Craniopharyngiomas represent 1–15% of all primary intracranial neoplasms (1–3) and 5.6–15% of intracranial tumors of children (2). Although it is the most common lesion involving the hypothalamic–pituitary area in children, about half of cases are diagnosed in adults (1, 3, 4), with a peak incidence around 65–74 years. The symptoms associated with the presence of craniopharyngiomas are due to the development of a space-occupying mass in a non-expandable region and are characterized by headache, visual changes, hydrocephalus, pituitary deficits, and hypothalamic disease (diabetes insipidus, obesity, dysphoria, numbness, temporal-spatial disorientation and alterations in the sense of hunger or thirst, sleep–wake rhythm, and thermoregulation) (5–12). In particular, the hypothalamic obesity associated with this condition is believed to be due to an alteration of both the signals that reach the hypothalamus from the periphery, mainly mediated by leptin, an anorectic action protein that induces a reduction in the sense of hunger and an increase of energy expenditure, and the signal that goes from the hypothalamus to the periphery, with an increase in vagal tone, insulin secretion, and adipogenesis (13–15).

Obesity is associated with severe metabolic and psychological consequences, inducing comorbidities, reduced quality of life, and life expectancy (13, 14). Furthermore, abdominal obesity, measured as waist circumference (WC), is, with other parameters such as arterial hypertension, hyperglycemia, hypertriglyceridemia, and reduced high-density lipoprotein (HDL) cholesterol levels, one of the components of the metabolic syndrome (MS), the elements of which occur, in patients with craniopharyngioma, more frequently than in the remaining population (16, 17).

On these bases, this study aimed to evaluate metabolic status in patients with craniopharyngioma at the time of diagnosis and after a 5-year follow-up, which compares these data with controls.

The study was approved by the local ethics committee and complied with the Declaration of Helsinki, in line with the Guidelines for Good Clinical Practice. All patients provided written informed consent before entering the study, with respect to study participation, and confidentiality statement of data collection according to the Italian privacy policy.

This is a single-center retrospective observational study on the long-term prevalence of MS in adult patients with craniopharyngioma compared with age-, sex-, WC-, and BMI-matched controls.

Up to now, the studies that have investigated the metabolic aspect of this disease have been conducted above all in pediatric patients (16, 17, 23, 24). Some studies have evaluated the prevalence of MS in pediatric patients with craniopharyngioma (16, 17, 23, 24). Srinivasan et al. (16) and Sahakitrungruang et al. (17) found that children and adolescents treated for craniopharyngioma had a higher prevalence of altered MS parameters, in particular abdominal obesity and lipid profile, compared with healthy controls of the same age, sex, BMI, and pubertal status. Moreover, these conditions were directly correlated with age: the greater the age, the greater the alteration.

Metabolic impairments that appear in patients with craniopharyngioma are probably due to the hypothalamic involvement, because of the prevalent localization of craniopharyngiomas near the hypothalamus. In fact, the extension of tumor at this level can cause an alteration in the ventromedial portion of the hypothalamus and can induce, through a wrong regulation of hunger and satiety mechanisms, severe obesity (25, 26).

In particular, some authors (13, 25) have studied the pathogenetic mechanism that leads to “hypothalamic” obesity by identifying alterations both in the afferent signal, from the periphery to the hypothalamus, and in the efferent one, from the hypothalamus to the periphery. In fact, in these patients, leptin, a protein with an anorectic action that reduces the sense of hunger and increases energy expenditure, has an impaired function that is associated with increased insulin secretion, vagal tone, and adipogenesis (13, 15, 25). Moreover, a higher preoperative BMI seems to be an important risk factor for developing postoperative hypothalamic obesity (27).

On the other hand, it is known that obesity is linked to metabolic and psychological consequences, and it is also associated with arterial hypertension, hyperglycemia, hypertriglyceridemia, and reduced levels of HDL cholesterol, which are the components of the MS (28, 29).

Some authors focused metabolic attention on the adult population (30–33), and our results are in agreement with these, which confirm a higher prevalence of MS in patients with craniopharyngioma in adulthood. In particular, the major alterations regarded the lipid profile (30, 31).

In this study, at baseline, all subjects were selected to match BMI and WC as well as gender and age.

After 5 years of follow-up, although there was a higher prevalence of MS in patients than controls, weight and BMI were not different. This could be partially justified by the fact that MS in our patients is related not much to weight or BMI but to other parameters.

In fact, in our cohort, we found higher levels of TC and LDL values in patients at the first and the late evaluation compared with controls. In addition, in our study, patients had a worse HDL profile than controls.

Furthermore, in our sample, SBP and DBP were significantly higher in patients than controls after 5-year follow-up. These conditions contribute to the finding of higher MS prevalence in this group and are in line with literature data (31).

In our patients' group, metabolic parameters did not significantly improve during follow-up, despite the disease treatment and usual medical indications for metabolic impairments. Probably, other non-classical mechanisms are involved in the metabolic impairment of patients with craniopharyngioma. In this context, a new hypothesis spreads about the alterations of circadian rhythm (34).

Our findings reveal that patients with craniopharyngioma have a higher cardiometabolic risk than the control population. In fact, cardiometabolic risk is defined as a condition favorable to the development of type 2 diabetes mellitus and cardiovascular pathologies (35, 36). Key elements are abdominal obesity, insulin resistance, and metabolic abnormalities, such as high levels of triglycerides, total and LDL cholesterol levels, and low HDL cholesterol levels (37).

This is one of the few Italian studies to consider only patients with craniopharyngioma compared to the general population in a single center for a such long follow-up period. Points of the strength of this study are the presence of a control group, the absence of them in some of the studies analyzed (30, 32, 33), and the single-center recruitment reducing the possibility of any selection bias.

Limitations of this study are the absence of data on ethnicity, lifestyle factors, and histological subtypes of craniopharyngioma. Furthermore, the body composition and the percentage of fat have not been measured with dual-energy X-ray absorptiometry (DXA), which is considered the best predictor of the risk of developing cerebrovascular and cardiovascular events (38, 39).

Another limitation is the relatively small number of samples even though we are talking about a rare disease.

In conclusion, this study demonstrated a higher prevalence of MS in patients with craniopharyngioma compared with the general population.

An alteration in the lipid profile and blood pressure was evident in patients compared with controls, but there were no significant differences with the values recorded at baseline and at 5-year follow-up, by considering the two groups separately. It remains to be established whether, in patients with craniopharyngioma, other non-classical mechanisms are involved in metabolic impairment. In particular, there is some interest in the evidence of a correlation among circadian rhythm alterations, different chronotypes, and diseases. According to this evidence, the sleep–wake regulatory system and circadian rhythm synchronization could play an additional key role to provide new indications in the management of craniopharyngioma comorbidities. Further studies, therefore, appear necessary in this regard. It may be useful, in the future, for larger-scale and longer follow-up studies to analyze the increase in the prevalence of MS and mortality in adult patients with craniopharyngioma.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Comitato Etico Università Federico II, Dipartimento di Medicina Pubblica e della Sicurezza Sociale-Sezione di Medicina Legale, Università Federico II, Naples Italy. The patients/participants provided their written informed consent to participate in this study.

ES and CD were responsible for the concept of this paper and drafted the manuscript. DS, ER, RA, TS, LC, FR, and AC provided a critical review of the paper. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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