Introduction
As results of advances in treatment, almost 80% of children and adolescents who receive a diagnosis of cancer become long-term survivors. In the United States, there are approximately 270.000 survivors of pediatric cancer reaching the amount of about 1 every 640 adults between the ages of 20 and 39 years [
1]. The improved survival rates have resulted in increased attention on late side-effects. They can include second malignancies, cardiovascular abnormalities, pulmonary complications, endocrine consequences and obesity. In the Childhood Cancer Survivor Study, the survivor population is considered a high-risk population. Thirty years after a diagnosis of cancer, almost three fourths of survivors have a chronic health condition, more than 40% have a serious health problem and one third have multiple conditions [
2]. Some of these adverse health effects may be modifiable and, therefore, the long-term monitoring of survivors has became an important part of their overall health care and the identification of treatment and patient factors that contribute to them is now crucial.
Obesity is a well-recognized complication of tumors localized in the hypothalamic-pituitary region. In childhood, craniopharyngioma is the most common neoplasm of the hypothalamic-pituitary area, accounting for approximately 80% of tumors in this location and represents 5-15% of intracranial tumors [
3]. A Childhood Cancer Registry estimates an incidence of craniopharyngioma of 1.4 cases per million children per year in Italy [
4]. Similar data are provided by other registries in Western countries, while higher rates have been observed in Asia and Africa. Craniopharyngioma has a bimodal age distribution with a peak between 5 and 14 years of age, and a second one in adults older than 65 years. Even if it is not truly malignant, it is locally invasive and grows slowly in the suprasellar region. During its growth, craniopharyngioma could invade surrounding tissue including the hypothalamus and optic chiasm. Consequently, even if survival has dramatically improved in the last years (overall 10-years survival rate: 91-98%), this attachment makes the complete excision of the tumor difficult and the affected children may be visually impaired and often develop multiple endocrine deficiencies [
5]. Management of craniopharyngioma is therefore still complex and controversial. Aiming the preservation of the hypothalamic function, a complete resection of the tumor is the treatment of choice only in patients with favorable localization. When the tumor localization is unfavorable, a limited resection followed by local irradiation is recommended [
6].
In brain tumors, the location of the primary tumors might be one of the principal factors affecting body weight and composition. The hypothalamic obesity is defined as a rapid, unrelenting and intractable weight gain, not responsive to diet and exercise and usually associated with others symptoms, including headache, impaired vision, increased somnolence and behavioral disturbances, especially severe hyperphagia and abnormal food seeking behaviors [
7].
Hypothalamic involvement can derive by infiltration of the tumor itself. In such cases, weight gain could be a sign of the disease leading, together with other symptoms, to the diagnosis of craniopharyngioma. In a large study of 63 children, 17% had a history of significant weight gain in the 3.5 years before the diagnosis of craniopharyngioma [
8].
After tumor resection, survivors of childhood craniopharingioma experienced an about 50% increased rate of obesity [
9‐
11]. In a study conducted in the St. Jude Children's Research Hospital, 65% of 55 patients treated for craniopharyngioma during childhood (about 90% surgery plus radiotherapy) were found overweight or obese after 7.6 years (range 5-21.3 years) from diagnosis [
12]. Muller showed that the extension of the tumor to the hypothalamus was found in 76% of obese and 96% of severely obese patients compared to 33% of normal weight survivors [
13]. Following surgery, mean Body-Mass Index (BMI) Standard Deviation Score (SDS) increased from 0.0 to 2.7 at 6 months and to 2.4 at 1 year [
8]. The increase of BMI correlates with the severity of hypothalamic damage evaluated both on preoperative [
9,
14] and postoperative imaging [
15,
16].
In craniopharyngioma, a distinctive pattern of weight gain has already emerged. Children who developed hypothalamic obesity have a significant and rapid BMI increase over the first 6 months after treatment, followed by stabilization, with no subsequent loss of weight [
15]. That is the reason why an early and rapid postoperative weight gain seems to be a significant predictive factor for severe long-term obesity [
10,
17]. In addition, patients who remained at normal weight during follow-up after diagnosis of childhood craniopharyngioma presented a lower BMI SDS at the time of the diagnosis [
9,
10]. Therefore, an increased BMI at diagnosis of craniopharyngioma is reported as another significant risk factor predictive of the development of severe obesity [
18,
19]. It could derived from the presence of a hypothalamic dysfunction prior the diagnosis of craniopharyngioma, but it could also prove the presence of an unhealthy lifestyle, already existing independently of the subsequent diagnosis of craniopharyngioma.
An increased risk of cardio- and cerebrovascular mortality was observed in a study of 60 patients treated for craniopharyngioma compared to the general population during a median follow-up time of 12 years [
49]. All the factors identified as causes of developing hypothalamic obesity, especially hypopituitarism and radiotherapy can be interpreted as risk factors for cardiovascular disease (CVD) later in life. Nevertheless, there is only limited data on the development of CVD in long term survivors of childhood central nervous system (CNS) cancer. It has already been demonstrated convincingly that adult GHD subjects are at increased risk for CVD [
50,
51]. In a retrospective study of patients with hypopituitarism, the risk of cardiovascular mortality was twice than in age- and gender-matched healthy controls. In long-term survivors of childhood CNS tumors (70% cases of medulloblastoma) who received cranial irradiation exceeding 45 Gy, Heikens et al described an altered risk profile for CVD with evidence of elevated systolic blood pressure, increased waist-hip ratio and adverse lipid profile [
52]. Moreover, patients with GHD due to cranial irradiation presented a more pronounced altered metabolic profile as well as an increased intima-media thickness (IMT) of the carotid artery bulb [
52]. The abnormalities were particularly pronounced in untreated GHD patients [
53,
54]. Srinivasan and colleagues were the first authors documenting an increased risk of metabolic syndrome (MS) in children with GHD and hypothalamic obesity after craniopharyngioma surgery. In fact, 9 patients post-craniopharyngioma surgery presented a higher fasting level of triglycerides and a lower high density lipoprotein cholesterol to total cholesterol ratio compared to those of healthy age-, sex-, pubertal stage- and BMI-matched controls [
19]. Recently, after 4.9 ± 3.0 years from the diagnosis of craniopharyngioma, MS was detected in 73.3% (10/15) of survivors and in 20% (3/15) of age-, gender-, pubertal stage- and BMI-matched controls [
27]. Moreover, children and adolescents with hypothalamic obesity following craniopharyngioma resection exhibited significantly more features of MS compared controls if they had a greater degree of impaired glucose tolerance, higher TNF-alpha and free fatty acids levels. All of these factors are known to contribute to increased cardiovascular risk in adults.
Conclusion
The comprehension of the natural history and aetiology of obesity in craniopharyngioma survivors as well as the identification of modifiable risk factors should facilitate preventive interventions in the future. In fact, the management of obesity and eating disorders remains difficult, especially in patients with hypothalamic lesions. Nowadays, the best recommendation is the early beginning of prophylactic and therapeutic interventions in patients at risk of obesity. They should focus on promotion of a reduction in sedentary behavior and increases in physical activity. The American Cancer Society has developed specific guidelines on diet, nutrition and cancer prevention for the maintenance of health in the general population as well as in survivors of cancer [
55]. The suggested diet is characterized by five or more servings of fruits and vegetables per day, the choice of whole grain foods and a limited amount of red meat, foods high in fat content and alcoholic beverages. In addition, 30-60 minutes of moderate to vigorous exercise at least or more than five times per week should be performed. Such interventions should be helpful in obesity prevention, but could also have a wide range of additional benefits in the prevention or amelioration of other late effects of cancer treatment. A multidisciplinary approach has to be offered to patients soon after the diagnosis of childhood cancer, continue through long-term follow up and extent into adulthood.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
Both the authors contributed to the conception of the review and were involved in writing, revising and approving the final draft of the manuscript.