The incidence of psGBM is very low, many related topics have been hotly discussed. We present a relatively large series of this disease from a single to explore further about its clinical, imaging features, long-term outcome, and prognostic factors. In our study, mean age of diagnosis is 12.8(14 in median). In previous studies, mean age of pediatric GBM patients ranges from 8.8 to 13.3 years, our result support the view that mean age at the time of diagnosis is around the beginning of the second decade of life [5,15,22,25,29].In our series, male to female ratio was 3:2 , this proportion is in line with previous studies[17], it is also in concordance with the majority of other studies reporting male predominance in both the pediatric and adult population [7,15,20,22].We found no evidence of longer survival based on the patient’s age or gender ,which is comparable to data on pGBM available in literature [5,20,32]. The tumors were commonly located in the frontal, accounting for 29%. Unfortunately, there are 10 people that their tumor involved multi-lobe or thalamus, this makes the operation more difficult and result in the low rate of gross total resection in this series. The primary symptoms of the patients were mainly related to increased intracranial pressure, about half of the patients had headache, nausea and vomiting, followed by limb dysfunction, and epilepsy, similar results can also be found in other literatures [17]. We believe that symptoms of intracranial hypertension may relate to the high degree of malignancy and rapid progress of the tumor. Epilepsy, as a symptom of cortical stimulation by tumor, usually occurs in patients with slow-growing brain tumors, such as oligodendroglioma. In general, the clinical manifestations of psGBM are generally nonspecific and depend on the tumor location and size.
Imaging findings in glioblastoma can often have prognostic significance as well, imaging differences between children and adults are still ambiguous. We divide our patients into two categories according to the enhancement characteristics: annular and inhomogeneous enhancement. In our study, the ratio of annular and inhomogeneous enhancement is 4:3(16:12). Median survival was 12 months and 9 months, respectively. It indicates psGBM with annular enhancement may have a better prognosis. Seung won Choi et al. have done in-depth research on the enhancement characteristic of glioblastoma, their study showed a better prognosis of annular enhancement [4]. GBM with annular enhancement implies a less heterogeneity in tumor. Genomic signatures associated with lysosomal activity and autophagy were enriched in inhomogeneous enhancement tumor, lysosome is considered as an important recycling organelle associated with autophagy, and also functions as a relay hub for signaling pathways driven by the mechanistic target of rapamycin complex 1 (mTORC1) [6,21]. Autophagy is known to have dual functions in respect to tumorigenesis [30], and its pro-tumorigenic role inducing the treatment resistance against temozolomide (TMZ) is often emphasized in GBM studies [2,16,26]. Nevertheless, in our study, enhancement character isn’t a statistically significant prognostic factor, it may explain by the fact that our subjects are all children while their study population covers all ages and 144 patients were included. After all, many differences among patients of different age group have been found, and if possible, we should conduct a larger sample size study to evaluate the role of enhancement character in prognosis of psGBM.
Cystic necrosis is one of the common imaging features of GBM. We found it always appears in tumor with annular enhancement, however, some inhomogeneous enhanced tumor can also have cystic necrosis in central. Ji-ping Zhao et al. found that cystic necrosis happened in 7/8 adults diagnosed with epithelioid glioblastoma(eGBM) [33]. We found that children and adults had similar results，in our study, such imaging changes were observed in 6/7 of the children, however, we didn't find it a significant factor of prognosis, and there is less report about the relationship between cystic necrosis and prognosis .In general, cystic necrosis is considered to be a common feature of intracranial malignant tumors.
Glioblastoma originates from the white matter of the brain, and it usually occurs in the deep brain. However, it has been reported that glioblastoma can also be closely related to dura mater and even showed dura tail sign [8,9,31], but pathological examination showed that the tumor only infiltrated the pia mater, no proliferative tumor cells were found in the adjacent dura. In our study, we found that there was a close relationship between dura mater and tumor in 4 patients (Fig.5). Relationship between the tumor and dura is so close that there is no obvious boundary on MRI, but none of them showed dura tail sign, and there was no dura attachment or thickening at surgery. Since this is a retrospective study, there is a lack of pathological evidence to find tumor cells in dura tissue. we didn’t find any evidence to prove that close relationship between dura and tumor can affect prognosis, but the close relationship between the tumor and dura means that the tumor is located in the superficial part of the brain, which makes it easier to remove the tumor completely by surgery, this subject can be studied in the future. Studying the behavior of tumor is very helpful to the treatment of disease. All in all, the imaging research needs a further step.
As we all know, preoperative evaluation often plays an important role in clinical treatment, which determines the main way of treatment. Karnofsky Performance Status (KPS) score is a widely accepted method to evaluate the physical condition of patients. In our study, the mean preoperative KPS score was 71(range 30–90). 17 (60.1%) patients had KPS scores ≥70, and their survival was better than the remaining patients on univariate analysis（p=0.017). Many studies in adults have emphasized the prognostic significance of the preoperative performance status on survival [23, 24]. We found it was not an independent risk factors on multivariate analysis, but in multivariate analysis, it can’t be considered as a significant factor [5]. The possible reason is that the KPS value of the patients was influenced by many other prognostic factors, KPS value indirectly reflects the degree of preoperative disease development, meanwhile, KPS score is also a very important factor that determines the patient’s ability to withstand the entire treatment. In our investigation, many parents give up active treatment for serious complications of radiotherapy and chemotherapy.
Maximal surgical resection followed by adjuvant radiotherapy with concomitant chemotherapy has become the current standard of care in glioblastoma [13,19, 20, 24,25,27]. Stupp et al. [28] demonstrated the efficacy of oral temozolomide in primary adult glioblastomas, chemotherapy has gradually become the mainstream treatment of glioblastoma in children. As for radiotherapy, its toxicity and long term side effects can never be ignored，especially children are in an important stage of growth and development. In our center, resect as much as possible in a safe range followed by concurrent chemoradiotherapy is preferred. We found that postoperative CCRT is an effective way to prolong the survival time and delay the recurrence for psGBM patients. Although current studies have found many differences between childhood and adult GBM, but the effect of the same treatment in adults and children is not consistent, however, many new treatment options are still in active investigation [3,11,14]. Nowadays, electric field therapy is being hotly debated, it is an emerging treatment that can extend the life span of several months, it is also noninvasive and has little effect on children's growth and development. In the future, it may be an important way to prolong the life of psGBM patients.
Although we have collected patient data since 2014, the prognosis of psGBM has not been improved by modern treatment. In our study, the median OS was 11 months, and the half year survival rate was 64.3%, one-year survival rate was 42.9%, and two-year survival rate was 14.3%.PFS of half-year, one-year and two-year are 53.6%,21.4%and9.5%, respectively. Perkins et al. and Marina et al. reported median OS is 13.5 months in their study [17,20]. Karremann et al. performed a retrospective analysis on a relatively large group, nearly 200 children with GBM enrolled in their trials, the median OS was still about one year, just like in adults [12]. Some authors reported longer median OS time even reach 20 months and 43 months [10,25]. Deference of prognosis between children and adults is still a hot topic under discussion. We hold the belief that children have better prognosis and should be treated actively, however, our results show that there is no difference between the survival of our patients and that of adults. This may be attributed to the low gross-total resection rate in our group and some realistic factors, because of the high malignancy of this disease, many children didn’t receive active treated. Studies have shown that gross total tumor resection can significantly delay the disease progression as well [1,10,32,33]. With the improvement of conventional microsurgical techniques and the application of advanced supplementary techniques such as diffusion tensor tractography (DTI), intraoperative MRI, and navigational guidance, the surgically related morbidity in critical locations has remarkably declined. Thus, we should take necessary measures to try our best to achieve gross total tumor resection.
At the last follow-up, three patients are still alive, one patient remained for 43 months without any evidence of recurrence, the other 2 patients accepted reoperation after the first recurrence and are in stable condition now. Although the current data is not enough for statistical analysis, it seems necessary to give active reoperation after recurrence. We will continue to follow up, looking for more related factors to prolong the survival period from the process of diagnosis and treatment.