Long- term outcome for patients with craniopharyngiomas

Transcription

1 1 Long- term outcome for patients with craniopharyngiomas Eric Tande Håland Tutor: Jon Berg- Johnsen Department of Neurosurgery Oslo University Hospital Faculty of Medicine UNIVERSITY OF OSLO 2017

2 2 Contents Abstract 3 Introduction 4 Material and methods 5 Patient characteristics at baseline 6 Presenting symptoms 8 Results 10 Treatment 11 Histology 14 Recurrence 14 Mortality 14 Morbidity 16 Illustrative case 18 Discussion 19 Conclusions 26 Note 26 Ethical approval 26 Limitations 27 References 28

3 3 Long- term outcome for patients with craniopharyngioma Objective: Craniopharyngioma (CP) is a histological benign tumor, but can have a clinically malignant course due to its proximity to the pituitary gland/stalk, hypothalamus, the optic apparatus and the vasculature. A considerable portion of the patients experience recurrence, and the quality of life may be seriously impaired. The aim of this work was to study the long- term outcome for CP patients. Methods: Our series consisted of all cases of diagnosed CP in the department of neurosurgery, Oslo University Hospital in the period The medical records were retrospectively surveyed. Assessment was based on treatment, survival, neuroendocrine function, obesity, neurological deficits and quality of life. Results: A total of 71 patients were diagnosed with CP in this 24- year period, whereof two were lost to follow- up. There were 39 males and 30 females. Twenty- two patients were below 18 years of age. The most common presenting symptoms were visual disturbances in 50 patients (72 %) and pituitary dysfunction in 25 patients (36.5%). Sixty- three out of 69 patients were surgically treated, three received radiotherapy alone, and three were followed without treatment. Twenty- nine patients (42 %) were treated more than once. There were no surgical deaths. Mean follow- up was 92 months. Sixteen patients (23%) died during follow- up. The 10- year survival rate was 81 %. Fifty- four patients needed substitution for pituitary insufficiency. Twenty patients developed obesity after surgery. Twenty- two patients had persisting visual disturbances. Conclusion: There is a bimodal age distribution in patients with CP. These tumors tend to recur and are associated with increased mortality and morbidity. The overall survival rates are relatively high, but neuroendocrine disorders such as obesity and metabolic syndrome due to involvement and/or treatment- related hypothalamic lesions have major negative impact on survival and quality of life. Visual disturbances were in the majority of patients improved after surgery. Key words: Craniopharyngioma, outcome, neuroendocrinology, hypothalamic obesity, quality of life

4 4 Introduction Craniopharyngioma was the name introduced by Cushing for tumours derived from epithelial rests ascribable to an imperfect closure of the hypophysial or craniopharyngeal duct.(1) Craniopharyngioma is a rare, partly cystic, solid and calcified tumour arising from embryonic squamous cell rests of an incompletely involuted hypohyseal- pharyngeal duct with low histological grade (WH0 grade I). All these tumours grow in the suprasellar region and some with parasellar extension. By virtue of their location, they compress the optic chiasm anteriorly, the diaphragm sellae and pituitary gland inferiorly, and the hypothalamus and the third ventricle superiorly. Despite their benign histologic appearance, many of these tumours follow a malignant course and result in significant disability. Craniopharyngiomas are relatively uncommon tumours, with an annual incidence rate between 0.5 and 2 cases per million population. A bimodal age distribution is seen with a peak incidence between 5 and 10 years and a second peak between 45 and 60 years. Craniopharyngioma has a higher annual incidence of 5.25 cases per million in the paediatric population, in whom it represents the second commonest of all childhood intracranial tumours accounting for 6 to 13%. (2) (3). Due to the tumours close relation to the optic chiasm, pituitary stalk and third ventricle, the most common presenting symptoms are visual impairment, endocrine deficits and headache. Controversy continues to surround the issue of their management, whether it be radical surgery, radiotherapy, or a combination of these modalities. Radical surgery is always the preferred choice of treatment. Many surgeons take, however, a critical view of planned radical resection in these cases because of the risk of surgically induced deficits and the high rate of recurrence especially in infants and small children despite apparent complete resection. In case of hypothalamic involvement, subtotal resection with hypothalamic- sparing strategies followed by local radiotherapy is recommended in order to prevent hypothalamic damage and associated severe neuroendocrine sequels.

5 5 Although overall survival rates are relatively high, difficulties associated with location, treatment and recurrences can lead to significant morbidity in long- term survivors. The most notable sequels are endocrine deficits, visual impairment and hypothalamic dysfunction mainly manifested as hypothalamic obesity. There are two histopathologic subtypes of craniopharyngioma, classic adamantinomatous tumours representing up to 95% of paediatric cases, and the papillary type mainly found in adults. True long- term follow- up studies in patients with craniopharyngiomas have been scarce. The relative rarity of the disease makes it difficult to collect large patient populations in single centres, and specialized referral centres are seldom able to provide follow- up on patients for decades. Norway is well suited for population- based epidemiological studies due to its stable population and public health care system. The aim of this study was therefore to provide knowledge about the long- term outcome of patients with craniopharyngiomas. This is the first extensive report on craniopharyngioma patients from Norway. In this report we quantify some of the most important factors that contribute to craniopharyngioma morbidity in order to discuss the best way of treating this group of patients. Material and methods Between 1992 and 2015, 71 patients were diagnosed. Two patients (2.8%) were lost to follow- up and eliminated from further assessment, so this series consists of 69 patients diagnosed with craniopharyngioma at the Department of Neurosurgery, Oslo University Hospital. The hospital was responsible for treatment of patients with craniopharyngiomas in the south- east part of Norway with a population of 2.9 million people. The incidence of craniopharyngioma in our cohort of patients is 2.4 cases per million per year (the population that our department serves is 2.9 million people). In all patients the diagnosis was made on MRI, often supplemented by CT to show calcifications in the tumour. These modalities can categorize the lesion in terms of its anatomical location and to show the relationship of the tumour to the pituitary gland, optic apparatus, third ventricle, and major intracranial vessels. In some patients with large tumours, cerebral- or CT angiography was performed. Obstructive hydrocephalus is a possible accompanying feature of large tumours.

6 6 Patient data and mode of presentation were retrospectively collected. The following background data were obtained from the patients medical journals: age, sex, symptoms at diagnosis, weight, tumour size, localization, histology, treatment, recurrence, sequels and quality of life Craniopharyngiomas have a high recurrence rate, and a large proportion of the patients have persisting visual disturbances and endocrine dysfunction. The patients are therefore followed regularly with MRI- scans to see whether the tumour regrows. They are furthermore followed, some of them life- long, by an endocrinologist and ophthalmologist. The medical records were retrospectively surveyed in after being granted permission by REK. Statistics Statistical analysis was performed using Excel and IBM SPSS, version 23.0 (SPSS Inc., Chicago, IL). Patients Of the 71 patients diagnosed with a craniopharyngioma, two were eliminated from further analysis due to lack of data regarding their baseline characteristics. Baseline data for the remaining 69 patients are summarized in table 1. There were 39 (56.5%) males and 30 (43.5%) females, which gives a male/female ratio of Mean age at diagnosis was 35.4 years, ranging from 1 to 78 years, see figure 1 for age distribution at time of diagnosis. The tumour was categorized as small when less than two cm in largest diameter, medium- sized between two and four cm, and large greater than four cm.

7 7 Table 1. Clinical characteristics at baseline (n=69) Clinical characteristics at baseline Age at diagnosis in years, mean (range) 35 (1-78) Sex, n Male 39 (56.5) Female 30 (43.5) Presenting symptoms, n Visual impairment 50 (72.5) Pituitary dysfunction 25 (36.2) Headache 32 (46.4) Hydrocephalus 11 (15.9) Tumour size, n <2 cm 9 (13) 2-4 cm 37 (53) >4 cm 7 (10) Unkonwn 16 (23)

8 8 Age distribution As can be seen from figure 1, there is a bimodal age distribution with a peak incidence at 0-10 years of age and a second peak incidence at years of age. Figure 1. Age distribution in patients with craniopharyngiomas (n=69) 25 Numbers in % Years The patients were therefor divided into two groups; those < 18 years (children) and those 18 years (adults). There were 22 children (32%) and 47 adults (68%) at diagnosis. Our childhood- onset craniopharyngioma population revealed that most of them (86.3%) were younger than 15 years of age at the time of diagnosis, affecting twice as many males and a median age at diagnosis of 8.6 years. Presenting symptoms The most common presenting symptom was visual disturbances in 50 of the 69 patients. Thirty- two had headache, 25 had endocrine dysfunction and eleven had hydrocephalus (table 2).

9 9 Table 2. Presenting symptoms at diagnosis of craniopharyngioma Presenting symptoms Children, n Adults, n Total, n Visual impairment 12 (54.5) 39 (82.9) 50 (72.5) Headache 12 (54.5) 20 (42.6) 32 (46.4) Endocrine deficits 9 (40.9) 16 (34.0) 25 (36.2) Total pituitary deficiency 0 2 (12.5) 2 (8.0) Partial pituitary deficiency (>2 hormones) 0 2 (12.5) 2 (8.0) Growth hormone deficiency 7 (77.8) 0 7 (28.0) Hypothalamic dysfunction - obesity 1 (11.1) 3 (18.8) 4 (16.0) Irregular menstruation 1 (11.1) 2 (12.5) 3 (12.0) TSH-deficiency 0 3 (18.8) 3 (12.0) Gynecomasti 0 1 (6.3) 1 (4.0) Diabetes insipidus 0 1 (6.3) 1 (4.0) Testosteron deficiency 0 1 (6.3) 1 (4.0) Hypogonadisme 0 1 (6.3) 1 (4.0) Hydrocephalus 4 (18.2) 9 (19.1) 11 (15.9) Among childhood- onset craniopharyngioma patients the most common manifestation was visual impairment (hemianopia, uniocular visual impairment and diplopia) affecting 12 patients (54.5%). The second most common symptom at diagnosis was headache affecting 12 patients (54.5%), and endocrine deficiencies were the third most common presenting symptom affecting nine patients (40.9%). Of those with endocrine deficiencies seven out of nine lacked growth hormone. Four patients (18.2%) of our children presented with hydrocephalus. Among our adult onset craniopharyngioma patients, visual impairment affected 39 patients (82.9%), 20 patients had headache (42.6%) and 16 patients had endocrine deficits (34 %). Two of these patients (12.5%) had total pituitary deficiency at diagnosis, whereas three patients (18.8%) had exclusively a TSH deficiency. Another three patients (18.8%) had experienced a considerable weight gain during the last 3-9 months prior to diagnosis, implying some kind of hypothalamic involvement. Nine patients (19.1%) of our adults presented with hydrocephalus.

10 10 Results Our assessment was based on treatment, survival and long- term outcome consisting of neuroendocrine function, obesity, visual impairment, neurological deficits, cognitive function and quality of life. In this series quality of life was defined as achieving independent living with social interrogation, normal professional occupation or school status. Treatment Sixty- three out of 69 patients were surgically treated. The resection was classified as Gross total resection (GTR) or radical surgery if there was no evidence of tumour on postoperative MRI. The resection was classified as subtotal-, partial- or non- radical surgery if the surgeon not was able to remove all the tumour or if the tumour was evident on postoperative MRI. The resection is called a biopsy when only a minor part of tumour was removed. Postoperative adjuvant radiotherapy was not administered routinely, but on indication. The patients were followed with serial MRI and clinical evaluation.

11 11 Table 3. The different types of treatment given Treatment in % Children n Adults, n Total, n Radical surgery 8 (36.4) 21 (44.6) 29 (43.0) Radical surgery and radiotherapy 2 (9.0) 4 (8.5) 6 (8.6) Non-radical surgery 5 (22.7) 11 (23.4) 16 (23.1) Non-radical surgery and radiotherapy 6 (27.3) 4 (8.5) 10 (14.5) Surgery, but radicality unknown 0 2 (4.3) 2 (2.9) Radiotherapy and chemotherapy 0 3 (6.4) 3 (4.3) No treatment 1 (4.5) 2 (4.3) 3 (4.3) Radical surgery 8 (36.4) 21 (44.6) 29 (43.0) Total 22 (100) 47 (100) 69 (100) In our childhood- onset population eight patients (36.4%) received radical surgery (gross total resection - GTR). Six patients (27.3%) had a subtotal resection followed by radiotherapy (non- radical surgery and radiotherapy). It was two patients (9,0%) of our children that received subtotal resection alone. In three patients (13.6%) of our childhood- cases the surgeon (- s) described a gross total resection although post- operative MRI showed a less complete resection. When that is said 11 patients (50%) of our childhood onset craniopharyngioma patients underwent one or multiple reoperations. Only one patient (4.5%) of our childhood- onset population has not received any treatment yet, and none of our childhood onset patients received radiotherapy or chemotherapy as only treatment. In our adult onset population 21 patients (44.6%) received radical surgery (GTR gross total resection). Four patients (8.5%) had a subtotal resection followed by radiotherapy (non- radical surgery and radiotherapy). It was nine patients (19.1%) of our adult patients that received subtotal resection alone. In two patients (4.3%) our adult onset cases the surgeon (- s) thought they had performed a gross total resection although post- operative MRI or follow- up scans showed something different on a later stage.

12 12 Fourteen patients (30%) of the adult onset craniopharyngioma patients underwent one or multiple reoperations. Five patients (10.6%) in the adult population underwent one or several shunt- operations. Three of the adult onset patients (6.4%) received radiotherapy or chemotherapy as only treatment and two of these patients (4.3%) have not received any treatment yet. They are still, however, under observation. Neurosurgical approach Table 4. Treatment and surgical approach Treatment/ approach Patients, n Children, n Adults, n Craniotomy 44 (69.8) 15 (71.4) 29 (69,0) Transventricular 3 (4.8) 1 (4.8) 2 (4.8) Interhemispheric 1 (1.6) 0 1 (2.4) Fenestration + biopsy 1 (1.6) 0 1 (2.4) Transsphenoidal 10 (15.8) 2 (9.5) 8 (19.0) Unknown 4 (6.4) 3 (14.3) 1 (2.4) Total 63 (100) 21 (100) 42 (100) Craniotomy ((e.g subfrontal, pterional, transventricular, transcallosal, transcortical or bifrontal) was performed in 49 patients (77,8%). Ten patients (15.8%) were operated through the transsphenoidal surgical approach. In the childhood- onset population 15 patients (71.4%) had a craniotomy performed and two patients (9.5%) had a transsphenoidal surgical approach. In the adult- onset population 29 patients (69.0%) had a craniotomy done and eight patients (19%) underwent a transsphenoidal surgical approach for their tumour. Thirteen patients (18.8%) got a shunt due to hydrocephalus. Eight children (36.4%) and five adults (10.6%) got a shunt revision as a part of their treatment.

13 13 Irradiation Table 5. Different types of radiotherapy treatment Irradiation Children, n Adults, n Total, n Conventional external radiotherapy 2 (9.1) 5 (10.6) 7 (10.1) Stereotactic radiotherapy 8 (36.4) 5 (10.6) 13 (18.8) Proton beam therapy 1 (4.5) 0 1 (1.4) Instillation of sclerotic substances 1 (4.5) 4 (8.5) 5 (7.2) Total 12 (54.5) 14 (29.8) 26 (37.7) Overall 26 patients (37.7%) in this study got irradiation as only- or adjunct treatment. Only three patients (4.3%) included in this study received radio- or chemotherapy as solely treatment. In total 12 childhood- onset craniopharyngioma patients (54.5%) received adjuvant irradiation.it was eight patients (36.4%) in the childhood- onset population that received stereotactic radiosurgery as adjuvant treatment. Conventional external radiotherapy was given to two patients (9.1%) in the childhood- onset population. Proton beam therapy and instillation of sclerotic substances was given to one patient (4.5%) in the childhood- onset population, respectively. In total 14 patients (29.8%) of adult- onset patients had adjuvant radio- or chemotherapy. Stereotactic radiosurgery was given to five adult- onset patients (10.6%) as adjuvant treatment. Another five patients (10.6%) from the same group got conventional external radiotherapy. None of the adult- onset patients got proton beam therapy. Instillation of sclerotic substances was given to four patients (8.5%).

14 14 Histology Table 6. Histological subtypes of craniopharyngioma Histology Children, n Adults, n Total, n Adamantinomatous type 16 (76.2) 28 (66,7) 44 (69.8) Papillary type 0 4 (9.5) 4 (6.4) Unknown subtype 5 (23.8) 10 (23.8) 15 (23.8) Adamantinomatous craniopharyngiomas were found in 16 children (76.2%) and amongst the childhood- onset patients five of them (23.8%) had an unknown histological subtype. None of the children had the papillary subtype. In the adult- onset population 28 patients (66.7%) had the adamantinomatous subtype and 4 adults (9.5%) the papillary subtype. Ten adults (23.8%) had unknown histological subtype. Recurrence It was 25 patients (36.2%) that were reoperated for their recurrent tumour. It was eleven children (50%) and 14 adults (20.2%). Mortality The mean follow- up was 92 months (range 0-23 years). Sixteen patients (23%) died during follow- up. The mean age at death was 46 years (range years). Two of the patients died within few months after surgical treatment probably as a consequence of the treatment. Two patients died later from tumour progression. One patient died from unrelated cause (rectal cancer). For the rest of the patients, the cause of death has not been established. The survival curves for children and adults are shown in figure 2.

15 15 Figure 2. Kaplan- Meier plot showing survival curves for children (n=22) and adults (n=47) 1,2 Survival in % 1 0,8 0,6 0,4 0,2 0 Childhood onset Adult onset In this study the overall survival rates in the childhood- onset population range from 100% survival at 5 years and 20 patients were alive after 10 and 20 years which give a 90% survival. After 23 years 19 children is alive which gives a 23year- survival of 80.8%. In the adult- onset group we observed that 38 patients (80.8%) were alive after 5 years and 36 adults (76.5%) were alive after 10, 15, 20 and 23 years.

16 16 Morbidity - Long- term outcome Table 7. Long- term outcome Long-term sequelae Children, n Adults, n Total, n Visual impairment 12 (54.5) 10 (21.3) 22 (31.9) Total pituitary deficiency 17 (77.3) 23 (48.9) 40 (58.0) Partial pituitary deficiency (> 2 hormones) 1 (4.5) 13 (27.7) 14 (20.3) Growth retardation 3 (13.6) 0 3 (4.3) Hypothalamic obesity 9 (40.9) 11 (23.4) 20 (29.0) Cognitive failure 1 (4.5) 7 (14.9) 8 (11.6) Loss of libido 0 2 (4.3) 2 (2.9) Depression 1 (4.5) 0 1 (1.4) Nevrological deficits 5 (22.7) 2 (4.3) 7 (10.1) - 1: Pituitary deficiencies Overall this study showed that 40 patients (58%) experienced total pituitary deficiency after treatment, mainly after their first surgery: 17 children (73.3%) and 23 adults (48.9%). Partial pituitary deficit (> 2 hormones) occurred in 14 patients (20.3%): One child (4.5%) and 13 adults (27.7%). Eleven of the adults got it after surgery and two presented with partial pituitary deficiency. - 2: Visual and neurological outcome It was 38 adults that presented with visual impairment at diagnose. It was 25 patients that improved after treatment. Two adult patients (2.9%) got their preoperative loss of vision back after surgery. In this study 22 patients (31.9%) experienced some kind of persisting visual impairment: In the childhood- onset population 12 children (54.5%) was affected and 10 adults (21.3%).

17 17 Neurological sequels include hemiparesis, epilepsy, cranial nerve deficits and cerebrovascular disease manifestations. In this study five children (22.7%) got neurological sequels after their treatment. Neurological sequels manifested themselves in two adults (4.3%). - 3: Hypothalamic dysfunction In the childhood- onset group nine patients (30.9%) experienced hypothalamic dysfunction, here observed as obesity. One child (4.5%) presented with rapid weight gain a few months prior to diagnosis. Eight other children developed hypothalamic obesity after surgery (3 6 months postoperative). In our adult- onset population 11 patients (23.4%) experienced hypothalamic obesity. Four adults (8.5%) presented with hypothalamic obesity and three adults (6.3%) developed postoperative obesity. - 4: Cognitive failure Cognitive failure in this study includes dementia, mental retardation, and cognitive failure that made the patients unable to live alone without healthcare personnel. This comprises one child (4.5%) and seven adults (14.9%) with sequels after treatment. - 5: Quality of life Good quality of life has been defined as achieving independent living with social interrogation, normal 100% professional occupation or school status. In this study we lack information about 13 patients (27.7%) in the adult- onset group. During the mean observation period of 92 months, 14 children (63.6%) and 11 adults (23.4%) achieved independent living (table 8). Table 8. Quality of life Quality of life Children, n Adults, n Total, n Good quality of life 14 (63.6) 11 (23.4) 25 (36.2) Unknown 1 (4.5) 13 (27.7) 14 (20.3)

18 18 Illustrative case Beside this paragraph is the preoperative MRI- scan (fig.3) of a typical patient in our population. It is a 20- year- old female student. She was studying Russian and was admitted to our department after a six months medical history of visual impairment, irregular menstruation and two episodes of syncope. The clinical examination revealed reduced vision (0.4 o.d., 0.3 o.s.) papillary oedema, reduced general condition and unsteady gait. The MRI shows a typical craniopharyngioma in the suprasellar area growing into the third ventricle causing hydrocephalus. The tumour is partly solid with contrast enhancement and partly cystic (Fig. 4). adamantinomatous subtype. She was operated with a fronto- orbital approach (Fig. 4). Post operatively she was oriented and in good condition. Her vision had improved. She had some postoperative CSF leakage, got a lumbar drain and a percutaneous injection of sealants to stop the CSF leakage. The histological sample showed an

19 19 (Fig.5). Postoperative MRI- scan (Fig. 5) revealed satisfactory results without signs of remnant tumour. She made a fast recovery, but gained 30 kg in weight within a few months. Even though her vision improved she had some remnant bitemporal hemianopia and had to live with pituitary deficiency (substituted with cortison, levaxin, minirin and sexhormon). She re- entered university, studying Russian. Discussion In this study we have investigated the treatment and long- term outcome in patients with craniopharyngioma. This is a retrospective, single institution study including all patients diagnosed with craniopharyngioma over a period of 24 years with a mean follow- up for 92 months. Our incidence of 2.4 cases per million per year is somewhat higher compared to what other series` report. This might be due to the fact that we only have been studying cases as far back as early 1990`s, all our cases being verified with MRI. Before MRI scans the incidence of craniopharyngioma might have been lower, which might be the reason of a lower reported incidence in other series. Age The age distribution in our study confirms that there is a bimodal age distribution in patients with craniopharyngioma. A median age at diagnosis of 8.6 years in our childhood- onset population together with the fact that most of the children (86.3%) were under the age of 15 at the time of diagnosis corresponds partly with the vast German Pediatric Cancer Registry. Their data from comprises 496 childhood- onset craniopharyngioma patients diagnosed at <18 years of age, and revealed that 459 of the patients (91%) were younger than 15 years of age at the time of diagnosis with an 1:1 sex ratio and a median age at diagnosis of 8.8 years. However,

20 20 researchers in England have reported that males are affected 30% more often than females (4). Our study suggests that the sex ratio may be even higher. Presenting symptoms Since the majority of craniopharyngiomas have their bulk located in the suprasellar area, the symptoms are characteristically visual dysfunction, disturbance of the hypothalamic- pituitary axis, and raised intracranial pressure as a result of obstruction of flow of cerebrospinal fluid. We found that the most common manifestations amongst childhood patients were visual impairment and headache, both affecting approximately half of the population. Mûller (5) found that up to 80% of childhood patients manifested their disease with visual impairment. Furthermore, they found that up to 80% presented with some kind of endocrine deficits, whereas only 2/5 in our childhood population presented with some kind of endocrine deficit. In the adult population nearly 81% presented with visual impairment and approximately 1/3 presented with some kind of endocrine deficiency in corroboration with the literature (1). Treatment The literature to date has not settled the controversy over the best treatment strategy for craniopharyngioma (intended primary gross total resection, versus biopsy/partial resection followed by irradiation). This retrospective, single institution study showed that intended primary gross total resection as only treatment was the treatment of choice in both the adult and childhood- onset population. Seventy- five percent of those that got gross total resection as solely treatment in our childhood- onset population, had no restrictions in quality of life. However, this series comprises 22 children and only eight of these patients (36%) received gross total resection. So there are too few patients included to draw any conclusions on the matter of treatment, but this finding speaks in favour of intended primary gross total resection.

21 21 Surgical approach Craniopharyngioma pose a significant challenge due to the size and location of the tumour, even with the advent of modern neurosurgical techniques. The strategy of choice was by far craniotomy at our department, and 65% of our patients underwent craniotomy. Even though potential advantages of transsphenoidal approaches include the avoidance of craniotomy, brain retraction and neurovascular manipulation, only 14.5% of our patients underwent transsphenoidal approach, mainly due to size and extension of the tumours. Irradiation Approximately 1/3 of the patients in this study received radio- or chemotherapy as only- or adjunct treatment. This corresponds to what other European studies have reported previously. The site and rate of progression of craniopharyngioma, as well as the patients age, are important considerations when deciding whether reoperation and/or radiotherapy should be performed. Only two patients from our childhood- onset population got conventional external radiotherapy due to the risk for side effects like reduced intellectual capacity in small children. Fitzek and co- workers have published a report on 15 craniopharyngioma patients treated with combined proton- photon irradiation for residual or recurrent disease (6). Actuarial 5 and 10- year local control rates were 93 and 85%, respectively. This report corresponds to our overall survival rates, but only one of our patients got proton beam therapy, given in Heidelberg, Germany since this treatment is not available in Norway. Compared with conventional irradiation, stereotactic radiotherapy adopts reduced safety margins and offers optimal sparing of the normal tissue surrounding the tumour, thereby possibly minimizing the acute and long- term toxicities of irradiation. The data on the usefulness of stereotactic radiotherapy for the management of craniopharyngiomas are limited, but the largest series published thus far provide promising results. At Oslo university hospital 36% of childhood- onset and 11% of adult- onset patients received stereotactic radiosurgery as adjunct treatment. Cavalherio et al. have published the most extensive reports in treating cystic childhood craniopharyngiomas (7). Their last publication included 60 children with a mean age of 11 years treated at three different hospitals with promising results. There was only one

22 22 patient in our study with a cystic childhood craniopharyngioma, who got instillation of a sclerotic substance after initial surgery. The outcome was eventually bad after multiple surgeries due to regrowth of tumour. The patient was left blind and hemi- paretic. It was therefore impossible to evaluate the usefulness of the sclerotic substance. Four of our adult onset patients also got instillation of sclerotic substance after primary surgery with better results, although not comparable to the results of Cavalherio et al. (7). Histology The two histological subtypes are present in the Norwegian population analysed here. About 30% of adult onset craniopharyngiomas are reported to be papillary (1), but only a minor percentage in our adult onset group had verified this papillary subtype. All the others had an adamantinomatous craniopharyngioma. This might be due to the fact that 1/3 of the histology did not differentiate between subtypes in the patient s records, which represent one of the limitations in this study. Mortality In this study the overall survival rates in the childhood- onset population was 100% survival at 5 years, 90% survival at 10 and 20 years, and 80.8% survival after 23 years. Patients that were treated in the 1990`s had a lower survival rate than those diagnosed after The overall survival rates described in exclusive children series range from 83 to 96% at 5 years and 65 to 100% at 10 years and an average 62% at 20 years (2). In this study s adult- population 89% survival rate was found at 5 years, 81% survival after 10, 15, 20 and 23 years. In adults or mixed- age- range population series, the overall survival rates range from 54 to 96% after 5 years, from 40 to 93% at 10 years and 66 85% after 20 years (2). Our findings are in line with the upper margin of survival rates worldwide, which probably means that patients treated at Oslo University Hospital between 1992 and 2015 has been given the best medical treatment available.

23 23 Recurrence The management of recurrent tumours remains difficult because scarring from previous operations or radiation decreases the possibility of successful excision. Daubenbucler and Mûller states that In such cases, the success rate of total removal drops dramatically (0-25%) when compared with primary surgery and there is also increased perioperative morbidity and mortality ( %), suggesting that for many recurrent lesions, radio- oncological treatment options should be considered (2). In a series of 22 children or young adults irradiated for recurrence, Minniti al. found an actuarial 10- year local control rate of 83% (8). This is findings that do not correspond to our retrospective study were nearly 50% and 30% of our childhood- and adult onset patient respectively, experienced regrowth. Most of them were reoperated once or multiple times. Morbidity Fitzek and colleges reported that 67-82% of patients with normal baseline values of GH, ACTH, TSH and gonadotropins before surgery developed a new deficiency of the respective pituitary axe after surgery (6). This corresponds to our findings that also indicate that total pituitary deficiency is more common among the childhood- onset patients, affecting approximately 70% of the cases, compared to 45% of adult- onset cases. Fitzek et al states that The risk of new endocrine deficits appears to be lower after the transsphenoidal surgical approach (6). In our study we do not find the same. Of the 8 adults that underwent CGH, four had total pituitary failure and four partial pituitary deficiencies. Amongst the childhood- onset patients that underwent CGH, one had an intact pituitary gland, and the rest had a partial pituitary deficit. Hypothalamic dysfunction The rate of hypothalamic dysfunction was dramatically increased after radical surgery, and in our childhood cases nearly 40% experienced hypothalamic dysfunction mainly expressed as obesity. Approximately 20% of our adult cases experienced the same. Such excellent surgical outcome regarding hypothalamic dysfunction, has not been reported elsewhere. In some European series they report postsurgical hypothalamic

24 24 dysfunction in up to 65-80%. Karavitaki et al. reports that the degree of obesity frequently increases early after treatment and rapid weight gain often occurs during the first 6-12 months after treatment (3), corresponding to findings in this study. Furthermore: After treatment, the prevalence of severe obesity is high, reaching up to 55%. This study, however, observed that only 11% of childhood- onset patients developed hypothalamic obesity after surgery and only 20% of our adult- onset patients. Our results suggest that hypothalamic- sparing surgery might have been more successful at our department than elsewhere. Neurological complications In this study we found that 7 patients (10%) experienced neurological squeals. There is somewhat deviating reports on total prevalence of long- term neurological complications in the literature. Some studies report as low prevalence as 8% while others operate with a prevalence of nearly 40%, for large- sized tumours. Quality of life During the mean observation period of 92 months, 11 children (50%) and 30 adults (63.8%) achieved independent living. Van Effenterre and Boch found in their cohort of 122 patients treated mainly by surgery during a mean observation period of 7years, that 16% of adults and 26% of children did not achieve independent living with social interrogation and normal professional occupation or school status (4). They used the same parameters as we have done in our single institution study, and we have not found a good explanation why they reported better results than we were able to report on quality of life. In a series of 121 subjects treated surgically with or without adjuvant radiotherapy and follow- up for a mean period of 10 years, the authors found poor outcome in 40% of patients (the outcome was based on motor deficits, vision, and dependence for activities of daily living. Karnofsky performance scale assesses the ability to perform normal activity and to do active work and the need for assistance) (10). What Duff et al. had based their findings on corresponds somewhat to the end- results we used to quantify our meaning of Quality of life.

25 25 Wiener et al. found that the Karnofsky performance status was significantly lower in patients who underwent two or more operative procedures (11). We did not use Karnofsky performance status and has not been able to investigate whether it is the same for the patients treated at Oslo University hospital. This series suggest that quality of life, neurological outcome and psychosocial functioning after treatment depends on the chosen treatment strategy: with worse outcomes for non- radical surgery followed by irradiation and multiple operations for tumour recurrence compared to radical surgery alone.

26 26 Conclusions There is a bimodal age distribution in patients with craniopharyngioma. These tumors tend to recur and are associated with increased mortality and morbidity. The overall survival rates are relatively high, but neuroendocrine disorders such as obesity and metabolic syndrome due to involvement and/or treatment- related hypothalamic lesions have major negative impact on survival and quality of life. The most common presenting symptoms correspond to what previous studies have reported: Visual impairment, headache and endocrine deficits. However, this study found that ⅔ of the long- term survivors of both childhood and adult- onset patients suffered from total endocrine deficiency. This is higher than in other trails done elsewhere. This might be explained by Oslo University Hospital`s more aggressive approach with several attempts at radical surgery. At Oslo University Hospital radical surgery (gross total resection) approached by craniotomy is the treatment of choice for craniopharyngioma patients. It leaves the patients with least long- term complications: In the childhood- population treated with radical surgery alone, ¾ reached independent living with no quality of life compromising sequels. In our adult- population, after radical surgery alone ½ reached independent living with social interrogation and normal professional occupation or school status. We also observed that apart from those treated with radical surgery alone many (½ of childhood- cases and 2/3 of adult- cases) did reach independent living. The second most common long- term sequels were visual and neurological impairment and the third most common was hypothalamic dysfunction. Note The data were presented as an oral presentation at the Norwegian Neurosurgical Society meeting in Oslo, Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

27 27 Limitations The study is a retrospective analysis and may suffer from anticipated deficiencies related to loss of patient information. This has limited our study to variables exclusively reported in the medical journals. One of the variables we wanted to assess was the degree of depression amongst the patients included, but such information was not noted in the medical records. Based on our findings only a single patient had clinical signs of depression. This is hardly true, when we consider the substantial morbidity that long- term survivors suffer due to sequelae caused by injury to vital structures of the brain. Due to time limitations we were not able to obtain the cause of death, unless noted in the medical records. This was another limitation in our study, because some of the patients might have died from unrelated cause. Compared to other studies in Europe, this series is a medium sized study.

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