Neonatal adrenal masses are not new to most pediatric surgeons and neonatologists. The reason for this is that it is not rare. In the past, surgical exploration was the only means of definitive diagnosis and radical treatment. As awareness of the spectrum of this disease has increased and reliable data from well-designed prospective studies have been validated, the management of neonatal adrenal masses has increasingly moved towards a “wait and watch” approach. Here, we present the evolution of the international understanding and treatment of neonatal adrenal masses. The incidence of neonatal adrenal masses is not low, and they can be detected prenatally, or postnatally through screening or the development of symptoms. Clinically, neonatal adrenal masses tend to be mainly cystic, mostly cystic or cystic-solid neuroblastoma, but not always. Diseases that need to be differentiated include adrenal hematoma, adrenal cortical cyst or cortical tumor, pulmonary isolation, and teratoma. Adrenal hematoma can be caused by birth injury, prolonged labor, hypoxia, asphyxia, sepsis, and coagulation disorders. However, in general, neuroblastoma is detected slightly earlier and can be detected in the middle or late stages of pregnancy. The nature of the mass detected in the late stages of pregnancy is very difficult to differentiate from an adrenal hematoma by imaging and clinical means. Adrenal epithelial cysts or cortical tumors and their rarity, and the cause and course of their onset in the neonatal period are also currently unknown. Pulmonary isolation is a condition that needs to be differentiated from neuroblastoma, which is similar in terms of gestational age of occurrence, location, and ultrasound presentation. Pulmonary isolation tends to occur in the middle of pregnancy, with about an 84% chance of occurring on the left. Neuroblastoma tends to be evident in late pregnancy and has about a 39% chance of occurring on the left side. Unlike the other masses, pulmonary isolation can present as a dumbbell shape. Despite this, however, the differential diagnosis of neonatal adrenal masses remains a difficult one in the clinical setting. On imaging, CT tends to show an irregular adrenal mass, mostly cystic, which may contain parenchymal heterogeneous components, rimming a substantial mass or a mass with hemorrhage or necrosis. When the mass appears cystic, it is difficult to differentiate between a simple cyst, tumor, or adrenal hemorrhage. Even with MRI, it is difficult to identify adrenal hemorrhage or cystic neuroblastoma hemorrhage. Existing imaging techniques make it difficult to make a diagnosis with a single examination and still appear to be helpless in the differential diagnosis. The means of fine needle aspiration is often not feasible because of the cystic mass being confronted. The Affiliated Pediatric Hospital of Fudan University reviewed the imaging data of 28 cases of neonatal adrenal masses and found that neonatal adrenal masses could be presented as cystic or substantial masses in both ultrasound and enhanced CT, but the tumors tended to show blood flow signals within the mass in ultrasound (P=0.02) and enhancement within the mass in CT enhancement (P=0.007) compared with hemorrhagic cases, which is worthy of reference. The management of neonatal adrenal masses has been controversial. There are several reasons for this: 1) Is the mass a tumor or a hemorrhage? 2) What are the consequences due to the mass and does it resolve on its own? 3) Does handling the mass cause more harm than the mass itself? Authors in favor of aggressive exploration believe that neonatal adrenal masses are inherently difficult to identify, and that if the mass is substantial, inaction may lead to tumor progression and delayed treatment, with the determination that “it is better to kill a thousand than to spare one”. On the other hand, opponents believe that a large proportion of neonatal adrenal masses are hematomas and cystic neuroblastomas of the adrenal gland that may resolve on their own, and that the overall mortality rate of surgery for adrenal masses in small infants is about 2% or higher, so the surgical and anesthetic risks should not be ignored, and “wait and see what happens” may be a more effective way to protect the patient. The risks of surgery and anesthesia should not be ignored. 2. “Wait and watch” is called for Since the different opinions mentioned above are mostly based on the clinical experience of some doctors and small-sample retrospective studies, there is insufficient evidence of evidence-based medicine. In order to resolve these disputes, the COG (Children’s Oncology Group) set up a prospective experimental study in 2001-2010, in which they envisioned that by giving expectant observation to newborns with adrenal masses, and intervening only when the tumors grew or progressed, could a large portion of the children avoid the trauma of surgery without affecting the overall prognosis? Therefore, according to strict inclusion criteria (1) age less than 6 months and (2) no more than 120 days from the date of detection of the mass to enrollment in the trial. Prenatal diagnosis was no more than 120 days postpartum; (3) substantial mass less than 3 cm in diameter and cystic solid mass, less than 5 cm in diameter with >25% cystic component and not exceeding the midline; (4) mass confined to the adrenal gland area; (5) no prior surgery or chemotherapy. (6) Tests to exclude metastasis from other sites, such as bone puncture, bone scan, MIBG, and other sites were desirable. A total of 87 children were enrolled. Ultrasound, urine VMA/HVA, abdominal CT or MRI were used for ancillary examinations and follow-up. They were withdrawn from the observational study if they were found to have (1) an increase in mass volume greater than 50%, (2) an increase in VMA or HVA greater than 50%, (3) VMA/HVA <50%, and (4) tumor progression, secondary tumor, or death. The goal of this study was to improve quality of life and survival, and the "watch and wait" approach was considered to be discontinued if the clinical study found a survival rate of less than 95% and a resection rate of more than 75%. It was found that of the 87 cases, 4 were operated on immediately and 83 were put on observation. Of the 87 cases, 4 were operated on immediately and 83 went into observation and follow-up. 56 completed observation and 27 dropped out (of which 13 were lost to follow-up). 27 were diagnosed immediately prenatally/postnatally, and the remaining 60 were diagnosed at a mean age of 14 d. M:F = 2:1. 26% had an elevated VMA at the time of the initial diagnosis, and 33% had cystic components greater than 25%. 56 children in the observation group had varying degrees of volume loss at the end of the period of observation. 48% had no mass remaining, and 23% had 0-1% of the mass remaining. In the group, 23% had 0-1mL of residual mass, 14% had 1-2mL of residual mass, and 14% had greater than 2mL. i.e., 71% had less than 1mL of residual mass, and 85% had less than 2mL. 54 of the cases had VMA testing at the end of follow-up, and 50 (93%) had normal VMAs. Twenty cases underwent surgery, of which 4 were immediate and 16 were referred for surgery during observation. Of these, 15 were transferred midway and 1 was operated on at the end of observation.Of the 16 cases, 10 were NB, 2 had adrenocortical tumors, 2 had adrenal hemorrhage, and 2 had pulmonary isolation.Of the 10 cases of NB, 7 were children with INSS stage 1, and 2 had progression of the tumors.Of the 7 cases, 6 presented with a 50% increase in volume, and 1 was due to an elevated VMA. Of the 2 cases of progression, 1 developed liver metastases and 1 developed stage 2B with enlargement of contralateral lymph nodes. The 13 children who were lost to follow-up had a mean observation time of 342 days up to the time of loss of follow-up, of which 1 was resected on day 491 and confirmed to be a hematoma, and 12 were not operated on and lost to follow-up, whereas all of these 12 cases had a mass volume of less than 1 mL at follow-up, and 10 of these cases had a normal VMA. Overall, the 3-year tumor-free (neuroblastoma) survival rate was 97.7% ± 2.2%, and the 3-year overall survival rate was 100%. 81% (67/83) could avoid surgery, and the 3-year surgery-free survival rate was 79.8% ± 6.0%. In particular, children with cystic masses had a fairly good prognosis, with a 3-year neuroblastoma-free survival rate of 100% and a 3-year surgery-free survival rate of 88.6 ± 8.6%, while children with substantial masses had a 3-year neuroblastoma-free survival rate of 96.4 ± 3.4% and a 3-year surgery-free survival rate of 75.9 ± 7.6%. Thus, the COG study demonstrated that neuroblastoma survival in neonates with adrenal glands, and overall survival, did not differ from previous studies of surgical treatment and chemotherapy for stage I neuroblastoma, and that the COG believes that "wait and watch" is practical and theoretically justified, as long as enrollment criteria are rigorous and follow-up is close. and has a theoretical basis, and incorporates the routine of neuroblastoma treatment in the low-risk group. Consensus and benefits, dare to ask where the road is COG is not conceived and practiced, Holgersen in 1996 reported that prenatal adrenal masses can disappear spontaneously within 4 months after birth, and a retrospective survey by Sauvat F in 2002 confirmed the same finding. In Japan, a prospective study of expectant therapy for suspected adrenal neuroblastoma was carried out in 2004 by VMA and HVA screening, and the inclusion criteria were a mass less than 5 cm in diameter, Evan stage I or II, and no invasion of the vertebral canal or large vessels. The rate of spontaneous regression was found to be 59-70% with no recurrence. A prospective clinical trial was then conducted in Germany, expanding and upgrading the Japanese trial, and in 2008 the German Pediatric Hemato-Oncology Specialty Group enrolled neuroblastomas less than 1 year of age, biopsy-proven, N-myc-unamplified, stage 1, 2, and 3, for follow-up. 47% of the children observed showed some degree of regression, of which 17% had complete regression and 4% progressed to stage 4. Studies by specialized groups in various countries seem to coincide in demonstrating that neuroblastoma is a clinically biologically heterogeneous tumor with a bipolar clinical presentation. The "wait and watch" approach, which is safe and effective in the follow-up of children confined to an adrenal mass who meet the low-risk criteria (cystic mass, young age, early staging, and negative biologic parameters), and for which surgery can be avoided in up to 80% of the cases, is a reform and a step forward that will benefit the vast majority of neonatal patients. The "wait and watch" approach is a reform and an improvement that will benefit the majority of neonates. In 2011, the Pediatrics Hospital of Fudan University retrospectively analyzed the clinical data, treatment and prognosis of 28 neonates with adrenal gland mass in a single center from 2004 to 2008. Six cases (21.5%) were found to be true tumors, including 5 neuroblastomas and 1 teratoma, and the remaining 22 cases (78.5%) were adrenal hematomas. The bleeding children were treated conservatively and the hematoma disappeared within 6 months of diagnosis. 6 true tumors were treated surgically, 2 of the 5 neuroblastomas were stage 1, 1 stage 3, and 2 stage IVs. All children survived. It was concluded that "1-month follow-up of adrenal masses that are difficult to identify does not affect the outcome and prognosis of children with tumors". Although this retrospective study is a single-center study with few cases, little follow-up time and many active interventions, it is the earliest attempt to pay attention to neonatal adrenal masses in China, and has accumulated experience for prospective studies and multicenter cooperation in the future. It has to be said that there is a lack of uniform standardized treatment standards for the management of neonatal adrenal masses in China at present. This is manifested in the fact that multicenter studies have not yet been initiated, the laxity of inclusion and exclusion criteria, the incompleteness of data, the arbitrariness of treatment, the imperfect follow-up, the absence of large case reports, and the absence of well-documented conclusions. Where is the road to domestic research? The authors believe that by learning from the experiences of other countries and professional groups, establishing a multi-center study of neonatal adrenal masses in China, and forming a consensus and a system that can become an important part of international research and also benefit the children, is an invaluable validation of the practice and application of evidence-based medicine in the field of pediatric surgery.