Radiol Oncol 2019; 53(4): 388-396. doi: 10.2478/raon-2019-0036 388 review Advances in the management of craniopharyngioma in children and adults Mojca Jensterle1,2, Soncka Jazbinsek2,3, Roman Bosnjak2,4, Mara Popovic2,5 , Lorna Zadravec Zaletel2,6, Tina Vipotnik Vesnaver2,7, Barbara Faganel Kotnik2,8, Primoz Kotnik2,3 1 Department of Endocrinology, Diabetes and Metabolism, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Medical Faculty, University of Ljubljana, Ljubljana, Slovenia 3 Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 4 Department of Neurosurgery, University Medical Centre Ljubljana, Ljubljana, Slovenia 5 Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia 6 Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia 7 Clinical Institute of Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 8 Department of Hematology and Oncology, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia Radiol Oncol 2019; 53(4): 388-396. Received 21 June 2019 Accepted 11 July 2019 Correspondence to: Asst. Prof. Primož Kotnik, M.D., Ph.D., Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Center Ljubljana, Bohoričeva 20, SI-1000 Ljubljana, Slovenia. Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Bohoričeva 20, SI-1000 Ljubljana, Slovenia. E-mail: primoz.kotnik@mf.uni-lj.si Disclosure: No potential conflicts of interest were disclosed. Background. Childhood and adult-onset craniopharyngioma is a rare embryogenic tumor of the sellar, suprasellar, and parasellar region. Survival rates are high; however, tumor location and treatment sequalae including endocrine deficits, visual impairment, metabolic complications, cognitive and psychosocial deficits can significantly impair pa- tient’s quality of life. There is considerable controversy regarding the optimal management of craniopharyngiomas. Subtotal resection of the tumor followed by targeted irradiation to avoid further hypothalamic damage is currently indicated. Novel insights in the tumor’s molecular pathology present the possibility for targeted therapy possibly de- creasing the rate and severity of treatment-associated morbidity. Conclusions. Craniopharyngioma should be seen as a chronic disease. To achieve optimal outcomes a multidis- ciplinary team of specialized neurosurgeons, neuro-radiologists, neuro-oncologists, pathologists and endocrinologists should be involved in the diagnosis, planning of the surgery, irradiation and long-term follow-up. Key words: craniopharyngioma; hypopituitarism; metabolic syndrome; proton beam therapy; CTNNB1 gene; MAPK/ ERK pathway Introduction Craniopharyngioma (CP) is a rare epithelial tumor of the sellar and parasellar region, histologically of low-grade (WHO grade I). They represent approxi- mately 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 over- all incidence of CP is 1.24–1.46 per million/year with no difference between gender and race.1-5 In 1904, Austrian pathologist Jakob Erdheim first reported that CP arises from squamous cell rests occurring in the region of the remnant hypo- physeal/pharyngeal duct, most frequently origi- nating around the infundibulum. Rarely CP arises in less typical locations along the remnants of the primitive craniopharyngeal duct including the na- sopharynx, sphenoid bone, or as primary intraven- tricular lesions.6,7 Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults 389 The growth of CP is slow, but their location ena- bles them to be large at the time of diagnosis, ex- tending 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, expos- ing 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 so- cial and physical functionality and a negative im- pact on quality of life (QoL) in all patients. Because of this, strict follow up by a specialized multidisci- plinary team is paramount.8-13 High morbidity rates following aggressive com- plete surgical removal were reported, therefore a change in the paradigm towards a subtotal re- moval of the tumor mass has now been proposed. As CP is known to recur frequently, postoperative irradiation has become a part of the standard treat- ment.14-16 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 panhypo- pituitarism, visual and neurological deficits, hy- pothalamic obesity (HO), increased cardiovascu- lar issues and reduced quality of life, inciting the demand for alternative therapies to surgery.8,18-22 Novel insights into the molecular pathogenesis of adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) have of- fered the possibility of pharmaceutical therapy tar- geting 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 na- tional 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. Clinical presentation Initial symptoms of CP are frequently unspe- cific, and the diagnosis can be made relatively late. According to the data from HIT Endo and Craniopharyngioma 2000 study data the most fre- quent symptoms before the diagnosis in children are headache (68%), followed by visual impair- ment (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 impair- ment (40–84%), headache (56%), menstrual irregu- larities 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 ini- tial symptoms to the diagnosis does not correlate with tumor size, hypothalamic involvement, func- tional capacity or survival.26 It is however empha- sized 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 be- cause of tumor obstructing CSF pathways leading to obstructive hydrocephalus can also be the first manifestation, according to Mortini et al. more of- ten identified in children.26 In these patients, ur- gent surgical decompression is required and their presenting symptoms are the only ones connected with lower 10-year overall survival.25 Imaging and treatment There is evidence that adequate presurgical imag- ing and assessment of hypothalamic involvement of CP is extremely important in estimating prog- nosis and long-term quality of life. Initial tumor involvement of the third ventricular floor, mam- millary bodies and/or posterior hypothalamus on imaging are associated with a worse long-term prognosis due to hypothalamic obesity, regardless of chosen treatment strategies.28-32 Magnetic reso- nance imaging (MRI) is the standard imaging mo- dality in CP, but reliable discrimination between ACP and PCP based on neuroradiological criteria is not possible.33 In addition, computer tomogra- phy (CT) limited to the sellar area and excluding orbital areas for better determinations of calcifica- tions within the tumor is recommended. Papillary CP namely lacks calcifications and can be misdi- agnosed as another type of a suprasellar tumor (Figure 1).34 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 Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults390 (gross total resection - GTR), with preservation of visual, pituitary and hypothalamic function. For tumors located unfavourably (type 2 – hypothala- mus not visible on MRI scan) GTR is not recom- mended. For prevention of severe morbidity, a subtotal resection (STR) should be performed, fol- lowed by adjuvant therapy.28,35,36 The optimal therapeutic strategy for CP is how- ever still controversial. Surgical treatment of these lesions remains among the most challenging for neurosurgeons because of their complex and high- ly 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 treat- ment paradigm exists, and the extent of surgical re- section or adjuvant therapy should be considered on a case-to-case basis. Previous studies show that the most signifi- cant factor associated with recurrence is the ex- tent of surgical resection regardless of the histo- logical 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 essen- tial.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 adju- vant therapy. STR without adjuvant therapy is as- sociated 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 ex- ternal beam radiotherapy (RT) is presently standard of care to achieve an optimal progression-free sur- vival.13,41-44 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 ex- tent. 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 fa- vorable outcomes, and this rate is even higher in the modern era.43 The most recent advances in the treat- ment of craniopharyngioma have focused on mini- mizing treatment-related toxicity. These advances include endoscopic surgery and precision radio- therapy. In the last decades radiation therapy tech- nology has improved dose conformality and pro- vided decreased doses to adjacent critical structures (hypothalamus, optic tract, pituitary gland, carotid A B C FIGURE 1. Large, partially solid, partially multicystic adamantinomatous craniopharyngioma in a 5-year old boy. (A) Coronal T2 sequence through sellar region; solid part of the tumor (white arrow) involves enlarged sella turcica, parasellar regions, occupies the suprasellar cistern and the third ventricle. The cystic portion of the tumor (black arrow) extends into the lateral ventricles and on the right side it infiltrates the adjacent brain parenchym (small arrow). Lateral ventricles are enlarged with a band of periventricular transependimal edema as a sign of acute hydrocephalus. (B) Sagital T2 sequence through the sellar region; Hypothalamus and mammillary bodies are not visible (arrow). (C) SWI sequence through the multicystic portion of the tumor shows multiple calcifications in the cyst walls (arrow). Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults 391 arteries, medial temporal lobe structures, etc.) with the goal of reducing long-term sequelae, especially endocrinologic and visual ones. Conformal RT ena- bles a better coverage of the tumor while preserv- ing surrounding tissue therefore decreasing the risk of adverse effects. Current techniques include fractionated three-dimension conformal RT, inten- sity 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 prom- ising.46 Harrabi et al. with colleagues reported that FSRT leads to excellent results in patients with CP regarding local control, overall survival and preser- vation 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 ma- jor advantage of proton therapy is the high degree of dose conformity to the target. Beltran et al. ret- rospectively evaluated proton treatment plans with IMRT plan. He concluded that compared with pho- ton IMRT proton therapy has the potential to sig- nificantly 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 ris- ing 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, care- ful monitoring during radiotherapy is necessary. Namely, dynamic cyst changes can occur through- out the 6 weeks of RT, recommending weekly MRIs during treatment to identify these changes, and to adapt RT plan according to changes in tumor vol- ume.13,46,50 Stereotactic radiosurgery is an alternative to fractionated treatments in patients with crani- opharyngioma harboring smaller lesions, but cau- tion 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. Molecular pathology There are two main histological CP subtypes – adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP). ACPs are more common and can be diagnosed at any age but are predominantly observed in the pediatric popu- lation. The average age of diagnosis of this subtype shows an asymmetric bimodal distribution, with a larger peak at 5–14 years and a smaller at 50–74 years.1 PCPs account for approximately 11–14% of CPs and mainly occur in adults. The average age of diagnosis for this subtype is 44 ± 15 years.27 PCPs have higher 5-year survival rates and less aggres- sive disease progression. PCPs are solid, more well circumscribed, while ACPs adhere to the sur- rounding, consist of a mixture of cysts and nodules and changes like fibrosis, calcifications and hemor- rhages are seen.52,53 Important advances were made lately regard- ing the determination of the genes involved in the pathogenesis of the tumor that could have an im- portant effect on the treatment modalities. ACPs are mainly caused by activating mutations of the Wingless pathway (WNT pathway) gene CTNNB1, encoding the β-catenin. Activating mutations in the gene are determined in more than two-thirds of CPs in recent studies.54 They increase the resistance of β-catenin to proteasomal degradation resulting in its intranuclear accumulation. These clusters are pathologically unique for human ACP and are not present in any other pituitary tumour.55,56 In one third of ACP the CTNNB1 mutation is not identified, suggesting other genetic/epigenetic events might also be the cause of WNT activation.54 Recently involvement of MAPK/ERK pathway in the tumorigenesis of ACP has been determined, which opens novel therapeutic opportunities by suppression of this pathway with chemical agents as is MEK inhibitor trametinib.57 In PCP subgroup BRAF V600E mutations were detected in about 90% and appear to be the critical event in the pathogenesis.54,56 The same mutation is present in 7% of human cancers.58 BRAF is a proto- oncogene encoding serine-threonine kinase and is involved in growth factor signaling and regulation. Its mutation results in a constitutively active form promoting cell proliferation and tumor growth. Although rarely, a coexistence of both mutations may occur.59 Previous studies did not show larger chromosomal aberrations in any type of CP.60 While agents that target WNT signaling remain in development, the availability of BRAF inhibitors such as vemurafenib and dabrafenib suggests that Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults392 patients with papillary craniopharyngiomas could immediately benefit from such targeted thera- peutics.23,24,61-63 Vemurafenib and dabrafenib are already used as targeted therapy in other types of tumors with the same mutation. One of the most recent studies with the longest follow-up period, Himes BT et al., demonstrated reduction of the tu- mor size using dabrafenib as a monotherapy for the treatment of recurrence of PCP. Patients re- mained symptom-free 1 year after administration and there was no radiographic evidence of tumor progression.24 Recently a successful combination therapy with a dabrafenib and trametinib in reduc- ing PCP in a subject with BRAF V600E mutation was published.23 Prieto and Pascual published a comprehensive overview about tissue biomarkers being currently used as predictors of tumour recurrence and ag- gressiveness of their behaviour, stressing that their precise impact still needs to be closely evaluated in conjunction with the degree of tumor removal, the tumor topography, the pattern of tumor attach- ment, and the histological variant observed in each case. Their early identification could also improve patient outcome, but so far tumor remnant after initial surgery remains the only well-established factor for recurrence.54 Long term consequences and prognosis The long-term morbidity of craniopharyngiomas is associated with damage to critical neuronal structures by the primary or recurrent tumor com- bined 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 sig- nificantly more panhypopituitarism, morbid obesi- ty, epilepsy and psychiatric conditions in compari- son 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, re- ducing 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 child- hood population. Endocrine consequences Hypotalamo-pituitary hormone deficiencies are determined in 40–87% of children at the time of childhood-onset CP and 73% adults present with at least one deficient hypothalamic-pituitary ax- is.8,13,21,35,65,66 As shown in Table 1, after initial treat- ment the prevalence of endocrine deficits ranging from single hormone insufficiency to panhypopi- tuitarism increases and it is seen in almost all pa- tients, requiring lifelong follow-up by an endocri- nologist. In children with CP growth hormone deficiency is most frequently seen, occurring in up to 96%, adrenocorticotropic (ACTH), gonadotropin, thy- roid stimulating hormone (TSH) deficiency follow in decreasing order. Central diabetes insipidus resulting from anti-diuretic hormone (ADH) de- ficiency occurs almost twice more frequently in children than in adults, can be transient after the procedure and it persists in 65–96% of childhood- onset CP subjects.8,18,21 Substitution therapy with hr-GH is safe, effective and does not affect relapse and progression rates.67 In patients with GH sub- stitution, a better QoL has been reported.11 In chil- dren after the surgery, despite their GH deficiency, a normal or accelerated growth pattern has been observed. Activation of IGF-1 by hypothalamic hy- perphagia/obesity induced hyperinsulinism is sug- gested to explain this growth pattern.68 Sixty-one % of adults have panhypopituitarism after treatment for CP, most commonly affecting gonadotropin axis.8 Post-surgical onset of central diabetes insipidus was observed in up to 69.6% of the patients.33 Adequate timing and dosing of glu- cocorticoids, thyroxine, sex steroid and ADH is es- sential. Concerning GH substitution, observational studies suggest that GH replacement in adult-on- set CP does not increase the risk of tumor recur- rence. Lifelong surveillance by an endocrinologist is required.33 Metabolic consequences Damage of the posterior hypothalamic region re- sults 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 hy- pothalamic 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 Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults 393 or impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, altered energy ex- penditure, 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 involve- ment of a dietician, psychologist and physiothera- pist 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 sup- port 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 child- hood 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 pa- tients (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- TABLE 1. Comparison of pediatric and adult-onset craniopharyngioma characteristics Pediatric-onset Adult-onset 30–50 % of all CPs Age at presentation Peak at 5–14 years1 Peak at 40–44 years2 Gender distribution (m/f) Equal8,21 Equal8,27 Most frequent presentation Headache (68–85%) Visual impairment (36– 55%) Growth failure (7–36%)9,35,66 Visual impairment (40–84%) Menstrual irregularities (57%) Headache (42–56%)13,26,27 Pathohistological type Adamantinomatous 99%Papillary extremely rare* Papillary 14–50% 33 Initial hypothalamic involvement 42–66%8,9,35 42%18 Endocrine deficits at diagnosis Any 40–87%8,13,21,35,65,66 41–73%8 GH 41–75%8,13,21,35,65,66 18–86%8,13 FSH/LH 20–56%8,13,21,35,65,66 29–74%8,13 ACTH 8–68%8,13,21,35,65,66 35–58%8,13 TSH 15–32%8,13,21,35,65,66 35–56%8,13 ADH 7–17%8,13,21,35,65,66 6–17%8,13 Pituitary hormone deficiencies after treatment Any 64–100%8,64 48–97%8,64 GH 93–96%8,18,21 52–68%8,18 FSH/LH 59–95%8,18,21 70–94%8,18 ACTH 78–100%8,18,21 74–88%8,18 TSH 86–100%8,18,21 81–92%8,18 ADH 65–96%8,18,21 43–70%8,18 Panhypopituitarism*** 43–100%8,18,64 59–74%8,18,64 Obesity** 44–64%8,9,19,64 41–47%8,19,64 * Only 23 identified cases since 1995.83 ** Obesity was defined with BMI > 30 kg/m2 in adults and BMI >95. percentile for their age in children. *** Panhypopituitarism was defined as present when 3 anterior pituitary deficiencies were diagnosed in one patient (growth hormone deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, and late puberty in children or hypogonadism in adults). ACTH = adrenocorticotropic hormone; ADH = vasopressin (antidiuretic hormone); FSH/LH = follicle stimulating hormone/luteinizing hormone; GH = growth hormone; TSH = thyroid stimulating hormone Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults394 onset CP patients with HI, especially in patients treated with stimulants for their daytime sleepi- ness 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.10,72-75 Visual impairment Defoort et al. reported the presence of visual distur- bances 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 pre- surgical 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 Cognitive and psychosocial deficits Memory, attention, impulse control, motivation and socialization deficits are present in CP pa- tients.77,78 They cannot be fully explained by a le- sion 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 in- volvement 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 so- cial deficits in patients with adult-onset CP to the best of our knowledge. Quality of life Patients with childhood onset CP rated their so- cial and emotional functioning lower than their healthy controls. The most frequent problems re- ported 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 iso- lation and difficulties in social functioning. Adult- onset patients also performed worse on the depres- sion score than childhood-onset patients. The main independent predictors for decreased QoL were visual field defects, female gender, repeated sur- gery and HO.81,82 Conclusions CP is a low grade tumor with locally aggressive behaviour resulting in high morbidity in both chil- dren and adults. A multidisciplinary team of neuro- surgeons, neuro-radiologists, neuro-oncologists pa- thologists 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 irra- diation 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 de- crease the morbidity associated with endocrine and metabolic consequences of the tumor and its man- agement, 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 treat- ment modalities, enabling a less aggressive surgical and radiation therapy and possibly better neuroen- docrine and metabolic outcomes. References 1. Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM. The descriptive epidemiology of craniopharyngioma. J Neurosurg 1998; 89: 547-51. doi: 10.3171/jns.1998.89.4.0547 2. Nielsen EH, Feldt-Rasmussen U, Poulsgaard L, Kristensen LO, Astrup J, Jorgensen JO, et al. Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults. J Neurooncol 2011; 104: 755-63. doi: 10.1007/s11060-011-0540-6 Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults 395 3. Ostrom QT, Gittleman H, Liao P, Vecchione Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol 2017; 19(Suppl. 5): 1-88. doi: 10.1093/neuonc/nox158 4. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol 2016; 18: 1-75. doi: 10.1093/neuonc/now207 5. Thapar K, Kovacs K. Neoplasms of the sellar region. Russell and Rubinstein’s Pathology of tumors of the nervous system., 6th edition. McLendon RE, Rosenblum MK, Bigner DD, editors. Bica Raton, Florida: CRC Press Taylor & Francis Group; 1998. p. 629-80. 6. Zada G, Lin N, Ojerholm E, Ramkissoon S, Laws ER. Craniopharyngioma and other cystic epithelial lesions of the sellar region: a review of clinical, imag- ing, and histopathological relationships. Neurosurg Focus 2010; 28: E4. doi: 10.3171/2010.2.FOCUS09318 7. Pascual JM, Prieto R, Rosdolsky M, Strauss S, Castro I, Verena D. Cystic tumors of the pituitary infundibulum: seminal autopsy specimens (1899 to 1904) that allowed clinical-pathological craniopharyngioma characteriza- tion. Pituitary 2018; 21: 393-405. doi: 10.1007/s11102-018-0889-z 8. Wijnen M, Van Den Heuvel-Eibrink MM, Janssen JAMJL, Catsman- Berrevoets CE, Michiels EMC, Van Veelen-Vincent MLC, et al. Very long-term sequelae of craniopharyngioma. Eur J Endocrinol 2017; 176: 755-67. doi: 10.1530/EJE-17-0044 9. Sterkenburg AS, Hoffmann A, Gebhardt U, Warmuth-Metz M, Daubenbüchel AMM, Müller HL. Survival, hypothalamic obesity, and neuropsychological/ psychosocial status after childhood-onset craniopharyngioma: Newly re- ported long-term outcomes. Neuro Oncol 2015; 17: 1029-38. doi: 10.1093/ neuonc/nov044 10. Erfurth EM, Holmer H, Fjalldal SB. Mortality and morbidity in adult crani- opharyngioma. Pituitary 2013; 16: 46-55. doi: 10.1007/s11102-012-0428-2 11. Müller HL, Merchant TE, Puget S, Martinez-Barbera JP. New outlook on the diagnosis, treatment and follow-up of childhood-onset craniopharyngioma. Nat Rev Endocrinol 2017; 13: 299-312. doi: 10.1038/nrendo.2016.217 12. Heinks K, Boekhoff S, Hoffmann A, Warmuth-Metz M, Eveslage M, Peng J, et al. Quality of life and growth after childhood craniopharyngioma: results of the multinational trial KRANIOPHARYNGEOM 2007. Endocrine 2018; 59: 364-72. doi: 10.1007/s12020-017-1489-9 13. Karavitaki N, Brufani C, Warner JT, Adams CBT, Richards P, Ansorge O, et al. Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up. Clin Endocrinol (Oxf) 2005; 62: 397-409. doi: 10.1111/j.1365-2265.2005.02231.x 14. Muller HL. Craniopharyngeoma - a chronic disease. Swiss Med Wkly 2018; 148: w14548. doi: 10.4414/smw.2017.14548 15. Schoenfeld A, Pekmezci M, Barnes MJ, Tihan T, Gupta N, Lamborn KR, et al. The superiority of conservative resection and adjuvant radiation for craniopharyngiomas. J Neurooncol 2012; 8: 133-9. doi: 10.1007/s11060- 012-0806-7 16. Hoffmann A, Warmuth-Metz M, Gebhardt U, Müller H. Childhood craniopharyngioma – changes of treatment strategies in the tri- als KRANIOPHARYNGEOM 2000/2007. Klin Padiatr 2014; 226: 161-8. doi: 10.1055/s-0034-1368785 17. Ajithkumar T, Mazhari AL, Stickan-Verfürth M, Kramer PH, Fuentes CS, Lambert J, et al. Proton therapy for craniopharyngioma - an early report from a single European centre. Clin Oncol 2018; 30: 307-16. doi: 10.1016/j. clon.2018.01.012 18. Kendall-Taylor P, Jönsson PJ, Abs R, Erfurth EM, Koltowska-Häggström M, Price DA, et al. The clinical, metabolic and endocrine features and the qual- ity of life in adults with childhood-onset craniopharyngioma compared with adult-onset craniopharyngioma. Eur J Endocrinol 2005; 152: 557-67. doi: 10.1530/eje.1.01877 19. Wijnen M, Olsson DS, Van Den Heuvel-Eibrink MM, Hammarstrand C, Janssen JAMJL, Van Der Lely AJ, et al. The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up. Eur J Endocrinol 2018; 178: 11-22. doi: 10.1530/EJE-17-0387 20. Andereggen L, Hess B, Andres RH, El-Koussy M, Mariani L, Raabe A, et al. A ten-year follow-up study of treatment outcome of craniopharyngiomas. Swiss Med Wkly 2018; 148: 1-8. doi: 10.4414/smw.2017.14521 21. Tan TSE, Patel L, Gopal-Kothandapani JS, Ehtisham S, Ikazoboh EC, Hayward R, et al. The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres. Eur J Endocrinol 2017; 176: 359-69. doi: 10.1530/EJE-16-0812 22. Bosnjak R, Benedicic M, Vittori A. Early outcome in endoscopic extended en- donasal approach for removal of supradiaphragmatic craniopharyngiomas: a case series and a comprehensive review. Radiol Oncol 2013; 47: 266-79. doi: 10.2478/raon-2013-0036 23. Brastianos PK, Shankar GM, Gill CM, Taylor-Weiner A, Nayyar N, Panka, DJ, et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst 2016; 108: 1-5. doi: 10.1093/jnci/djv310 24. Himes BT, Ruff MW, Gompel JJ Van, Park SS, Galanis E, Kaufmann TJ, et al. Recurrent papillary craniopharyngioma with dabrafenib: case report. J Neurosurg 2018; 1: 1-5. doi: 10.3171/2017.11.JNS172373 25. Hoffmann A, Boekhoff S, Gebhardt U, Sterkenburg AS, Daubenbüchel AMM, Eveslage M, et al. History before diagnosis in childhood craniophar- yngioma: Associations with initial presentation and long-term prognosis. Eur J Endocrinol 2015; 173: 853-62. doi: 10.1530/EJE-15-0709 26. Mortini P, Losa M, Pozzobon G, Barzaghi R, Riva M, Acerno S, et al. Neurosurgical treatment of craniopharyngioma in adults and children: early and long-term results in a large case series. J Neurosurg 2011; 114: 1350-9. doi: 10.3171/2010.11.JNS10670 27. Crotty TB, Scheithauer BW, Young WF, Davis DH, Shaw EG, Miller GM, et al. Papillary craniopharyngioma: a clinicopathological study of 48 cases. J Neurosurg 1995; 83: 206-14. doi: 10.3171/jns.1995.83.2.0206 28. Müller HL. Hypothalamic involvement in craniopharyngioma—Implications for surgical, radiooncological, and molecularly targeted treatment strate- gies. Pediatr Blood Cancer 2018; 65: e26936. doi: 10.1002/pbc.26936 29. Roth CL, Eslamy H, Werny D, Elfers C, Shaffer ML, Pihoker C, et al. Semiquantitative analysis of hypothalamic damage on MRI predicts risk for hypothalamic obesity. Obesity 2015; 23: 1226-33. doi: 10.1002/oby.21067 30. Mortini P, Gagliardi F, Bailo M, Spina A, Parlangeli A, Falini A, et al. Magnetic resonance imaging as predictor of functional outcome in craniopharyngio- mas. Endocrine 2016; 51: 148-62. doi: 10.1007/s12020-015-0683-x 31. Müller HL. Craniopharyngioma and hypothalamic injury: latest insights into consequent eating disorders and obesity. Curr Opin Endocrinol Diabetes Obes 2016; 23: 81-9. doi: 10.1097/MED.0000000000000214 32. Pascual JM, Prieto R, Carrasco R, Barrios L. Displacement of mammillary bodies by craniopharyngiomas involving the third ventricle: surgical-MRI correlation and use in topographical diagnosis. J Neurosurg 2013; 119: 381- 405. doi: 10.3171/2013.1.JNS111722 33. Zoicas F, Schöfl C. Craniopharyngioma in adults. Front Endocrinol (Lausanne) 2012; 3: 46. doi: 10.3389/fendo.2012.00046 34. Amelot A, Borha A, Calmon R, Barbet P, Puget S. Child dermoid cyst mim- icking a craniopharyngioma: the benefit of MRI T2-weighted diffusion se- quence. Child’s Nerv Syst 2018; 34: 359-62. doi: 10.1007/s00381-017-3602-z 35. Puget S, Garnett M, Wray A, Grill J, Habrand JL, Bodaert N, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg Pediatr 2007; 106: 3-12. doi: 10.3171/ped.2007.106.1.3 36. Elowe-Gruau E, Beltrand J, Brauner R, Pinto G, Samara-Boustani D, Thalassinos C, et al. Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab 2013; 98: 2376-82. doi: 10.1210/jc.2012-3928 37. Weiner HL, Wisoff JH, Rosenberg ME, Kupersmith MJ, Cohen H, Zagzag D, et al. Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery 1994; 35: 1001-11. http://dx.doi.org/10.1227/00006123-199412000-00001. 38. Müller HL, Gebhardt U, Teske C, Faldum A, Zwiener I, Warmuth-Metz M, et al. Post-operative hypothalamic lesions and obesity in child- hood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol 2011; 165: 17-24. doi: 10.1530/EJE-11-0158 39. Gu Y, Zhang X. Letter to the Editor: mammillary body angle and craniophar- yngioma. J Neurosurg 2014; 120: 1241-5. doi: 10.3171/2013.11.JNS132343 40. Coury JR, Davis BN, Koumas CP, Manzano GS, Dehdashti AR. Histopathological and molecular predictors of growth patterns and recurrence in craniophar- yngiomas: a systematic review. Neurosurg Rev 2018. doi: 10.1007/s10143- 018-0978-5 41. Karavitaki N, Cudlip S, Adams CB, and Wass JA. Craniopharyngiomas. Endocr Rev 2006; 27: 371-97. doi: 10.1210/er.2006-0002 42. Clark AJ, Cage TA, Aranda D, Parsa AT, Sun PP, Auguste KI, et al. A systematic review of the results of surgery and radiotherapy on tumor control for pedi- atric craniopharyngioma. Child’s Nerv Syst 2013; 29: 231-8. doi: 10.1007/ s00381-012-1926-2 Radiol Oncol 2019; 53(4): 388-396. Jensterle M et al. / Craniopharyngioma in children and adults396 43. Kiehna EN, Merchant TE. Radiation therapy for pediatric craniopharyn- gioma. Neurosurg Focus 2010; 28: E10. doi: 10.3171/2010.1.FOCUS09297 44. O’steen L, Indelicato DJ. Advances in the management of craniopharyn- gioma. F1000Research 2018; 7: 1632. doi:10.12688/f1000research.15834.1 45. Kortmann RD. Different Approaches in Radiation Therapy of Craniopharyngioma. Front Endocrinol (Lausanne) 2011; 2: 100. doi: 10.3389/fendo.2011.00100 46. Bishop AJ, Greenfield B, Mahajan A, Paulino AC, Okcu MF, Allen, PK, et al. Proton beam therapy versus conformal photon radiation therapy for child- hood craniopharyngioma: Multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys 2014; 90: 354-61. doi: 10.1016/j.ijrobp.2014.05.051 47. Harrabi SB, Adeberg S, Welzel T, Rieken S, Habermehl D, Debus J, et al. Long term results after fractionated stereotactic radiotherapy (FSRT) in patients with craniopharyngioma: maximal tumor control with minimal side effects. Radiat Oncol 2014; 9: 203. doi: 10.1186/1748-717X-9-203 48. Beltran C, Roca M, Merchant TE. On the Benefits and Risks of Proton Therapy in Pediatric Craniopharyngioma. Int J Radiat Oncol 2012; 82: 281-7. doi: 10.1016/j.ijrobp.2011.01.005 49. Regine WF, Kramer S. Pediatric craniopharyngiomas: Long term results of combined treatment with surgery and radiation. Int J Radiat Oncol 1992; 24: 611-17. doi: 10.1016/0360-3016(92)90705-M 50. Winkfield KM, Linsenmeier C, Yock TI, Grant PE, Yeap BY, Butler WE, et al. Surveillance of Craniopharyngioma Cyst Growth in Children Treated With Proton Radiotherapy Int J Radiat Oncol 2009; 73: 716-21. doi: https://doi. org/10.1016/j.ijrobp.2008.05.010 51. Losa M, Pieri V, Bailo M, Gagliardi F, Barzaghi LR, Gioia L, et al. Single frac- tion and multisession Gamma Knife radiosurgery for craniopharyngioma. Pituitary 2018; 21: 499-506. doi: 10.1007/s11102-018-0903-5 52. Buslei R, Nolde M, Hofmann B, Meissner S, Eyupoglu IY, Siebzehnrübl F, et al. Common mutations of β-catenin in adamantinomatous craniopharyn- giomas but not in other tumours originating from the sellar region. Acta Neuropathol 2005; 109: 589-97. doi: 10.1007/s00401-005-1004-x 53. Pekmezci M, Louie J, Gupta N, Bloomer MM, Tihan T. Clinicopathological characteristics of adamantinomatous and papillary craniopharyngiomas: University of California, San Francisco experience 1985-2005. Neurosurgery 2010; 67: 1341-9. doi: 10.1227/NEU.0b013e3181f2b583 54. Prieto R, Pascual JM. Can tissue biomarkers reliably predict the biological behavior of craniopharyngiomas? A comprehensive overview. Pituitary 2018; 21: 431-42. doi: 10.1007/s11102-018-0890-6 55. Apps JR, Martinez-Barbera JP. Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice. Neurosurg Focus 2016; 41: E4. doi: 10.3171/2016.8.FOCUS16307 56. Brastianos PK, Taylor-Weiner A, Manley PE, Robert T, Dias-Santagata D, Thorner AR, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014; 46: 161-5. doi: 10.1038/ng.2868 57. Apps JR, Carreno G, Gonzalez-Meljem JM, Haston S, Guiho R, Cooper JE, et al. Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel thera- peutic target. Acta Neuropathol 2018; 135: 757-77. doi: 10.1007/s00401- 018-1830-2 58. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949. doi: 10.1038/ nature00766 59. Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O. BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coex- ist with CTNNB1-mutated adamantinomatous craniopharyngioma. Acta Neuropathol 2014; 127: 927-9. doi: 10.1007/s00401-014-1270-6 60. Bi WL, Larsen AG, Dunn IF. Genomic Alterations in Sporadic Pituitary Tumors. Curr Neurol Neurosci Rep 2018; 18: 4. doi: 10.1007/s11910-018- 0811-0 61. Aylwin SJB, Bodi I, Beaney R. Pronounced response of papillary craniophar- yngioma to treatment with vemurafenib, a BRAF inhibitor. Pituitary 2016; 19: 544-6. doi: 10.1007/s11102-015-0663-4 62. Roque A, Odia Y. BRAF-V600E mutant papillary craniopharyngioma dramati- cally responds to combination BRAF and MEK inhibitors. CNS Oncol 2017; 6: 95-9. doi: 10.2217/cns-2016-0034 63. Rostami E, Witt Nyström P, Libard S, Wikström J, Casar-Borota O, Gudjonsson O. Recurrent papillary craniopharyngioma with BRAFV600E mutation treat- ed with neoadjuvant-targeted therapy. Acta Neurochir (Wien) 2017; 159: 2217-21. doi: 10.1007/s00701-017-3311-0 64. Caldarelli M, Massimi L, Tamburrini G, Cappa M, Di Rocco C. Long-term results of the surgical treatment of craniopharyngioma: the experience at the Policlinico Gemelli, Catholic University, Rome. Child’s Nerv Syst 2005; 21: 747-57. doi: 10.1007/s00381-005-1186-5 65. Müller HL. Childhood craniopharyngioma. Pituitary 2013; 16: 56-67. doi: 10.1007/s11102-012-0401-0 66. Boekhoff S, Bogusz A, Sterkenburg AS, Eveslage M, Müller HL. Long-term effects of growth hormone replacement therapy in childhood-onset crani- opharyngioma: results of the German Craniopharyngioma Registry (HIT- Endo). Eur J Endocrinol 2018; 179: 331-41. doi: 10.1530/EJE-18-0505. 67. Geffner ME. The growth without growth hormone syndrome. Endocrinol Metab Clin 1996; 25: 649-63. doi: 10.1016/S0889-8529(05)70345-5 68. Holmer H, Pozarek G, Wirfält E, Popovic V, Ekman B, Björk J, et al. Reduced energy expenditure and impaired feeding-related signals but not high energy intake reinforces hypothalamic obesity in adults with childhood onset craniopharyngioma. J Clin Endocrinol Metab 2010; 95: 5395-402. doi: 10.1210/jc.2010-0993 69. Bereket A, Kiess W, Lustig RH, Müller HL, Goldstone AP, Weiss R, et al. Hypothalamic obesity in children. Obes Rev 2012; 13: 780-98. doi: 10.1111/j.1467-789X.2012.01004 70. Hoffmann A, Bootsveld K, Gebhardt U, Daubenbüchel AMM, Sterkenburg AS, Müller HL. Nonalcoholic fatty liver disease and fatigue in long-term sur- vivors of childhood-onset craniopharyngioma. Eur J Endocrinol 2015; 173: 389-97. doi: 10.1530/EJE-15-0422 71. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425-31. doi: 10.1016/S0140-6736(00)04006-X 72. Rosén T, Bengtsson BA. Premature mortality due to cardiovascular dis- ease in hypopituitarism. Lancet 1990; 336: 285-8. doi: 10.1016/0140- 6736(90)91812-O 73. Bülow B, Attewell R, Hagmar L, Malmström P, Nordström CH, Erfurth EM. Postoperative prognosis in craniopharyngioma with respect to cardiovascu- lar mortality, survival, and tumor recurrence. J Clin Endocrinol Metab 1998; 83: 3897-904. doi: 10.1210/jc.83.11.3897 74. Holmer H, Ekman B, Björk J, Nordstöm CH, Popovic V, Siversson AB, et al. Hypothalamic involvement predicts cardiovascular risk in adults with child- hood onset craniopharyngioma on long-term GH therapy. Eur J Endocrinol 2009; 161: 671-9. doi: 10.1530/EJE-09-0449 75. Defoort-Dhellemmes S, Moritz F, Bouacha I, Vinchon M. Craniopharyngioma: ophthalmological aspects at diagnosis. J Pediatr Endocrinol Metab 2006; 19(Suppl 1): 321-4. http://europepmc.org/abstract/MED/16700306 76. Pierre-Kahn A, Recassens C, Pinto G, Thalassinos C, Chokron S, Soubervielle JC, et al. Social and psycho-intellectual outcome following radical removal of craniopharyngiomas in childhood. A prospective series. Child’s Nerv Syst 2005; 21: 817-24. doi: 10.1007/s00381-005-1205-6 77. Riva D, Pantaleoni C, Devoti M, Saletti V, Nichelli F, Giorgi C. Late neu- ropsychological and behavioural outcome of children surgically treated for craniopharyngioma. Child’s Nerv Syst 1998; 14: 179-84. doi: 10.1007/ s003810050207 78. Özyurt J, Müller HL, Warmuth-Metz M, Thiel CM. Hypothalamic tumors impact gray and white matter volumes in fronto-limbic brain areas. Cortex 2017; 89: 98-110. doi: 10.1016/j.cortex.2017.01.017 79. Poretti A, Grotzer MA, Ribi K, Schonle E, Boltshauser E. Outcome of crani- opharyngioma in complications and quality of life. Dev Med Child Neurol 2004; 46: 220-9. doi: 10.1111/j.1469-8749.2004.tb00476.x 80. Dekkers OM, Biermasz NR, Smith JWA, Groot LE, Roelfsema F, Romijn, JA, et al. Quality of life in treated adult craniopharyngioma patients. Eur J Endocrinol 2006; 154: 483-9. doi: 10.1530/eje.1.02114 81. Gautier A, Godbout A, Grosheny C, Tejedor I, Coudert M, Courtillot C, et al. Markers of recurrence and long-term morbidity in craniopharyngioma: a systematic analysis of 171 patients. J Clin Endocrinol Metab 2012; 97: 1258- 67. doi: 10.1210/jc.2011-2817 82. van Iersel L, Meijneke RWH, Schouten-van Meeteren AYN, Reneman L, de Win MM, van Trotsenburg ASP, et al. The development of hypotha- lamic obesity in craniopharyngioma patients: a risk factor analysis in a well-defined cohort. Pediatr Blood Cancer 2018; 65: e26911. doi: 10.1002/ pbc.26911 83. Borrill R, Cheesman E, Stivaros S, Kamaly-Asl ID, Gnanalingham K, Kilday J-P. Papillary craniopharyngioma in a 4-year-old girl with BRAF V600E mutation: a case report and review of the literature. Child’s Nerv Syst 2019; 35: 169-73. doi:10.1007/s00381-018-3925-4.