Advances in the management of craniopharyngioma in children and adults

Craniopharyngioma (CP) is a rare epithelial tumor of the sellar and parasellar region, histologically of low-grade (WHO grade I). They represent approximately 1% of all primary intracranial neoplasms in adults and 1.2–4% in children, making them the most common sellar tumors in the latter. The overall incidence of CP is 1.24–1.46 per million/year with no difference between gender and race.1, 2, 3, 4, 5

In 1904, Austrian pathologist Jakob Erdheim first reported that CP arises from squamous cell rests occurring in the region of the remnant hypophyseal/pharyngeal duct, most frequently originating around the infundibulum. Rarely CP arises in less typical locations along the remnants of the primitive craniopharyngeal duct including the nasopharynx, sphenoid bone, or as primary intraventricular lesions.6,7

The growth of CP is slow, but their location enables them to be large at the time of diagnosis, extending supero-posteriorly into the third ventricle and hypothalamus, compressing supero-anteriorly the optic pathways and inferiorly the pituitary gland, impairing their functions. Adherence to these critical structures often limits the ability of the surgeon to completely resect the lesion, exposing patients to a high risk of recurrence. The overall 5-year survival rate is high (ranging from 91–98%). Unfortunately, the morbidity rate is equally high with severe neuroendocrine sequelae, impaired social and physical functionality and a negative impact on quality of life (QoL) in all patients. Because of this, strict follow up by a specialized multidisciplinary team is paramount.8, 9, 10, 11, 12, 13

High morbidity rates following aggressive complete surgical removal were reported, therefore a change in the paradigm towards a subtotal removal of the tumor mass has now been proposed. As CP is known to recur frequently, postoperative irradiation has become a part of the standard treatment.14, 15, 16 The first reports after the introduction of proton beam therapy show a decrease in adjuvant therapy induced morbidity, but long-term follow up data is still needed to evaluate its role in CP treatment.17

Despite all these recent improvements, we still observe high morbidity rates, especially panhypopituitarism, visual and neurological deficits, hypothalamic obesity (HO), increased cardiovascular issues and reduced quality of life, inciting the demand for alternative therapies to surgery.8,8, 9, 10, 11, 12, 13 Novel insights into the molecular pathogenesis of adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) have offered the possibility of pharmaceutical therapy targeting pathogenic pathways, which could decrease the chance of recurrence and possibly the initial tumor size.23,24

The aim of the present review is to accumulate up-to-date data to help in the development of national guidelines for the management of subjects with CP and the national registry of these patients. The review is presented on behalf of the national multidisciplinary craniopharyngioma working group.

Initial symptoms of CP are frequently unspecific, and the diagnosis can be made relatively late. According to the data from HIT Endo and Craniopharyngioma 2000 study data the most frequent symptoms before the diagnosis in children are headache (68%), followed by visual impairment (55%), growth failure (36%), nausea (34%) neurologic deficits (23%), polydipsia/polyuria (19%) and weight gain (16%).25 In adults, the most common presenting symptoms are visual impairment (40–84%), headache (56%), menstrual irregularities in women (57%), loss of energy (32–48%) nausea and vomiting (26%), lethargy (26%), and weight gain (13–15%).13,26,27 The period from initial symptoms to the diagnosis does not correlate with tumor size, hypothalamic involvement, functional capacity or survival.26 It is however emphasized that weight gain and growth retardation are early signs of CP in children that should lead the investigator to further diagnostic workup. Raised intracranial pressure and/or acute vision loss because of tumor obstructing CSF pathways leading to obstructive hydrocephalus can also be the first manifestation, according to Mortini et al. more often identified in children.26 In these patients, urgent surgical decompression is required and their presenting symptoms are the only ones connected with lower 10-year overall survival.25

There is evidence that adequate presurgical imaging and assessment of hypothalamic involvement of CP is extremely important in estimating prognosis and long-term quality of life. Initial tumor involvement of the third ventricular floor, mammillary bodies and/or posterior hypothalamus on imaging are associated with a worse long-term prognosis due to hypothalamic obesity, regardless of chosen treatment strategies.28, 29, 30, 31, 32 Magnetic resonance imaging (MRI) is the standard imaging modality in CP, but reliable discrimination between ACP and PCP based on neuroradiological criteria is not possible.33 In addition, computer tomography (CT) limited to the sellar area and excluding orbital areas for better determinations of calcifications within the tumor is recommended. Papillary CP namely lacks calcifications and can be misdiagnosed as another type of a suprasellar tumor (Figure 1).34

Figure 1

A preoperative radiological grading system has been developed for pediatric patients.35 Using this grading, the treatment of choice for CP without hypothalamic involvement (HI) (type 0 – no HI on MRI scan and type 1 – distorts or elevates the hypothalamus) is an attempt of complete resection (gross total resection - GTR), with preservation of visual, pituitary and hypothalamic function. For tumors located unfavourably (type 2 – hypothalamus not visible on MRI scan) GTR is not recommended. For prevention of severe morbidity, a subtotal resection (STR) should be performed, followed by adjuvant therapy.28,35,36

The optimal therapeutic strategy for CP is however still controversial. Surgical treatment of these lesions remains among the most challenging for neurosurgeons because of their complex and highly variable topographical relationships with crucial neural and vascular structures such as the optic chiasm, hypothalamus, third ventricle, and vessels of the circle of Willis. So far, no single best treatment paradigm exists, and the extent of surgical resection or adjuvant therapy should be considered on a case-to-case basis.

Previous studies show that the most significant factor associated with recurrence is the extent of surgical resection regardless of the histological subtype, but attempts of GTR in patients with tumor invading the hypothalamus results in significant morbidity in terms of hypothalamic dysfunction.16,37,38 Therefore, the treatment focus is on prevention of additional hypothalamic injury. Precise presurgical imaging for defining the type based on location (primary third ventricle CP or primary suprasellar CP) and topography is essential.30,32 Functional MRI of the infundibulum, tuber cinereum, mammillary bodies, and hypothalamus, although not currently feasible, may be helpful in distinguishing precise topography of CPs and planning the surgical approach.39

No significant difference was observed in 5- and 10-year overall survival (OS) and progression-free survival between GTR and STR followed by adjuvant therapy. STR without adjuvant therapy is associated with worse OS than STR with adjuvant therapy, with unacceptably high recurrent rates up to 63%.15,40,41

In patients that underwent STR postoperative external beam radiotherapy (RT) is presently standard of care to achieve an optimal progression-free survival.13,41, 42, 43, 44 In most studies, attention has been paid to radiation fibrosis syndrome while the impact of RT on QoL has been studied to a much lesser extent. Kiehna and Merchant reported results of meta-analysis of studies on pediatric CPs. They found out that more than two-thirds of patients treated with surgery and radiation therapy in childhood have favorable outcomes, and this rate is even higher in the modern era.43 The most recent advances in the treatment of craniopharyngioma have focused on minimizing treatment-related toxicity. These advances include endoscopic surgery and precision radiotherapy. In the last decades radiation therapy technology has improved dose conformality and provided decreased doses to adjacent critical structures (hypothalamus, optic tract, pituitary gland, carotid arteries, medial temporal lobe structures, etc.) with the goal of reducing long-term sequelae, especially endocrinologic and visual ones. Conformal RT enables a better coverage of the tumor while preserving surrounding tissue therefore decreasing the risk of adverse effects. Current techniques include fractionated three-dimension conformal RT, intensity modulated radiotherapy (IMRT), fractionated stereotactic radiotherapy (FSRT) or recently proton beam therapy (PBT). Tumor control between 80 and in access of 90% can be achieved.45 Greenfield et al. published the first work on the use of IMRT in children with CPs and found this technique promising.46 Harrabi et al. with colleagues reported that FSRT leads to excellent results in patients with CP regarding local control, overall survival and preservation of organ function.47 Lately, in order to lessen adverse effects of radiation, PBT is increasingly used for the treatment of CPs in children. The major advantage of proton therapy is the high degree of dose conformity to the target. Beltran et al. retrospectively evaluated proton treatment plans with IMRT plan. He concluded that compared with photon IMRT proton therapy has the potential to significantly reduce whole brain and body irradiation. Result of that is lower collateral damage to critical structures thus reducing the risk of complications and secondary cancers.48

Regine and Kramer reported that a total dose of > 54 Gy is recommended for external radiation using conventional techniques with excessively rising recurrence rates for doses < 54 Gy. However, limitations are posed by the tolerance doses of vital organs in the vicinity. Therefore, commonly doses between 50–55.8 Gy, delivered in 1.5- to 2.0 Gy fractions, 5 days per week for a period of 6 weeks are used.45,49

If a cystic component in a tumor is present, careful monitoring during radiotherapy is necessary. Namely, dynamic cyst changes can occur throughout the 6 weeks of RT, recommending weekly MRIs during treatment to identify these changes, and to adapt RT plan according to changes in tumor volume.13,46,50

Stereotactic radiosurgery is an alternative to fractionated treatments in patients with craniopharyngioma harboring smaller lesions, but caution is needed because high dose applied in single fraction can carry higher risk for damage of vital structures.45,51

With the future development of targeted therapy, we should strive towards more personalized risk-adapted treatment strategy, taking the histological type of tumor and its mutations into consideration.

The long-term morbidity of craniopharyngiomas is associated with damage to critical neuronal structures by the primary or recurrent tumor combined with the adverse effects of the therapeutic interventions. Despite the improvements in the last decades, the outcome is still rather unfavorable. Patients with childhood-onset CP experience significantly more panhypopituitarism, morbid obesity, epilepsy and psychiatric conditions in comparison to patients with adult-onset disease.8,11,14,19,64 Long term outcomes were shown to be particularly worse in the case of hypothalamic involvement, reducing 20-year OS rate and quality of life of these patients.9,10,25 In this section, we will try to focus on differences in sequela between adult and childhood population.

Damage of the posterior hypothalamic region results in hypothalamic obesity (HO), which occurs in 40–66% of patients with childhood-onset CP and has a major impact on the outcome.9 Especially preoperative lesions that include the dorsal hypothalamic area and dorsomedial nucleus in the posterior hypothalamus are at very high risk for rapid and pathological weight gain during the first year following surgery, sometimes beginning in the months prior to surgery. Postsurgical diabetes insipidus was found to be an endocrine marker for the development of HO.29

The major mechanisms that reinforce HO are vagally mediated hyperinsulinemia, disrupted or impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, altered energy expenditure, reduced melatonin levels, increased daytime sleepiness and reduced physical activity. CNS stimulating agents, somatostatin analogs, a supraphysiological dosage of thyroid hormone, GLP-1 RAs in patients with intact hypothalamus and hindbrain and bariatric surgery have been considered as a potential treatment strategy in adult population based on some individual-level experiences or serial case reports.69 Early involvement of a dietician, psychologist and physiotherapist by providing individual lifestyle and dietary advice may decrease aggravation of HO. Regular visits to the outpatient clinic should be offered to closely monitor weight development and to support patients. Unfortunately, no treatment options for HO have been proven to be effective so far.69

In 178 patients with CP Wijnen et al. reported the prevalence of metabolic syndrome (MetS) in almost half of the patients with HI (48% with childhood onset and 45% with adult-onset CP). Obesity and reduced HDL cholesterol were more prevalent in childhood-onset patients, whereas hypertension and elevated triglycerides were more prevalent in adults. MetS, regardless of the age of onset, was more frequent in female patients than in male patients (54% vs 40%) and in patients not treated for their GH deficiency (57% vs. 43%).19 Non-alcoholic fatty liver disease occurs in about 50% of childhood-onset CP patients with HI, especially in patients treated with stimulants for their daytime sleepiness and severe fatigue.70,71 Increased mortality due to cardiovascular disease in hypopituitarism is already known and it is 3 to 19-fold higher in this specific subgroup of patients with CP. In women with CP, an even higher risk is reported.10,72, 73, 74, 75

Defoort et al. reported the presence of visual disturbances in up to 96% of patients at the diagnosis in pediatric CP cohort of twenty-nine patients. Typical manifestations are the loss of visual acuity, visual field defects, strabismus, papilledema or optic nerve atrophy. In children, the loss of visual acuity was most frequently observed, with post-surgical improvement in 46-66%.76 The risk of post-surgical visual impairment increases with the initial presurgical severe visual defect and localization of the tumor in pre-chiasmatic area.66 Wijnen et al. reports visual acuity disorder and visual field defect 63– 66% of pediatric and adult patients after surgery.8

Memory, attention, impulse control, motivation and socialization deficits are present in CP patients.77,78 They cannot be fully explained by a lesion in the hypothalamus alone.

In patients with childhood-onset CP, the most consistent findings in the cognitive domain are impairments in learning and episodic memory. There is also evidence that hypothalamic tumor involvement reduces gray and white matter volumes in fronto-limbic areas, outside the area of tumor growth. Focal hypothalamic lesions may trigger distal changes in connected brain areas, which then contribute to the above-mentioned impairments, not explicable by a hypothalamic lesion alone.79

There is no published data on cognitive and social deficits in patients with adult-onset CP to the best of our knowledge.

Patients with childhood onset CP rated their social and emotional functioning lower than their healthy controls. The most frequent problems reported were difficulties with learning, inability to control emotions, unsatisfactory peer relationships and concerns regarding their physical appearance. Impairment in QoL was rather psychosocial than physical.80 Patient’s parents asses their QoL worse than patients themselves.12

Adult-onset CP patients score worse than the previous group, but on the contrary, they describe impairments in QoL mainly due to general and physical fatigue, psychical condition and physical mobility. Younger adults reported also social isolation and difficulties in social functioning. Adult-onset patients also performed worse on the depression score than childhood-onset patients. The main independent predictors for decreased QoL were visual field defects, female gender, repeated surgery and HO.81,82

CP is a low grade tumor with locally aggressive behaviour resulting in high morbidity in both children and adults. A multidisciplinary team of neurosurgeons, neuro-radiologists, neuro-oncologists pathologists and endocrinologists should be involved in the diagnosis, treatment planning and lifelong follow-up of these patients to achieve the best outcomes. The development of a national registry increases the quality of management. At present subtotal resection of the tumor with localized irradiation is the treatment of choice to prevent further complications associated with the hypothalamic damage. Careful pituitary hormone replacement in addition to individualized nutritional intake and regular physical activity planning is essential to decrease the morbidity associated with endocrine and metabolic consequences of the tumor and its management, especially if the hypothalamic region has been significantly damaged. Further studies of the signalling pathways involved in the pathogenesis of the tumor will hopefully give rise to novel treatment modalities, enabling a less aggressive surgical and radiation therapy and possibly better neuroendocrine and metabolic outcomes.