Craniopharyngioma (CP) is a benign neoplasm of the central nervous system that is located in the sellar or parasellar regions. Adamantinomatous craniopharyngioma (ACP) originates from the epithelial remnants of Rathke’s pouch or embryonic craniopharyngeal duct, while papillary craniopharyngioma (PCP) is derived from the metaplastic squamous epithelium of the primitive stomodeum (1). These two histopathological types have distinct tumorigenic, radiological, histopathological, genetic, and methylation features (2). Patients with CPs typically present mass effect symptoms, such as headaches and visual disturbances, along with concomitant anterior pituitary dysfunction and hypothalamic syndrome (3, 4). Neuroendocrine dysfunction in these patients may be exacerbated by the destructive effects of tumor growth in the hypothalamic-pituitary region, and the iatrogenic damage from surgical intervention or radiotherapy, resulting in a significant reduction in long-term quality of life (QOL) (3, 5).

Previous studies have revealed significant heterogeneity in the functional status of the hypothalamic-pituitary axes in CP patients, which can be attributed to the age at onset, pathological type, tumor size/location, therapeutic approach, and recurrence status (6–8). The aim of the present study was to compare the pre-operative and post-operative patterns of neuroendocrine dysfunction in patients with adult-onset ACP and PCP, and identify the potential factors that influence the neuroendocrine outcomes of these two histopathological variants.

CPs frequently compress or infiltrate the hypothalamic-pituitary axes, resulting in complex endocrine disorders that significantly impair a patient’s QOL (12, 13). Despite increased post-operative endocrine surveillance in adult CP patients in recent years (14, 15), little is known regarding the differences in endocrine dysfunction between these two pathological types. In the present cohort, the prevalence of ACP was significantly higher than that of PCP, which is consistent with previous reports (4, 16). Furthermore, there was no significant predilection towards either gender in the ACP group, whereas the PCP group had a higher proportion of male patients. These findings align with the gender distribution patterns reported by Feng et al. (17), but contradict historical data that suggest equal gender distribution in CP cases (16).

Adult-onset CP primarily manifests as intracranial mass effects, such as nausea, headaches and visual impairment, followed by endocrine disorders, such as amenorrhea, hypogonadism, polyuria and polydipsia (18–20). Furthermore, sexual dysfunction secondary to hypogonadotropic hypogonadism and hyperprolactinemia is the most prevalent endocrine manifestation in adults (17). The hypothalamic damage and mass effects caused by CPs correlate to its anatomical origin and spatial relationship to the hypothalamus (21, 22). CPs that arise in the sellar region are more likely to infiltrate the anterior pituitary tissue, resulting in deficiencies in multiple pituitary hormones (pan-hypopituitarism). In contrast, suprasellar CPs mainly disrupt hypothalamic function, leading to abnormal hypothalamic hormone secretion and pituitary stalk effects, and increased risk of CDI and hyperprolactinemia. Consistent with this, the pre-operative rates of tumor mass effects in the present study were significantly higher in the PCP group, when compared to the ACP group, while suprasellar tumors were more frequent in the PCP group. However, the pre-operative tumor diameter and volume were similar in both groups. Most CP patients present with severe hypothalamic-pituitary dysfunction at diagnosis (23), the extent of which depends on socioeconomic factors, healthcare standards, and disease severity. Nevertheless, gonadal axis dysfunction and hyperprolactinemia are most common, while the adrenal axis is typically the last to be affected. Consistent with this, merely 36.7% of CP patients in the present cohort had intact pre-operative pituitary hormone levels, while 63.3% of the patients presented with at least one neuroendocrine abnormality at diagnosis. Furthermore, hyperprolactinemia was the most prevalent anterior pituitary hormone deficiency, followed by HPG dysfunction, HPT dysfunction, GHD, and HPA dysfunction. However, no significant differences were observed between the ACP and PCP groups.

Almost 54-100% of CP patients develop pituitary hormone deficiencies after surgical intervention (24), with a high prevalence of dysfunctional HPA/HPT/HPG signaling, GH deficiency, and CDI (25). Consistent with this, the deficiencies in ADH, TSH, GH, ACTH, and LH/FSH were exacerbated in both ACP and PCP patients after a median post-operative follow-up of 12 months, when compared to the pre-operative status. In addition, HPA axis impairment, GHD, and pan-hypopituitarism after surgery were more pronounced in the ACP group, when compared to the PCP group. This discrepancy may be attributed to the higher proportion of intrasellar tumors in ACP patients, which increases the risk of surgical damage to the pituitary tissue and function. A retrospective analysis of 500 CP patients who underwent surgery revealed that PCP tumors adhere less to hypothalamic structures, thereby facilitating safer GTR, when compared to ACPs. Karavitaki et al. reported better prognosis of PCPs vs. ACPs based on the 10-year endocrine follow-up data of 121 CP patients (26), although other studies have not replicated this finding (27). Recent evidence confirms that unlike pituitary adenomas, the surgical resection of CPs rarely restores pre-existing hormone deficiencies. Furthermore, secondary surgeries and radiotherapy can significantly exacerbate the risk and severity of long-term endocrine hormone deficiencies (28).

Unlike previous studies that have primarily focused on comparing isolated pituitary axis dysfunction in CP patients, the present study quantified the severity of pituitary dysfunction by counting the cumulative number of adenohypophyseal and neurohypophyseal hormone deficiencies. The frequency of post-operative hormone deficiencies was significantly higher in the ACP group, when compared to the PCP group. Furthermore, 4.6% of all CP patients with initially intact hypothalamic-pituitary function developed pan-hypopituitarism after the first surgical intervention. In a study that involved 148 CP patients, pituitary hormone deficiency increased in 63.6% of cases, which is consistent with the present findings. In the same study, transcranial surgery was associated to higher rates of CDI, HPA axis impairment, hypothalamic syndrome, and behavioral abnormalities, when compared to transsphenoidal approaches. However, due to the limited size of the PCP subgroup, the authors did not compare ACP and PCP patients (29). Although surgical resection is presently the preferred treatment for CP, there is ambiguity regarding the appropriate surgical approach, in terms of balancing GTR with the preservation of hypothalamic function, visual outcomes, and QOL (30–33). Elowe-Gruau et al. reported that hypothalamic-sparing surgery is associated with a higher proportion of patients with normal body mass index (BMI) after long-term follow-up, when compared to GTR. However, this did not offer any advantage when tumor recurrence and long-term sequelae associated with adjuvant radiotherapy were considered (34). In another study, CP patients with hypothalamic involvement had reduced 20-year overall survival rates. Notably, the 20-year progression-free survival was independent of the extent of surgical resection, which supports the notion that GTR confers no definitive advantage in preventing CP recurrence (25).

In the present study, multiple intraoperative measures were implemented to preserve pituitary function in CP patients, such as high-definition transnasal endoscopy and 3D endoscopy for enhancing the clarity of the surgical field, intraoperative neurophysiological monitoring and neuronavigation for improving the precision of delineating tumor tissues and its surrounding structures, and endoscopy-assisted compartmentalized resection for preserving the pituitary function in large and highly invasive CPs. Nonetheless, our data indicates that these surgical approaches still exacerbate the degree of pituitary function impairment in CP patients. The surgical approach, GTR rate, tumor recurrence rate, time to recurrence, tumor size at recurrence, and proportion of patients that opted for secondary surgery and radiotherapy upon recurrence were similar in the ACP and PCP groups. A systematic review and meta-analysis conducted by Dandurand et al. revealed no significant differences in tumor recurrence rates among patients who underwent GTR (17%) and subtotal resection followed by radiotherapy (27%) (35). Radiotherapy plays a critical role in the management of CP as an alternative to surgery (36, 37). In the present study, the PCP group had a higher proportion of patients who received radiotherapy, albeit without statistical significance. Recent retrospective studies have indicated that Gamma Knife radiosurgery (GKNS) may be superior to fractionated radiotherapy (FRT) in mitigating endocrine complications (38, 39). Furthermore, Habrand et al. reported cognitive deterioration in 29% of CP patients who underwent FRT, while GKNS was associated with a lower risk (40).

Hoffmann et al. reported that pre-diagnosis disease duration in pediatric CP patients was positively correlated to age and endocrine dysfunction rates, but unrelated to tumor size at diagnosis, extent of resection, hypothalamic involvement, or BMI (41). Furthermore, although some reports suggested higher 5-year overall survival rates for PCP patients, when compared to patients with ACP and mixed histology tumors (27), other reports described an increase in perioperative mortality in patients with adult-onset ACP without confirming the pathological type-specific survival differences (26, 42). We identified tumor histological type, tumor volume, and severity of pre-operative endocrine impairment as risk factors for endocrine outcomes in adult CP patients. Specifically, ACP was linked to a 1.51-fold higher risk of increased post-operative hypothalamic-pituitary impairment, when compared to PCP. Furthermore, patients with normal or mildly impaired pre-operative pituitary function had a higher risk of increased post-operative impairment, thereby confirming the challenges associated with the surgical resection of CPs. Nevertheless, hypothalamic integrity-preserving GTR is the primary goal of present surgical treatment for CPs, and is associated with improved recurrence-free survival rates (43). Long-term QOL and survival in CP patients are closely related to tumor recurrence patterns and therapeutic strategies (44–46). For instance, hypothalamic obesity increases the risk of non-alcoholic steatohepatitis (NASH) by 3- to 9-fold in CP patients (47). Female CP patients face a two-fold higher risk of metabolism-related cardiovascular mortality secondary to hypogonadism, when compared to the general population, which may be attributed to the insufficient attention to GH and gonadal hormone replacement therapy in adult CP patients (14, 48).

Overall, the surgical management of CPs continues to pose challenges in balancing GTR with the preservation of hypothalamic-pituitary function. Further prospective multicenter studies are needed to validate the long-term effects of surgical approaches and resection extent on hypothalamic-pituitary function in CP patients. In addition, standardized assessment of perioperative hypothalamic-pituitary function, long-term post-operative follow-up, and appropriate endocrine hormone replacement therapy would be critical to improving the clinical outcomes of CP patients.

ACP was the more prevalent histological type of adult-onset CPs, while PCP had a higher propensity for suprasellar growth, leading to greater tumor mass effects and a higher incidence of CDI, when compared to ACP. Surgical intervention significantly increased the spectrum of endocrine hormone deficiencies in both types, and the impact was more pronounced in ACP patients. Furthermore, the ACP histopathology, larger tumor volume, and mild pre-operative endocrine dysfunction were associated with a higher risk of aggravated post-operative hormone deficiencies.