Comparing the diagnostic value of 18F-FDG PET/CT scan and bone marrow biopsy in newly diagnosed pediatric neuroblastoma and ganglioneuroblastoma

Objective: This study aims to compare the diagnostic value of ¹⁸F-fluorodeoxyglucose (18-FDG) positron emission tomography (PET)/computed tomography (CT) (¹⁸F-FDG PET/CT) scan and bone marrow biopsy (BMB) for evaluating bone marrow infiltration (BMI) in newly diagnosed pediatric neuroblastoma (NB) and ganglioneuroblastoma (GNB).

Methods: We retrospectively reviewed 51 patients with newly diagnosed NB and GNB between June 1, 2019 and May 31, 2022. Each patient had undergone ¹⁸F-FDG PET/CT and BMB within 1 week and received no treatment. Clinical data were collected and statistically analyzed, including age, sex, pathologic type, and laboratory parameters. ¹⁸F-FDG PET/CT and BMB revealed the result of bone lesions.

Results: A concordance analysis showed that, in this study population, ¹⁸F-FDG PET/CT and BMB were in moderate agreement (Cohen’s Kappa = 0.444; p = 0.001), with an absolute agreement consistency of 72.5% (37 of 51). The analysis of the receiver operating characteristic (ROC) curve determined that the areas under the ROC curve (AUCs) of SUV_BM and SUV/HE-SUVmax were 0.971 (95% CI: 0.911–1.000; p < 0.001) and 0.917 (95% CI: 0.715–1.000; p < 0.001) to predict bone–bone marrow involvement (BMI), respectively.

Conclusion: ¹⁸F-FDG PET/CT detects BMI with good diagnostic accuracy and can reduce unnecessary invasive inspections in newly diagnosed pediatric NB and GNB, especially patterns C and D. The analysis of the semi-quantitative uptake of ¹⁸F-FDG, including SUV_BM and SUV_BM/HE-SUVmax, enables an effective differentiation between patterns A and B.

1 Introduction

Neuroblastoma is the most common pediatric solid tumor occurring in the sympathetic nervous system and accounts for approximately 15% of childhood cancer‐related mortality (1). A total of 70% of patients with NB have metastatic disease at the time of diagnosis, which commonly involves the cortical bone and the bone marrow (BM). However, metastatic bone–BM is a sign of advanced disease and implies a poor prognosis (2). Neuroblastoma presents a great heterogeneity in clinical behavior and survival rates; therefore, accurate staging is crucial to choose the appropriate treatment.

Bone marrow biopsy (BMB) is currently a “gold standard” modality in identifying bone marrow involvement (BMI) due to its advantages in diagnosis, staging, and treatment monitoring in childhood malignancies (3). BMB is obtained from the dorsal portion of the iliac crest and is the most easily accessible approach for BM evaluation. It is based on the assumption that, in cases of BMI, tumor cells spread non-focally through the bone–BM (4), which was demonstrated to be incorrect. However, it is a painful and invasive procedure, especially for children. More worrying still is the fact that a part of the patients repeatedly required BM punctures during the treatment. Additionally, the major drawback of BMB is that it may miss focal NB tumor cell deposits and bone metastases in areas far from the iliac bone because it yields information from a limited area (3). Using BMB to determine metastatic bone–BM is insufficient. Thus, another examination is needed to supplement the deficiency that BMB presents.

Nowadays, iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy is a mainstay method in pediatric NB (5). Nevertheless, ¹²³I-MIBG scintigraphy imaging has several disadvantages such as no concentration of MIBG in 10% of tumors, limited spatial resolution, and limited sensitivity in small lesions. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) (¹⁸F-FDG PET/CT) is commonly used to complete the staging and prognosis prediction of malignant tumors and can also be used to evaluate marrow infiltration. Compared with ¹²³I-MIBG scintigraphy imaging, the superiorities of PET are high ¹⁸F-FDG avidity of the BM and better identification of FDG abnormalities in the BM and bone (6, 7). Moreover, an important advantage of PET/CT over BMB is that PET/CT can assess all BM sites at once and find unintended BMI in areas where biopsies are not usually performed (8), thus avoiding the sampling limitation of BMB. ¹⁸F-FDG PET/CT has a good overall diagnostic accuracy with high sensitivity and specificity in the detection of bone or BMI in pediatric neuroblastoma (9, 10). The sample size of the study was small, and further research is needed (10).

Many investigators are concerned that BM FDG uptake may mask or mimic metastatic disease due to the initial use of chemotherapy or granulocyte colony-stimulating factor in NB patients, thereby reducing the sensitivity of ¹⁸F-FDG PET/CT scan (11, 12). To reduce this adverse effect, we compared ¹⁸F-FDG PET/CT and BMB in the assessment of BMI in patients with NB before receiving chemotherapy. Therefore, our retrospective analysis aimed to explore the diagnostic performance of ¹⁸F-FDG PET/CT in detecting BMI in newly diagnosed neuroblastoma (NB) and ganglioneuroblastoma (GNB).

2 Methods

2.1 Patients

We retrospectively collected all the data of patients with neuroblastoma (age <18 years) who had undergone ¹⁸F-FDG PET/T before treatment from June 1, 2019, to May 31, 2022. There were 51 patients included, including 41 patients with NB and 10 with GNB. They were diagnosed for the first time and underwent both ¹⁸F-FDG PET/CT and BMB within 1 week. Patients who had undergone any treatment procedures before ¹⁸F-FDG PET/CT were excluded.

The data obtained from the clinical medical records included age, sex, pathologic type, and laboratory parameters, such as lactate dehydrogenase (LDH), neuron-specific enolase (NSE), serum albumin (A), serum total protein (TP), hemoglobin (Hb), and blood platelet (BP). All methods were performed according to the relevant guidelines and regulations.

Pediatric neuroblastoma usually has three histological types: NB, GNB, and ganglioneuroma (GN). We excluded GN because it is a benign tumor (13) and does not present with bone metastasis.

2.2 ¹⁸F-FDG PET-CT imaging protocol

¹⁸F-FDG is produced on a MiniTrace Cyclotron and automatic synthesis system of GE Healthcare, with a radiochemical purity of more than 95%. The patients fasted for at least 6 h before the examination and had blood glucose lower than 10 mmol/L. The intravenous injection of FDG ranged from 4.44 to 5.55 MBq/kg. Thirty-six patients were given oral sedation for PET scans. PET/CT scans were performed 60 minutes after injecting radiolabeled ¹⁸F-FDG using a Siemens PET/CT system (Horizon). The examinations included a head-to-toe CT scan (80 kV; 50–100 mAs) and a three-dimensional (3D) PET scan (2 min per bed; six to seven beds). The rotation time was 0.6. The slice thickness was 3.75 mm. The increment was 3.27. The pitch was 0.984. The images were displayed on the Syngo.via workstation.

2.3 ¹⁸F-FDG PET/CT image analysis

2.3.1 Patterns of ¹⁸F-FDG uptake in bone marrow

All scans were read independently by two experienced nuclear medicine physicians who were blinded to clinical information, laboratory assessments, and BMB results. A third reader adjudicated the discrepancies.

The BM uptake was categorized (14, 15) (Figure 1). “A” was defined as no increased ¹⁸F-FDG uptake, “B” was defined as diffusely increased ¹⁸F-FDG uptake, “C” was defined as focal/multifocal only, which was one or more circumscribed areas of increased ¹⁸F-FDG uptake within the skeleton, “D” was defined as combined focal/multifocal, and diffuse ¹⁸F-FDG uptake appeared. Cases where BMI lesions appeared to be caused by a contiguous spread from the adjacent soft tissues were considered negative. The presence of osseous sclerosis at sites of uptake on the CT component indicating bone metastases was also recorded. However, the diffuse BM ¹⁸F-FDG uptake with patterns A and B was less likely to be diagnosed as BMI because this may also result from paraneoplastic bone marrow activation (16).

FIGURE 1

Figure 1 Different patterns of 18F-FDG PET-CT bone-bone marrow uptake of 18F-FDG.

2.3.2 Semi-quantitative ¹⁸F-FDG uptake

The maximum standardized uptake value (SUVmax) of the most hypermetabolic bone–BMI was measured (BM-SUVmax) in patterns C and D. Additionally, a circular region of interest (ROI) was drawn inside the normal area in segments VII and VIII of the liver. The average hepatic SUVmax was recorded (HE-SUVmax). To decrease the potential age-related differences, the ratio of BM-SUVmax to HE-SUVmax (BM-SUVmax:HE-SUVmax) was calculated. Patients with hepatic metastases and those with underlying destructive osseous lesions shown on the CT were excluded.

To assess the role of semi-quantitative ¹⁸F-FDG uptake in BM in differentiating BMI from normal or reactive BM, the SUVmax of BM (SUV_BM) was measured in patients with normal or homogeneously increased FDG uptake in BM (patterns A and B). A spherical volume of interest corresponding to the variable vertebral sizes of subjects was placed over the central part of the L5 vertebral body, and SUV_BM was measured. If L5 vertebrae were abnormal, in cases of tumor direct involvement or fracture, an alternative measurement of the L4 vertebral body was obtained, and so on. To account for the potential age-related differences, SUV_BM was further normalized by hepatic uptake (SUV_BM/HE-SUVmax) (14, 15).

2.4 Marrow disease identification using iliac crest trephine biopsy

A pediatric oncologist at our hospital took BMB from only the standard regions of the posterior superior iliac and no other sites. The biopsy results were reported based on histopathology, and immunophenotyping was evaluated by the oncology and pathology departments.

2.5 Identification of bone marrow involvement

Patients with BM uptake (patterns C and D) were considered BMI-positive on the ¹⁸F-FDG PET/CT scan (16). A final diagnosis of BMI was determined if BMB was positive if the focal/multifocal intense FDG uptake in BM on PET was confirmed by directed biopsy or supplementary targeted magnetic resonance imaging (MRI) or the resolution of the BM lesions in parallel with other lesions on the follow-up ¹⁸F-FDG PET/CT scan. The typical focal/multifocal pattern is easier to diagnose in children, as degenerative diseases are less likely to occur in children but are rather common in adult patients (16). For future analysis, patients were divided into four groups: PET-positive BMB-positive, PET-positive BMB-negative, BMB-positive PET-negative, and PET-negative BMB-negative. Ultimately, according to the results, the patients were divided into the bone–BMI group and the non-bone–BMI group.

2.6 Statistical analysis

Statistical analyses were performed using SPSS software (version 28.0 for Windows; SPSS Inc.). Continuous data were described as the mean ± standard deviation (mean ± SD) or median and interquartile, depending on whether they followed a normal distribution. The categorical variables were described as numbers. The degree of agreement between BMB and ¹⁸F-FDG PET/CT was assessed using Cohen’s Kappa. A k-value of 0.0–0.39 represented a slight agreement, 0.4–0.74 was moderate, and 0.75–1.0 was almost perfect. Differences between groups were compared using the Mann–Whitney U-tests for the continuous variables and chi-square tests and Fisher’s exact test for the categorical variables. Receiver operating characteristic (ROC) curves were used to determine the cutoff values of BM-SUVmax to predict BMI in patients with normal or homogenously increased BM ¹⁸F-FDG uptake. All tests were two-sided, and a probability of less than 0.05 was considered statistically significant.

3 Results

3.1 Patients’ characteristics

We retrospectively studied 51 patients with NB and GNB (age <18 years). This study included 22 girls and 29 boys, with an average age of 37.18 months. The general characteristics of the patients are summarized in Table 1. Among the 41 patients with NB, 27 (65.9%) had a final diagnosis that showed BMI. Among the 10 patients with GNB, eight (80%) had a final diagnosis that showed BMI. The status of bone–BMI in patients with NB and GNB (χ² = 0.747; p = 0.387) is shown in Table 2.

TABLE 1

Table 1 General characteristics of 51 patients.

TABLE 2

Table 2 Status of bone–BMI in patients with neuroblastoma (NB) and ganglioneuroblastoma (GNB).

3.2 The results of the bone assessment using ¹⁸F-FDG PET/CT and bone marrow biopsy

A final diagnosis of BMI was confirmed using directed biopsy or other multimodality imaging results, especially those of BM uptake patterns A and B.

The mean κ coefficient was 0.444 for BMB and ¹⁸F-FDG PET/CT agreement for BM uptake, indicating a moderate level of agreement (p = 0.001) with an absolute agreement consistency of 72.5% (37 of 51). Table 3 summarizes the bone–BM assessment results of ¹⁸F-FDG PET/CT and BMB. The distribution of the uptake ¹⁸F-FDG pattern in the bone–BM in different pathological subtypes and the results of BMB are shown in Table 4.

TABLE 3

Table 3 Bone–BM assessment results of ¹⁸F-FDG PET/CT and bone marrow biopsy (BMB).

TABLE 4

Table 4 Distribution of the absorbed 18F-FDG pattern in the bone–bone marrow in the different pathological subtypes and bone marrow biopsy (BMB) results.

3.3 Semi-quantitative analysis of bone marrow ¹⁸F-FDG uptake pattern

BM semi-quantitative ¹⁸F-FDG uptake was evaluated in 30 patients with patterns A and B. Eventually, 24 patients had pattern A, and six had pattern B. Their SUV_BM/HE-SUVmax showed no statistically significant difference (Z = -0.62; p > 0.05), and SUV_BM showed a statistically significant difference (Z = -3.5; p < 0.01). The ROC curve analyses determined that the AUCs of SUV_BM and SUV/HE-SUVmax were 0.971 (95% CI: 0.911–1.000; p < 0.001) and 0.917 (95% CI: 0.715–1.000; p < 0.001), respectively, for predicting bone–BMI (Figure 2). According to the Youden index, a cutoff value of 1.89 for SUV_BM was determined as the point with a maximum sum of sensitivity (100%) and specificity (95.65%). A cutoff value of 1.66 for SUV_BM/HE-SUVmax was determined as the point with a maximum sum of sensitivity (80%) and specificity (100%). In patterns C and D, the AUCs of BM-SUVmax and BM-SUVmax/HE-SUVmax were 0.398 (95% CI: 0.156–0.640; p = 0.456) and 0.582 (95% CI: 0.319–0.844; p = 0.551), respectively, for predicting bone–BMI.

FIGURE 2

Figure 2 Receiver operating characteristic curve of SUVBM and SUVBM/HE-SUVmax performance in the detection of BMI in NB and GNB patients in patterns A–B.

3.4 Clinical feature variables and status of bone marrow involvement

The different clinical features were compared among patients with different BM ¹⁸F-FDG uptake patterns. Patients with patterns of A and B showed statistically significant differences in terms of NSE and Hb. In the semi-quantitative analysis of ¹⁸F-FDG PET/CT, SUV_BM and SUV/HE-SUVmax also showed statistically significant differences. The different clinical features in patients with patterns C and D showed no statistically significant differences. The various clinical features and the semi-quantitative analysis of ¹⁸F-FDG PET/CT in patients with different BM ¹⁸F-FDG uptake patterns are shown in Table 5.

TABLE 5

Table 5 Various clinical features and semi-quantitative ¹⁸F-FDG PET/CT in patients with different patterns of bone–bone marrow.

4 Discussion

Many pediatric malignancies usually have bone–BMI, such as lymphoma and neuroblastoma (17, 18). In neuroblastoma, accurate staging is essential for prognosis and choosing appropriate treatment options (19). ¹⁸F-FDG PET/CT has become an available routine clinical practice, greatly modifying the diagnosis and staging approach of neuroblastoma. Neuroblastoma is often characterized by a high ¹⁸F-FDG uptake (19), including bone–BMI. Compared with traditional CT or MRI examination, ¹⁸F-FDG PET/CT could provide important information about neuroblastoma and show more extensive disease in one examination.

Research revealed that ¹⁸F-FDG PET/CT was more sensitive than BMB for detecting BMI in pediatric lymphoma staging and can even replace BMB (15, 17, 20). However, the current protocol calls for screening for BMI using BMB as the standard method for evaluating pediatric neuroblastoma. BMB is an invasive and expensive procedure, which samples only a limited part of the BM (17). Evaluating BMI using ¹⁸F-FDG PET/CT would unduly reduce the risk of staging (8). In their meta-analysis of seven studies, Sun et al. reported that ¹⁸F-FDG PET/CT has excellent overall diagnostic accuracy and high sensitivity and specificity in detecting bone–BMI in pediatric neuroblastoma (10). However, no study compared the diagnostic value of ¹⁸F-FDG PET/CT and BMB in detecting metastatic bone–BM in newly diagnosed pediatric neuroblastoma.

In our study, we used both ¹⁸F-FDG PET/CT and BMB, and 22 patients (43.1%; 22 of 51) were consistently considered BMI-positive, and 15 patients (29.4%; 15 of 51) were BMI-negative. However, 14 patients showed inconsistent results. After undergoing BMB and ¹⁸F-FDG PET/CT, nine were BMB-positive and ¹⁸F-FDG PET/CT-negative (seven NB and two GNB patients). In contrast, the remaining five patients with inconsistent results were BMB-negative and ¹⁸F-FDG PET/CT-positive (all NB patients). The concordance analysis showed a moderate agreement between ¹⁸F-FDG PET/CT and BMB in this study population (Cohen’s k = 0.444; p = 0.001), with an absolute agreement consistency of 72.5% (37 of 51). We found that ¹⁸F-FDG PET/CT and BMB are complementary in the evaluation of BMI in patients with neuroblastoma.

¹⁸F-FDG PET-CT represents 100% positivity in bone–BMI, which allows avoiding BMB in patients with pattern D. In some patients with patterns B and C, ¹⁸F-FDG PET/CT showed an abnormal focal bone–BMI at the acetabular bone or disease at other sites (e.g., femur, humerus). This phenomenon may be due to the BMB examining the iliac bone lesion, which provides information from a limited area. Thus, BMB is not perfect as a method for evaluating BMI in patients with patterns B and C. However, in patients with pattern C, ¹⁸F-FDG PET/CT can well identify bone involvement. There may be new value in improving bone–BMI uptake patterns for further research.

Meanwhile, a correct diagnosis of diffuse BM ¹⁸F-FDG uptake was a challenge in pediatric lymphoma (14, 15). Under normal conditions, the BM shows a homogenous low uptake of ¹⁸F-FDG, less intense than the liver. A diffuse BM ¹⁸F-FDG uptake can occur because of different reasons: malignancies or hematopoietic diseases, an inflammatory response, paraneoplastic BM activation as a result of recent chemotherapy, or administration of hematopoietic growth factors (21). In our study, 24 patients with pattern A showed no ¹⁸F-FDG uptake, and six patients with pattern B showed diffuse ¹⁸F-FDG uptake. Nine of 24 (20.8%) patients with pattern A and five of six (83.3%) patients with pattern B were BMB-positive.

In our study, to further distinguish between patterns A and B and assess the value of semi-quantitative ¹⁸F-FDG uptake, the L5 vertebrae SUV _BM was measured in patients with normal or homogeneously increased ¹⁸F-FDG uptake in BM. In patients with pattern A, only 11 had an L5 vertebrae SUV_BM lower than that of the liver (45.8%), but 13 patients showed a SUV_BM lower than 1.5 times that of the liver (54.2%). In patients with pattern B, all had an L5 vertebrae SUV_BM greater than that of the liver (100%). In contrast to model A, five model B patients had greater than 1.5 times as many livers (83.3%). From the ROC curve analyses, we found that the AUCs of SUV_BM and SUV_BM/HE-SUVmax were 0.971 (95% CI: 0.911–1.000; p < 0.001) and 0.917 (95% CI: 0.715–1.000; p < 0.001), respectively, for predicting BMI. These ¹⁸F-FDG PET/CT metabolic parameters can effectively differentiate between patterns A and B. Our data showed that the L5 vertebrae SUV_BM range was 0.47–2.1 in patients aged 2–67 months, consistent with the normal range of 1.3–2.1 in patients aged 2–15 months (22). Thus, the analysis of the semi-quantitative uptake of ¹⁸F-FDG, including SUV_BM and SUV/HE-SUVmax, allows an effective differentiation between patterns A and B.

In patterns of C and D, ¹⁸F-FDG PET/CT was more accurate for the diagnosis of bone–BMI. In pattern D, the diagnostic agreement rate for ¹⁸F-FDG PET/CT and BMB was 100%. In pattern C, the diagnostic inconsistency rate was 71.4%, and BMB had a high false negative. The ROC curve analyses showed that the AUCs of BM-SUVmax and BM-SUVmax/HE-SUVmax were 0.398 (95% CI: 0.156–0.640; p = 0.456) and 0.582 (95% CI: 0.319–0.844; p = 0.551), respectively, for predicting BMI. The ROC curve analyses cannot distinguish between patterns C and D. ¹⁸F-FDG PET/CT-guided BMB should be performed to reduce the harm of unnecessary BM aspiration biopsies in patients with pattern C (23).

Clinical features including age, NSE, and Hb showed statistically significant differences between patterns A and B. Many patients with pattern A have normal Hb, while patients with pattern B have low hemoglobin. Moreover, no statistically significant clinical indicators were found for patients with patterns C and D. Thus, clinical features offer greater advantages in diagnosing patterns A and B.

The main limitation of this study is its retrospective nature because we were unable to biopsy the bone lesions or perform other imaging examinations of bone lesions with ¹⁸F-FDG uptake. There is also the possibility of false negatives in some post-chemotherapy follow-up patients, particularly for pattern A.

5 Conclusion

This study suggests that ¹⁸F-FDG PET/CT can detect BMI with good diagnostic accuracy and reduce unnecessary invasive inspections in newly diagnosed pediatric NB and GNB, especially for patients with patterns C and D. For patients with pattern D, ¹⁸F-FDG PET/CT can replace BMB.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics statement

The study was conducted from a new perspective and with a new approach. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

Author contributions

ZF and JS conceived and designed the study and helped to draft the manuscript. JZ performed the data collection. JR performed the statistical analysis. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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