Tumor rupture is an uncommon, life-threatening presentation among NB patients. Due to the rarity of NB tumor rupture, the previous literature mainly comprises case reports, and large-series reports are lacking. To our knowledge, the current case series of patients with NB tumor rupture is the largest reported series to date from a single institution. The results affirm that 1) the main causes of NB tumor rupture include spontaneous rupture, tumor rupture during or after the first cycle of chemotherapy, and tumor rupture after core needle biopsy. 2) Tumor rupture occurs mostly in patients with high-risk NB. 3) After NB tumor rupture, symptomatic support treatment and chemotherapy are the main treatment, whereas surgery and interventional therapy are not usually the first choices. 4) NB tumor rupture is highly aggressive, disease progression or recurrence occurs early, and patients are susceptible to tumor recurrence with diffuse intraperitoneal lesions. 5) Finally, the value of maximum diameter of primary tumor > 13.20 cm and MYCN gene amplification are independent risk factors for high-risk NB tumor rupture.
Spontaneous NB rupture is very rare in infants or children. This condition is more common in neonates, which can be explained by the trauma of delivery, especially when a congenital adrenal mass is crushed between the spine and liver [8-10]. Generally, the mechanism of spontaneous NB rupture is not fully understood. In terms of anatomic position, neonatal adrenal NB, which originates from the right side and is located between the spine and liver, is more prone to rupture [1, 11]. Regarding tumor size, a larger tumor is more likely to rupture. In a previous report, the risk of rupture significantly increased when the maximum diameter of the tumor exceeded 10 cm [12, 13]. Regarding tumor components, tumors with solid components are less likely to rupture, while tumors with obvious cystic components and liquefaction necrosis are more likely to rupture. With regard to predisposing causes, some patients experience tumor rupture due to external forces, such as trauma, delivery and tumor biopsy, while chemotherapy could induce tumor necrosis and might lead to altered blood ﬂow to the capsule or surrounding tissue of the original tumor, resulting in coagulopathies that damage the tissue . Since 2013, our institute has carried out core needle biopsy for NB patients. Thus far, this procedure has been performed in more than 500 cases. In the present study, only 7 cases of tumor rupture were caused by core needle biopsy (7/500, 1.4%). However, there were no significant differences of clinical characteristics and prognosis (except for age and INRG stage) between spontaneous and secondary (chemotherapy and core needle biopsy) NB rupture groups (Supplementary Table 2). Regarding the molecular biological characteristics of the tumor, 5 cases of spontaneously ruptured NB were reported in previous studies, and MYCN amplification was positive in 3 of 4 examined cases, suggesting that the aggressive behavior of MYCN-amplified NB might predispose the tumor to spontaneous rupture .
Previous studies have confirmed that MYCN gene amplification plays an important role in promoting angiogenesis and the proliferation, invasion, and metastasis of NB cells to inhibit cell differentiation and apoptosis [14-16]. Targeting MYCN has significant potential for the treatment of highly vascularized NB. The structure of blood vessels in malignant tumors was also considered fragile compared with that of blood vessels in normal tissues, which could cause the infarction of the vessels and the necrosis of the tumor capsule . The above molecular biological basis is helpful to explain the relationship between MYCN gene amplification and NB tumor rupture, but the specific mechanism still needs further study in the future.
The operative indication for spontaneous rupture of NB should be thoroughly considered. Evaluating imaging-defined risk factors (IDRFs) plays an important role in judging whether upfront surgery can be performed. For stable patients with resectable tumors (without IDRFs), complete resection is the best choice to completely arrest the bleeding. In cases of unstable states or unresectable tumors (with IDRFs), interventional embolization or laparotomy for hemostasis as damage-control surgery might be applicable. Interventional embolization is an effective treatment for organ-origin tumors such as liver tumors and kidney tumors when spontaneous rupture occurs [17-20]. However, NB originates from the retroperitoneum and usually has no definitive blood supply. Thus, interventional embolization was usually ineffective. Considering the imaging characteristics of the patients in this study, most of the ruptured NB tumors were huge. Additionally, the tumors always encased important intraperitoneal blood vessels, and seriously infiltrated adjacent organs or structures. Thus, IDRFs were present in most of the ruptured NBs, and upfront surgical resection was extremely difficult. In this study, 3 patients with spontaneously ruptured NB underwent upfront surgery. During the operation, we found that the tumors were huge, fragile and bled easily; they also seriously invaded the adjacent organs and blood vessels. Therefore, an appropriate surgical treatment must be discussed according to the patient’s general state in addition to the tumor features (such as INRG staging, the origin, and local invasiveness). Exploration, hemostasis, and biopsy were the primary purpose if surgery was performed, and emergent removal of tumors was unnecessary when hemostasis was achieved.
In symptomatic support treatment, when a patient had a ruptured tumor, it was necessary to monitor the vital signs by ECG monitoring, recording urine volume, improving oxygenation by inhaling oxygen, correcting shock by intravascular fluid therapy, obtaining blood samples for blood product preparation, and fully sedating and immobilizing the patient. Moreover, laboratory examinations and emergency imaging examinations should be performed immediately. According to the relevant tests and examinations, blood products such as erythrocytes, plasma, platelets and fibrinogen should be transfused to correct anemia, coagulation disorder and thrombocytopenia. Additionally, empirical anti-infective therapy, symptomatic myocardial protection, diuresis, correction of water and electrolyte disorders, and nutritional support therapy should be performed.
To perform anti-tumor therapy, imaging examinations, nuclear medical examinations, and laboratory examinations should be performed as soon as possible. NB-related tumor markers, bone marrow aspiration and biopsy, MIBG or PET-CT, and cranial CT/MRI should be performed to determine the tumor burden and tumor stage. Histopathological biopsy specimens of primary or metastatic lesions should be obtained as soon as the patient is in a stable condition. Molecular biology tests of the MYCN gene, 1p36, 11q23 and DNA ploidy should also be carried out. If a patient's condition is too poor to apply general anesthesia and surgery, core needle aspiration biopsy under local anesthesia might be a more appropriate way to obtain tumor tissue with less impact on the patient. Through the above examinations, we determined the diagnosis of NB, INRG stage and risk group. Alternatively, in extreme cases, evidence of histology could not be obtained in some patients who were highly clinically suspected of NB without bone marrow metastasis. As a result, oncologists needed to communicate with the patients’ parents that clinical diagnosis of NB and empirical chemotherapy were necessary to save the patients’ lives. However, when a patient is in stable condition, pathological histology and molecular biology tests should be performed as soon as possible to correct the NB staging and grouping. For preventing tumor lysis syndrome, adequate hydration and alkalization played important roles in controlling tumor burdens and improving the overall conditions of patients. For high-risk NB patients in very poor condition who could not tolerate high-intensity chemotherapy, dose-induced chemotherapy could be performed in the first cycle of therapy, followed by standard protocols in the following cycles.
The results of this study showed that the prognosis of NB with tumor rupture was very poor. A few patients died directly due to MODS manifestations, such as hemorrhagic shock, heart failure, respiratory failure, and severe infection caused by tumor rupture. However, most patients could be discharged in stable condition after symptomatic support treatment and chemotherapy and received further stratified treatment according to their risk grouping. Through intensive preoperative induction chemotherapy, the majority of patients’ conditions were stabilized, the levels of tumor markers decreased, tumors shrank, and metastasis disease was relieved or disappeared. Patients usually had the opportunity for delayed surgery, but most patients were susceptible to progression or early recurrence. The median time of tumor progression or recurrence was 10 (6, 15) months in this study. Only one patient survived after tumor recurrence, whereas all other patients died. Researchers analyzed the clinical and prognostic information of 2266 patients with NB recurrence or progression in the INRG database . The median time of NB progression or recurrence was 13.2 months. The median recurrence time of patients with MYCN amplification was 11 months in 562 cases and 14.5 months in 1141 patients with no MYCN amplification, with a significant difference between the two groups (P < 0.05). The 5-year overall survival (OS) rate of 2266 patients with recurrence was only 20% ± 1%, and patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death (the peak value was approximately 12 months), which also supported the results of our study . According to previous clinical studies, the most common recurrence sites in high-risk NB patients are bone and bone marrow, while the 5-year local recurrence rate of the primary site is only 11.9% ± 2.2% . In this study, among 14 patients with disease progression or recurrence, 13 patients experienced intraperitoneal progression or recurrence, and these patients often presented with diffuse intraperitoneal lesions. These lesions strongly suggested that progression and recurrence were related to implant metastasis caused by tumor rupture.