During the period from January 2009 to January 2019, NB was diagnosed in approximately 1800 patients at our institute. A total of 47 ruptured NB patients (28 male and 19 female patients), with a median age at presentation of 29 months (range, 6 months to 8 years), were included in this study. Table 1 lists details regarding key patient characteristics. The median value of the maximum diameter of the primary tumor was 13.20 (10.99, 15.50) cm (range, 4.3 cm to 27.7 cm). Thirty-five patients (35/47, 74.47%) had INRG stage M disease, and metastatic sites included the bone marrow (22/35), bone (20/35), distant lymph nodes (19/35), liver (9/35), soft tissues (5/35), and brain (1/35).
Among the 47 ruptured NB patients, spontaneous tumor rupture occurred in 22 cases (46.81%); in 18 cases (38.30%), tumor rupture occurred during or after the first chemotherapy cycle (15 cases of CAV, 2 CBVP, and 1 CADO). From the first day of chemotherapy, the median time to rupture was 5 (2, 6) days. In another 7 cases (14.89%), tumor rupture occurred after core needle biopsy, with a median time to rupture of 6 (3, 7) days. Most patients experienced abdominal pain and abdominal distension and had a poor overall health status; all tumors were detected by ultrasound and/or CT scan (Figure 1), and these patients were ultimately diagnosed with tumor rupture. The laboratory data revealed varying degrees of anemia in most patients, with a median hemoglobin level of 74 (58, 88) g/L (range, 36 g/L to 130 g/L). After receiving a diagnosis of tumor rupture, 5 patients (10.64%) received symptomatic supportive therapy with or without chemotherapy; all of these patients died of hemorrhagic shock, disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS). Seventeen patients’ parents (36.17%) refused further therapy, and these patients were discharged in an unstable condition from the hospital against medical advice. The remaining 25 patients (53.19%) were discharged in a stable condition from the hospital after receiving symptomatic supportive therapy with or without chemotherapy and surgery. All 25 of these patients received further INRG risk-based therapy (Figures 2-4).
Of the 25 patients discharged in stable condition from the hospital, 23 (23/25, 92%) with high-risk NB received induction chemotherapy (CAV alternated with CVP), and 2 (2/25, 8%) with intermediate-risk NB received chemotherapy of CBVP alternated with CADO. Furthermore, 19 (19/25, 76%) underwent macroscopically complete resection of the primary tumor, 4 (4/25, 16%) underwent gross total resection (> 90%) of the primary tumor, and 2 (2/25, 8%) did not undergo resection surgery because of disease progression. Six patients received myeloablative therapy, autologous stem cell transplantation and further radiotherapy, while 9 received radiotherapy alone.
In this study, 5 patients died of tumor rupture, and 17 patients’ parents refused any further antitumor therapy at our institute after the diagnosis of NB tumor rupture; these patients were lost to follow-up. Among the remaining 25 patients, 6 (6/25, 24%) survived until the end of follow-up (with survival times of 11 months, 17 months, 23 months, 32 months, 42 months, and 46 months), 5 (5/25, 20%) continued to receive treatment and achieved stable disease, and 14 (14/25, 56%) died (13 patients died of tumor recurrence or progression, and one died of renal failure after surgery), with a median survival time of 11 (7, 21) months (range, 2 months to 37 months).
In this study, 14 patients experienced tumor recurrence or progression, with a median time of 10 (6, 15) months (range, 2 months to 22 months) after diagnosis. Among these patients, 7 experienced tumor progression during therapy and ultimately died (4 cases of local progression and 3 cases of combined local and distant metastatic progression), while 7 experienced tumor recurrence (4 cases of local recurrence, one case of distant metastatic recurrence, and 2 cases of combined local and distant metastatic recurrence). Of these 7 patients, 6 died; only one patient survived, with a survival time of 46 months after chemotherapy and tumor resection.
Tumor rupture risk factors
Since NB tumor rupture mainly occurs in children with high-risk NB (40/42, 95.24%), we further analyzed 93 cases of INRG high-risk NB patients with primary non-ruptured tumors in this study. By comparing the clinical characteristics between non-ruptured (n = 93) and ruptured (n = 40) high-risk NB (Table 2), we found significant differences in age, primary site, maximum diameter of the primary tumor, tumor marker levels, pathological characteristics, and the MYCN gene (P < 0.05).
In this study, some tumor marker results were obtained after tumor rupture, as some patients were admitted to the hospital after spontaneous tumor rupture. Thus, the tumor marker results were not included in the multivariate analysis. Ultimately, age, primary site, maximum diameter of the primary tumor, pathological characteristics (INPC categories, MKI, INPC), and MYCN gene were included in the multivariate logistic regression analysis. According to the maximum joint sensitivity and specificity values, the stratification value of age and maximum diameter of the primary tumor were calculated by ROC curve analyses. The cut-off values for the above characteristics were 29 months and 13.2 cm, respectively (Supplementary Figure 1).
In the multivariate logistic regression analysis, a maximum primary tumor diameter > 13.20 cm and MYCN gene amplification were two independent risk factors for high-risk NB tumor rupture, with adjusted odds ratios (ORs) of 6.401 (1.986, 20.626) and 7.874 (2.520, 24.603), respectively (Supplementary Table 1). The AUC-ROC of the model was 0.827, and the sensitivity and specificity were 96.2% (95% confidence interval: 78.4% - 99.8%) and 66.2% (95% confidence interval: 53.3% - 77.1%), respectively (Supplementary Figure 2).
As shown in Table 1 and Table 2, MYCN amplification was detected in 69.0% (20/29) of ruptured NB patients and in 76.9% (20/26) of ruptured high-risk NB patients. A maximum primary tumor diameter > 13.20 cm was found in 48.9% (23/47) of ruptured NB patients and in 55.0% (22/40) of ruptured high-risk NB patients. Finally, the percentages of patients with MYCN-amplified tumors and tumors with diameters > 13.2 cm that had ruptured in the high-risk NB cohort (between January 2017 and January 2019) were 46.43% (13/28) and 34.38% (11/32), respectively.