IGF-1 Levels In Pediatric Low-Grade Gliomas
Overview
This study investigated elevated insulin-like growth factor 1 (IGF-1) levels in children with low-grade glioma (LGG). Elevated IGF-1 levels in LGG are not well understood. The research aimed to determine the prevalence, connections with growth, body mass index (BMI), pituitary function, and tumor behavior in a national cohort of pediatric brain tumor survivors diagnosed between 2002 and 2012 (n=358). IGF-1 levels were assessed in only 45.5% of cases (n=163). Among those with measurements, 18.4% had elevated IGF-1 levels. The study found no link between elevated IGF-1 and tumor behavior or height standard deviation score (SDS) at follow-up. Logistic regression identified posterior pituitary disorder and BMI SDS at follow-up as significantly associated with elevated IGF-1 levels. The findings suggest a connection between elevated IGF-1 and worsening hypothalamic dysfunction over time in children with LGG. Larger prospective studies are necessary for deeper insights.
Introduction
Low-grade gliomas (LGGs) are common pediatric brain tumors, comprising around 30% of cases. While survival rates have improved (85%-96%), treatment challenges and late effects impact patients’ health. Survivors can experience cognitive, visual, and neuroendocrine issues. Children with suprasellar LGGs often exhibit elevated insulin-like growth factor-1 (IGF-1) levels, but the causes, prevalence, and consequences remain unclear. Possible factors include pressure on the hypothalamic-pituitary-GH-axis, hormonal changes, nutritional factors, and medications. Elevated IGF-1 is seen in infants with hypothalamic tumors and diencephalic syndrome, despite its paradoxical nature. Studies suggest links between prolonged elevated IGF-1 and cancer risk, though more research is needed. This study aims to assess the prevalence of elevated IGF-1 in children with LGG, understand its impact on growth, BMI, pituitary function, and tumor behavior, given the existing uncertainties in this domain.
Method
Inclusion Criteria
Data for this study was obtained from a previously described nationwide retrospective cohort in the Netherlands. The cohort comprised children (aged < 18 years) diagnosed with brain tumors between 2002 and 2012, and who survived for more than 2 years (n = 718). In this cohort, comprehensive endocrine data was collected for the majority of survivors (98.6%). For the current study, only children with confirmed low-grade gliomas (LGGs) verified through radiological and/or histological assessments were included (n = 358).
Exclusion Criteria
Patients who did not meet the age criteria (<18 years) or had survival duration of less than 2 years were excluded from the cohort. Additionally, individuals with brain tumors other than low-grade gliomas were not considered in this study.
Data Collection
Tumor and treatment-related information, such as tumor location, progression, relapse, treatment details (including relapse treatments), and disease status were collected from the cohort database. Anthropometric measurements and longitudinal endocrine laboratory data were also gathered.
– Elevated IGF-1 Concentration: Elevated IGF-1 concentration was defined as having a serum IGF-1 standard deviation score (IGF-1 SDS) of ≥ +2, considering the patient’s sex and age. Patients undergoing growth hormone (GH) replacement therapy were excluded from this evaluation. IGF-1 concentrations were calculated using specific references from individual hospitals, and standardization protocols were not universally applied.
– BMI Categories for Infants (0-2 years):
– Underweight: BMI SDS < -2.0
– Overweight: BMI SDS > +2.0
– Obesity: BMI SDS > +3.0
-BMI Categories for Children Aged ≥2 years:
– Underweight, overweight, and obesity were defined according to internationally recognized BMI cutoff points.
Pituitary Disorder at Follow-up
Any disorder of the hypothalamic-pituitary system, including deficiencies in anterior pituitary hormones (GH, TSH, ACTH, LH, FSH), and dysfunctions of the posterior pituitary (DI and CPP) diagnosed during follow-up (at least 1 month after diagnosis) were considered as pituitary disorders.
Follow-up Time
Follow-up time was calculated as the duration between the moment of tumor diagnosis and the last recorded outpatient clinic visit, as documented in the cohort database.
Statistical Analysis
The data in this study is presented either as mean ± standard deviation (SD) or as median (range) for continuous variables, depending on their distribution. Categorical variables are presented as percentages. Differences between groups were assessed using various statistical tests:
– Continuous Data with Normal Distribution: Student’s t-test was employed to compare continuous variables with a normal distribution.
– Skewed Continuous Data: For continuous variables with a skewed distribution, the Mann–Whitney U test was used for comparison.
– Categorical Data: For categorical variables, the χ^2 test or Fisher’s exact test was utilized for between-group comparisons.
To determine potential violations of normal distribution, methods such as QQ plot of residuals and the Shapiro–Wilk’s test were employed. The aim was to ensure robust statistical analysis.
Comparisons were made between children with and without elevated IGF-1 concentrations to assess differences in patient characteristics and tumor response at both diagnosis and follow-up. Relevant independent variables for univariate logistic regression were chosen based on their clinical significance.
A plot was constructed to visualize the relationship between IGF-1 measurements and tumor treatment, aiming to explore any potential associations.
A statistical significance level of p < 0.05 was considered meaningful. All statistical analyses were conducted using SPSS version 26.0 software.
Results
Among the 358 patients diagnosed with LGG, IGF-1 measurements were available for 163 (45.5%). Variability existed between patients with and without available IGF-1 measurements, with associations noted for factors such as age at diagnosis, follow-up time, tumor location, height SDS at follow-up, presence of pituitary disorders, treatment modalities, and tumor progression (p < 0.05).
Of the 163 patients with measurements, 96 (58.9%) had IGF-1 measured at diagnosis, 141 (86.5%) during follow-up, and 74 (45.3%) at both times. Median IGF-1 measurements per patient were 4 (range: 1-31).
Regarding tumor characteristics, LGG was found in the infratentorial region in 38.7%, supratentorial non-suprasellar in 24.5%, and suprasellar in 36.8%. The most common histological diagnosis was pilocytic astrocytoma (76.7%). Median age at diagnosis was 7.50 years, and median follow-up time was 7.14 years. Neurosurgery was undergone by 99.4%, chemotherapy by 25.8%, and radiotherapy by 27.0%. At follow-up, 30.7% were in complete remission, and 69.3% had stable residual disease.
In the study, 18.4% (30/163) of children had one or more elevated IGF-1 concentrations (≥+2 SDS). Among these, 40.0% of IGF-1 measurements were elevated, with a median value of +2.62 SDS. The presence of elevated IGF-1 was associated with factors such as suprasellar tumor location, age at diagnosis, neurofibromatosis type I, underweight or obesity at diagnosis, height SDS corrected for target height SDS, posterior pituitary disorder, and BMI SDS at follow-up.
Children with elevated IGF-1 concentrations were at a significantly increased risk of developing overweight or obesity during follow-up. Additionally, 76.7% of those with elevated IGF-1 had residual disease at the last follow-up, and 46.7% experienced tumor progression requiring treatment during follow-up. However, no significant association was found between elevated IGF-1 and tumor progression. Fluctuations in IGF-1 concentrations were observed in some patients and were linked to certain tumor treatment periods.
After LGG treatment, 46.7% of children with elevated IGF-1 had persistent elevated IGF-1 concentrations, 46.7% normalized, and 6.7% exhibited decreased IGF-1 along with GH deficiency. Pituitary disorders were more common in children with elevated IGF-1 concentrations, particularly central precocious puberty (CPP) and diabetes insipidus (DI).
Conclusion
This retrospective study aimed to provide a comprehensive overview of elevated IGF-1 concentrations in childhood LGG, shedding light on its prevalence and associations. However, it should be noted that the retrospective and non-systematic nature of the study, combined with the limited patient numbers, results in a purely descriptive analysis.
The findings revealed that IGF-1 concentrations were measured in only 45.5% of children, with 18.4% exhibiting elevated IGF-1 levels. Elevated IGF-1 seemed to correlate, though not exclusively, with suprasellar tumor location and younger age at diagnosis. A notable association was identified between elevated IGF-1 levels and a heightened risk of developing higher BMI SDS and posterior pituitary dysfunction during follow-up.
The perplexing observation that children with elevated IGF-1 levels were at risk of developing overweight or obesity might reflect an increasing hypothalamic dysfunction over time. This could be attributed to hypothalamic imbalance and maturation affecting appetite regulation, possibly impacting IGF-1 concentrations. Interestingly, hypothalamic damage or protective brain responses could play a role in the anorectic clinical picture observed in some cases.
Despite the absence of a clear association between elevated IGF-1 and tumor behavior, caution is advised due to the study’s limitations, including its retrospective nature and limited events. A lack of association between elevated IGF-1 and tumor relapse provides some reassurance.
The unexpected finding that elevated IGF-1 concentrations were not exclusive to suprasellar tumors prompts further investigation into the potential connection between hydrocephalus and elevated IGF-1 levels in cases of infratentorial tumors.
Although the study did not identify a direct effect of elevated IGF-1 on height SDS at follow-up, numerous factors, such as nutrition, endocrine influences, and the impact of chemotherapy or the tumor itself, can contribute to height changes. More research is necessary to comprehensively understand the relationship between IGF-1 and linear growth.
In conclusion, this nationwide cohort study discovered that elevated IGF-1 concentrations were present in 18.4% of children with LGG. Notably, such elevations were not exclusive to suprasellar tumors. Children with elevated IGF-1 levels were found to be at increased risk of developing (hypothalamic) overweight and posterior pituitary disorders during follow-up. This study underscores the need for prospective trials featuring standardized IGF-1 measurements at different stages of disease to further elucidate the etiology and potential associations of elevated IGF-1 concentrations with tumor behavior and clinical outcomes.
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