity measurements can be performed within regions of interest.

Statistical analysis

All statistical analyses were performed using SPSS software (version 26.0; IBM, Chicago, IL, USA), and a two-sided P-value < 0.05 was considered statistically significant. Continuous variables were converted into categorical variables by evaluating the area under the curve (AUC) using receiver operating characteristic (ROC) curves to obtain the optimal cutoff value. Texture features were evaluated for reproducibility using a two-way random absolute agreement intraclass correlation coefficient (ICC), as reported in our previous study [18]. We chose the lower bounds of the 95% confidence interval of the ICC value (ICClb95%) as a criterion to categorize the reproducibility: ICClb95% < 0.50, poor; ICClb95%: 0.50–0.75, moderate; ICClb95%: 0.75–0.90, good; and ICClb95% ≥ 0.90, excellent. Robust features with good or excellent reproducibility qualified for further analysis. Correlations among the PET parameters were determined by the Pearson and Spearman rank correlation. To avoid redundancy, factor with poorer predictive validity in the pairs of indices that showed correlation coefficient (r) ≥ 0.8 were omitted. The chi-square test or Fisher’s precision probability test was used to compare nominal variables between groups with PFS and without PFS. The relationship between ASPM and risk stratification was analyzed using Regression analysis. Since texture features are known to reflect the metabolic heterogeneity of neuroblastomas, we next evaluated the relationship between ASPM and texture features using PET/CT imaging by Spearman rank correlation. Survival estimates were evaluated using Kaplan–Meier analysis. Multivariate Cox regression analyses were conducted using a forward stepwise method to identify potential predictive variables.

Results

Patient characteristics

A total of 48 patients with a pathologically proven diagnosis of neuroblastoma from 2012 to 2021 were included in this retrospective study. The age of these patients was 36.25 ± 3.07 mo (range: 2–72 mo). There were 35 boys and 13 girls; 39 and 9 patients were diagnosed with neuroblastoma and ganglioneuroblastoma, respectively. Most patients were diagnosed with disseminated disease, 24 patients were classified as stage 4, 10 patients as stage 3, 2 patients as stage 1, and 1 patient each as stage 4s and stage 2, based on the International Neuroblastoma Staging System (INSS). According to the Children’s Oncology Group risk protocol, 3 patients were at low risk, 10 patients were at intermediate risk, and 25 patients were at high risk. All the patients received treatments according to the new COG risk stratification and the INRGSS. During follow-up, 22 events and 16 deaths occurred, with a median follow-up of 42 months (range: 3-100 mo). Patient characteristics are summarized in Table 1. The optimal cutoff values of the clinical factors to differentiate the event of progression are described in the supplemental material (Table S1).

Table 1 Clinical information
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ASPM expression and clinical parameters in predicting survival

In this study, we found that the extent of ASPM expression was significantly different between patients with and without progression (Fig. 2). As shown in Table 1, age, group stratification, and ASPM expression, ferritin, LDH, and NSE levels were significantly associated with progression-free survival (PFS). Patients with age ≥ 18 mo, high-risk stratification, high ASPM expression (relative intensity of immunofluorescence > 54.82), ferritin > 191.50 ug/L, LDH > 986.50 U/L, or NSE > 248.84 ng/ml underwent progression more easily than those without. Multivariate Cox proportional hazards regression analysis revealed that high ASPM expression and LDH levels were statistically significant predictors of PFS and overall survival (OS) (Table 2).

Fig. 2
figure 2

ASPM highly expressed in patients with NB with high-risk stratification. A: a 4-year-old boy with high-risk neuroblastoma who had a giant mass in the retroperitoneum; the uptake of FDG in this tumor was inhomogeneous, and SUVmax was 4.8. The patient had multiple systemic lymph node and right pleural metastases that progressed 20 months after diagnosis. B: a 1-year-old boy with a left adrenal mass; the SUVmax of the tumor was 4.5, accompanied by regional lymph node metastases (retrophrenic crural, retroperitoneal). There was no progression in 70 months. C and D: ASPM expression in patients A and B by IF. E: the relative expression rate of ASPM in high-risk NB patients. Footnote NB neuroblastoma; SUVmax maximum standardized uptake value; ASPM abnormal spindle-like microcephaly; IF immunofluorescence

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Table 2 Multivariate of ASPM and clinical information
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ASPM and risk stratification

MYCN amplification is a specific risk factor that determines high-risk stratification in neuroblastoma. In our study, no significant correlation was observed between MYCN amplification and ASPM (OR = 1.068, 95%CI: 0.497–9.583, p = 0.301). However, ASPM was also highly associated with risk stratification (OR = 5.295, 95%CI: 1.348–41.722, p = 0.021). Patients with NB with high ASPM expression had shorter PFS and OS than those with low ASPM expression (median time: 19.5 mo vs. 54 mo and 25.5 mo vs. 46 mo) (Fig. 3A and B). Our study demonstrated that patients with high-risk stratification and high ASPM levels had a lower 3-year PFS rate (14.28%) and 1-year PFS rate (57.14%) than those with low ASPM levels (57.14% and 93.75%, respectively), as shown in Fig. 3C and D.

Fig. 3
figure 3

The survival of patients with NB with high and low ASPM. Footnote  NB neuroblastoma; ASPM abnormal spindle-like microcephaly

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Multiple variables in predicting PFS and OS

The ICC analysis revealed that fifty-one first-and second-order features of the imaging features could be reproduced well (ICClb95% ≥ 0.75) in this study. The optimal cutoff values of these radiomic features were calculated based on ROC analysis and the Youden index, which are shown in the supplemental material Table S1. Ultimately, 13 features were found to be highly associated with ASPM using logistic regression. They are: CONVENTIONAL_SUVbwpeakSphere0.5mL, CONVENTIONAL_SUVbwpeakSphere1mL, CONVENTIONAL_TLG(mL), DISCRETIZED_SUVbwmax, DISCRETIZED_Standard uptake value body weight(SUVbw)peakSphere0.5mL, Gray-level zone-length matrices_short_zone low gray-level emphasis (GLZLM_SZHGE), Gray-level zone-length matrices_zone length non-uniformity(GLZLM_ZLNU), Neighbouring gray-level difference matrices (NGLDM_Coarseness), Gray-level run-length matrices_run length non-uniformity (GLRLM_RLNU), SHAPE_Volume(vx), SHAPE_Compacity, DISCRETIZED_Total lesion glycolysis (TLG)(mL), and DISCRETIZED_SUVbwpeakSphere1mL. Of these features, five (CONVENTIONAL_TLG(mL), GLRLM_RLNU, SHAPE_Volume(vx), SHAPE_Compacity, and DISCRETIZED_TLG(mL)) were significantly associated with PFS, and six (CONVENTIONAL_SUVbwpeakSphere0.5mL, CONVENTIONAL_TLG(mL), GLRLM_RLNU, SHAPE_Volume(vx), DISCRETIZED_SUVbwmax, DISCRETIZED_SUVbwpeakSphere0.5mL, and DISCRETIZED_TLG(mL)) were highly associated with OS (Table 3). In multivariate cox survival analysis, GLRLM_RLNU > 1178.78 and GLZLM_ZLNU > 53.69 showed significant statistic difference for PFS, while only GLZLM_ZLNU > 53.69 has a marginal significance for OS (supplemental material Table S2).

Table 3 The relationship of text futures between ASPM and survival analysis
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Next, we combined ASPM, LDH with GLZLM_ZLNU > 53.69 for multiple variable COX regression analysis (Table 4). Our results showed that ASPM and LDH were the independent risk factors for both PFS and OS, whereas GLZLM_ZLNU > 53.69 was only the risk factor for PFS. NB patients with high ASPM and LDH levels tended to progress compared with those with low ASPM and LDH levels.

Table 4 Multivariate of cox survival analysis
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Discussion

Patients with neuroblastoma receive treatment based on the risk of recurrence or progression as assessed before therapy. NB risk stratification was defined according to the patient’s INSS stage, age, histological category, tumor differentiation grade, MYCN status, presence/absence of 11q aberrations, and tumor cell ploidy [27]. Low-risk patients with NB have a favorable prognosis and a 5-year survival rate of more than 90%. However, the prognosis for high-risk patients is still poor [14]. Therefore, it is important for investigators to understand better how to identify patients with poor prognosis and develop novel treatments.

ASPM plays an important role in cell mitosis and tumorigenesis [9, 12] and is related to the pathological grade of malignant tumors. In this study, we found that the expression levels of ASPM were markedly different in neuroblastoma, and its level in high-risk patients with NB was higher than that in low-risk and median-risk patients. Considering the heterogeneity of neuroblastoma, the current risk stratification could not distinguish higher-risk patients from high-risk patients, resulting in recurrence and death rates in NB. Although MYCN is considered a biomarker of high-risk stratification, the heterogeneity of MYCN has been reported to be in the range of 1–2% overall and up to 17% in MYCN-amplified neuroblastoma [1], Marrano, Irwin and Thorner [19]). This also may cause inaccurate risk stratification and poor outcomes of neuroblastoma according to the current therapy schedules. This study showed that ASPM expression level was highly associated with risk stratification of NB, and high-risk patients with high ASPM had worse PFS, and the 3-year and 1-year PFS rates were 14.28% and 57.14%, respectively. Therefore, ASPM may be a supplementary risk factor to help physicians identify higher-risk patients with NB.

NBs are embryonic tumors with high heterogeneity [6, 26]. Intratumoral heterogeneity leads to phenotypic differences in histopathological divergence, including regions demarcated by various degrees of differentiation, proliferation, vascularity, and invasiveness [10]. Consequently, given the inadequate assessment of pre-therapy in patients with neuroblastoma, death was lethal owing to the high heterogeneity of NB. Recent studies have shown that tumor heterogeneity is reflected by glucose uptake on 18F-FDG-PET/CT imaging, and emerging evidence indicates that high heterogeneity, evaluated using radiomics, predicts a worse prognosis for many multiple malignancies [21, 23, 29]. However, only a few studies have explored the spatial relationship between radiomics and histopathology. Our previous study reported that PET-based texture features quantifying intratumoral heterogeneity are a powerful and non-invasive approach for predicting survival outcomes in newly diagnosed NB [18]. In this study, we further explored the relationship between ASPM expression and texture features in neuroblastoma and found that 13 features were highly associated with ASPM levels, including 9 first-order features and 4 s-order features. Of these features, four texture feature second-order indices, namely, GLZLM_SZHGE, GLZLM_ZLNU, NGLDM_Coarseness, and GLRLM_RLNU, were considered to reflect tumor heterogeneity. ASPM, as a protein involved in mitosis, regulates NB cell proliferation and differentiation, suggesting that ASPM may play an important role in regulating the heterogeneity of neuroblastoma. Further studies on the regulatory mechanisms of ASPM in NB are needed.

Radiomics has been increasingly used as a quantitative criterion to predict the prognosis of various tumor types [7, 11, 36]. By the univariate and multivariate analysis, our results showed that GLRLM_RLNU > 1178.78 and GLZLM_ZLNU > 53.69 were significantly associated with PFS, while only GLZLM_ZLNU > 53.69 has a marginal significance for OS. Consequently, we constructed a combination of clinical parameters, imaging features, and ASPM for multivariate Cox survival analysis. The results demonstrated that ASPM and LDH were the risk factors for both PFS and OS, whereas GLZLM_ZLNU > 53.69 was only a significant risk factor for PFS. NB patients with ASPM level > 54.82, LDH > 986.50 U/L and GLZLM_ZLNU > 53.69 would progress easily and have worse survival rates, and 5-year, 3-year, and 1-year PFS rates were 11.11%, 22.22%, and 77.77%, respectively. LDH as a risk prognosis marker for neuroblastoma has been reported in previous studies (Ren, Fu and Zhao [28], Moroz et al. [22]. However, our findings first revealed that ASPM may be a biomarker for predicting the prognosis of NB and expected to aid in treatment assignments in the future. Our results showed that the 5-year, 3-year, and 1-year PFS rates of patients with NB with high ASPM expression were 13.33%, 33.33%, and 85.41%, respectively, whereas those of patients with low ASPM levels were 59.09%, 70%, and 96.6%, respectively. The OS rate of patients with NB with high ASPM was 38.89%, whereas that of patients with a low ASPM was 83.33%.

Although our study showed that ASPM expression level and LDH could be independent risk factors for predicting the prognosis of neuroblastoma, there are some limitations. First, this was a single-center retrospective study, which may have caused selection bias. Second, a large number of patients with NB who had received treatment before the 18F-FDG PET/CT scan but whose tissue samples were not obtained were excluded, resulting in a small sample size, which may skew the results. Third, the ASPM expression level of patients with NB was evaluated by Image J software, a semiquantitative tool. Semi-quantitative analysis of protein immunofluorescence is affected by many factors, including staining and filming conditions. To reduce deviations caused by technical and human factors, all specimens in this study were stained under the same conditions based on the pre-test. Two experienced pathology researchers took photographs under the same conditions. No statistically significant differences were observed between the two researchers. The average value of the two groups of specimens was taken as the relative expression level of ASPM. Owing to the uncontrollable factors of time, there could be uncontrolled errors in the protein amount of semi-quantitative immunofluorescence analysis, which needs to be further verified by prospective studies or more reliable measurement techniques.

Conclusion

In conclusion, ASPM expression level may improve precise risk sub-stratification when combined with traditional risk stratification in NB and holds promise as a novel biomarker for predicting prognosis. NB patients with ASPM level > 54.82, LDH > 986.50 U/L and GLZLM_ZLNU > 53.69 would easily progress and have worse survival rates.

Data availability

No datasets were generated or analysed during the current study.

Change history

Abbreviations

NB:

Neuroblastoma

ASPM:

Abnormal spindle-like microcephaly-associated protein

PET/CT:

Positron emission tomography/computed tomography

MIBG:

Metaiodobenzylguanidine

LDH:

Lactate dehydrogenase

VMA:

4-hydroxy-3-methoxy-mandelic acid

HVA:

Homovanillic acid

VOI:

Volumes of interest

AUC:

Under the curves

ROC:

Receiver operating characteristic

ICC:

Intraclass correlation coefficient

ICClb95% :

Lower bounds of the 95% confidence interval of the ICC value

IF:

Immunofluorescence

NSE:

Neuron-specific-enolase

NGLDM:

Neighboring gray-level difference matrices

GLZLM:

Gray-level zone-length matrices

GLRLM:

Gray-level run-length matrices

TLG:

Total lesion glycolysis

SUV:

Standardized uptake value

SZHGE:

Short_zone low gray-level emphasis

ZLNU:

Zone length non-uniformity

RLNU:

Run length non-uniformity

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Acknowledgements

Not applicable.

Funding

This study was supported by the National Natural Science Foundation of China (grant numbers 81901775 and 81801731).

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Author notes

  1. Chao Li and Xueyuan Lu contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China

    Chao Li, Xueyuan Lu, Shuo Huang, Lin Ding, Hui Wang & Suyun Chen

  2. Department of Nuclear Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, China

    Fengxian Zhang

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  1. Chao Li
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Contributions

CL and XL conceived and designed the study; SC and LD contributed to data collection; SH and FZ performed the statistical analysis of the data; CL wrote the original draft; SC and HW reviewed and edited the manuscript. All the authors have read and approved the final manuscript to be published. HW and CL agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding authors

Correspondence to Hui Wang or Suyun Chen.

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Ethics approval and consent to participate

This retrospective study was approved by the local Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine; all data and images of patients were anonymized, and the written informed consent was waived by the local Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. This was a retrospective study and informed consent was waived.

Consent for publication

The authors affirm that human research participants provided informed consent for publication of the images in Fig. (2) A, B, C and D.

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The authors declare no competing interests.

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The original version of this article was revised: Hui Wang and Suyun Chen are co-corresponding authors.

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Li, C., Lu, X., Zhang, F. et al. Neuroblastoma with high ASPM reveals pronounced heterogeneity and poor prognosis. BMC Cancer 24, 1151 (2024). https://doi.org/10.1186/s12885-024-12912-4

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  • DOI: https://doi.org/10.1186/s12885-024-12912-4

Keywords

BMC Cancer

ISSN: 1471-2407

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