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Comparison of hypothalamopituitary axis dysfunction of intrasellar and third ventricular craniopharyngiomas in children
Brain & Development 30 (2008) 189–194 www.elsevier.com/locate/braindev
Original article
Comparison of hypothalamopituitary axis dysfunction of intrasellar and third ventricular craniopharyngiomas in children Yi-Yen Lee a, Tai-Tong Wong b,c, Yi-Ting Fang d, Kai-Ping Chang Yi-Wei Chen e,c, Dau-Ming Niu a,c
a,*
,
a
Department of Pediatrics, Taipei City Hospital, Renai Branch, NO.10, Sec. 4, Renai Road, Taipei 106, Taiwan, ROC Department of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC c National Yang-Ming University, School of Medicine, Taipei, Taiwan, ROC Institute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC e Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC b
d
Received 9 January 2007; received in revised form 22 June 2007; accepted 25 July 2007
Abstract In this study, we attempted to determine if different locations of a tumor influence the hypothalamopituitary axis function and outcomes with childhood craniopharyngiomas. The preoperative, postoperative, and long-term follow-up endocrinological disturbances of 66 children with a craniopharyngioma were retrospectively studied. The patients were divided into two subgroups according to the location of the tumor (intrasellar and third ventricle floor). The mean age at onset was 8.02 (range, 1.42–17.58) years. These patients were followed-up for a median duration of 7.2 (range, 2–22) years. Vision problems as the first symptom were more common in Group One (with intrasellar tumors) compared to Group Two (55.6% vs 15.4%; p = 0.001; Fisher’s exact test). Increased intracranial pressure was the most common initial symptom in patients in Group Two (51.3%) and the second most common symptom in Group One (37%). The majority of patients in both Group One and Group Two required some forms of pituitary hormone supplements (96% vs 84%). At the last follow-up, more patients with intrasellar craniopharyngiomas needed cortisone supplements (79.2% in Group One vs 45.9% in Group Two; p = 0.016; Fisher’s exact test); however, children with third ventricle floor tumors had more prevalent weight gain (4.2% in Group One vs 27.0% in Group Two; p = 0.038; Fisher’s exact test). There were different initial presentations and endocrinological outcomes between children with intrasellar and third ventricle floor craniopharyngiomas. The intrasellar tumors had greater pituitary hormone disturbance. However, at the long-term follow-up, children with third ventricle floor tumors had a greater prevalence of being overweight and obese, which was associated with hypothalamic dysfunction. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Craniopharyngioma; Hypothalamic–pituitary axis function; Endocrine; Location; Children
1. Introduction Craniopharyngiomas constitute of 5.6–12% of primary pediatric brain tumors in children [1]. These benign epithelial tumors arise and are located in the sellar–suprasellar region, involve the sellar turcica *
Corresponding author. Tel.: +886 2 2875 7128; fax: +886 2 2873 9019. E-mail address: [email protected] (K.-P. Chang). 0387-7604/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2007.07.011
and/or third ventricular floor, and commonly cause hypothalamic–pituitary dysfunction and endocrinopathies at diagnosis. Modalities of treatment include extensive surgical resection, limited resection along with radiation therapy, and sometimes additional intracystic injections of a radioisotope/bleomycin. These types of treatment may cause further injury to the hypothalamic–pituitary function. Because of the various endocrinological presentations in patients with craniopharyngiomas under similar treatments, we
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Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194
hypothesized that different craniopharyngioma locations might be prone to developing different phenotypes. Therefore in this retrospective study, we sought to examine the clinical associations between intrasellar and third ventricle floor craniopharyngiomas, as well as to determine the long-term outcomes of these patients. 2. Materials and methods There were 84 patients with craniopharyngioma treated at our center from May 1977 through May 2004. The medical records of 73 children were reviewed. All patients underwent neurosurgery. Two children who were older than 18 years old, one male who died of cardiac arrhythmia in the early postoperative period (within 1 month), three cases for whom much of the data of were lost, and another one who received only gamma knife radiosurgery were excluded. The data collected included age, gender, body weight, body height, presenting symptoms, duration of presenting symptoms to the diagnosis, complications, modalities, and recurrences. 2.1. Classification of craniopharyngiomas according to emergence and extension We followed Choux–Raybaud’s [2] classification to differentiate these tumors into intrasellar tumors and third ventricular (infundibulum and tuber cinereum) tumors through MRI/CT or operative findings (Figs. 1,2). Various extensions of the craniopharyngiomas were observed from tumors arising in these two locations. In our series, 27 cases (40.9%) were in Group One (intrasellar tumors) and 39 cases (59.1%) were in Group Two (third ventricular tumors).
2.2. Endocrine evaluation Preoperative, postoperative (within 3 months after surgery, except for seven patients within 1 year), and long-term follow-ups (with a mean duration of 7.2 years, and range of 2–22 years) for hypothalamopituitary function were assessed. Patients received hormonal therapy according to their endocrine insufficiency and the period (every 1–3 months) followed-up at the endocrinology clinic. The follow-up endocrinological data were taken from our own charts. Basal hormonal measurements were obtained. A provocation test was not performed preoperatively. Cortisol insufficiency was defined as a low serum level (baseline <5 lg/dl, peak <18 lg/dl), and/or synthetic adrenocorticotropic hormone (ACTH, 250 lg of Tetracosactrin Synathen)-stimulated cortisol levels with an increment of <7 lg/dl. Hypothyroidism was assessed by the total, free thyroxin (FT4), triiodothyronine (T3), and thyrotropin (TSH) levels. A precocious puberty study was selectively performed on patients (girls younger than 8 and boys younger than 9 years old) who were not of pubertal age but had pubertal findings on physical examination. On the other hand, when patients were at a puberty age (girls older than 13 and boys older than 14 years) and had no pubertal development, the hypothalamopituitary gonadal axis function was evaluated. The serum levels of testosterone in males and estradiol in females, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. A luteinizing hormone-releasing hormone (LHRH) test was performed. A peak LH/FSH ratio of >1 and a peak LH level of >10 IU/l were consider indicative of puberty. The growth hormone status was assessed by two pharmacological growth hormone provocation tests
Fig. 1. MRI (left) and CT (right) of intrasellar craniopharyngiomas.
Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194
191
Fig. 2. MRI (left) and CT (right) of third ventricular (infundibulum and tuber cinereum) craniopharyngiomas.
(clonidine, insulin tolerance, or levodopa test) during the follow-up period. GH deficiency was diagnosed when its peak level was <10 ng/ml during the provocation test. Central diabetes insipidus was diagnosed as follows: clinical presentation (polyuria/polydipsia), urine output of >5 ml/kg/h with a urine specific gravity of <1.010 or urine osmolality of <200 nmol/L and increased urine osmolality (>450 m Osm/kg) after nasal desamino-Darginine vasopressin (DDAVP) was used (DDAVP test). 2.3. Perioperative evaluation of CSWS and SIADH We diagnosed patients with electrolyte imbalance as having cerebral salt wasting syndrome (CSWS) or secretion of inappropriate antidiuretic hormone (SIADH) according to the above data. CSWS is characterized by polyuria, hyponatremia, and high urine sodium. SIADH is manifested as dehydration, hyponatremia (serum sodium <135 mEg/L), low serum osmolarity (<280 m Osm/kg), high urine osmolarity (usually greater than that of the serum), and urine sodium of >25 mEq/L. 2.4. Growth retardation, the overweight status, and obesity We reviewed the growth charts of these patients. The body mass index (BMI) was defined as the ratio of body weight in kilograms to the square of body height in meters (kg/m2). Thus, each child’s BMI value was calculated and compared with age- and gender-specific reference values currently used in Taiwan [3–5]. Growth retardation was manifested as heights more than 3 standard deviations (SDs) below the mean for the age and gender. Being overweight was defined as a BMI between the 85th and 95th percentiles, and obesity as a BMI
above the 95th percentile. The body weight and height and BMI data preoperatively, postoperatively (1–3 years after surgery), and at the last visit were recorded. 2.5. Surgery and radiotherapy The treatment policy employed at our hospital is total resection whenever possible, and repeats resection, total if possible, for disease progression, as long as this is practical. The decision to perform a total resection was made based on the surgeon’s operative report and a negative postoperative CT/MRI [6]. If a total resection was not possible, therapeutic alternatives included subtotal resection with postoperative radiotherapy or gamma knife radiation surgery, except in children younger than 3 years. Cyst aspiration and/or a bleomycin injection followed by radiotherapy were used if necessary. We treated craniopharyngioma cases with megavoltage irradiation using 6–10 MV linear accelerators. A three-dimensional (3D) conformational technique was initiated in 1997. Before 1997, we used a 2D technique with bilateral opposing portals. At that time, no accurate dose distribution plot was available before we began treatment. The 3D conformational technique was used for most patients to ensure that the treatment dose was well distributed. The treatment fields were arranged so that they encompassed the entire tumor locally plus margins of 0.5–1.0 cm. Treatment doses ranged from 50 to 60 (median, 54) Gy. 2.6. Statistical analysis Statistical analyzes were performed with the Statistical Package for Social Sciences (vers. 11.0, SPSS, Chicago, IL, USA). The Pearson chi-squared test and Student’s t-test were used to compare the data. Pearson
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correlation analysis or two-tailed Fisher’s exact test was applied. Differences were considered statistically significant at the p < 0.05 level. 3. Results 3.1. Patient characteristics Characteristics of the craniopharyngioma subjects are shown in Table 1. Patients consisted of 26 females (39.4%) and 40 males (60.6%). The mean age at onset was 8.02 (standard deviation (SD), 4.28; median, 7.0; range, 1.42–17.58) years. Tumor location included 27 patients (40.9%) in Group One and 39 patients (59.1%) in Group Two. Thirteen patients were at the age of puberty (P13 years in girls and P14 years in boys). There were no statistical differences in patient characteristics between groups one and two. 3.2. Clinical features There were 15 patients (55.6%) in Group One (intrasellar tumors) who presented with vision problems as the first symptom. There was a significant difference in the two locations (p = 0.001, Table 2). However, 20 patients (51.3%) in Group Two (third ventricle floor tumors) presented with increased intracranial pressure as the first symptom (p = 0.318). Fifteen cases (22.7%) had variable degrees of hyponatremia in the early postoperative period. Serum sodium levels were below 130 mEq/l during 1–8 days after the operation, lasting 3–5 days. Nine patients (13.6%) were diagnosed as having cerebral salt wasting syndrome. There was no significant difference in early postoperative hyponatremia between the different tumor locations. In the pituitary endocrine evaluation, patients were labeled with a number from 1 to 5, which indicated how many kinds of hormone deficiency they experienced. The results of the two groups were compared. Group One patients required more forms of hormone replacement than in the Group Two patients postoperatively (3.27 vs 2.72, p = 0.018, t-test) and at the last visit
Table 2 Initial presentation (first or major symptom) by the location of the craniopharyngioma First symptom
Intrasellar Number
Percentage
Number
Third ventricular Percentage
p value
Vision Endocrine IICP Othersb Total
15 2 10 0 27
55.6 7.4 37.0 0 100
6 8 20 5 39
15.4 20.5 51.3 12.8 100
0.001a 0.180 0.318 0.073
IICP, increased intracranial pressure (headache, nausea, vomiting). a p < 0.05. b Others including unsteady gait, facial palsy, hemiparesis, incontinence and hand tremor.
(2.92 vs 2.3, p = 0.020, t-test). Furthermore, we not only compared the two groups in terms of preoperative, postoperative, and last follow-up hormone (growth hormone, corticotrophin, thyrotrophin, gonadotrophin, and vasopressin) deficiencies (Table 3) but also compared the two groups in terms of changes in the hormone deficiencies postoperatively and preoperatively, and of the last visit with preoperative and postoperative levels. There were no significant differences between these two groups in terms of changes in hormone insufficiency. Hypothyroidism was more prevalent in Group One patients than in Group Two patients pre- and postoperatively (p = 0.039 and p = 0.009, respectively). And more Group One patients needed cortisone supplements than did Group Two patients at the last visit (p = 0.016). There were no significant differences between the anterior and posterior pituitary functions in these two groups. The two groups showed no differences in body weight, body height, or the body mass index preoperatively and postoperatively. In the longterm follow-up, obese and overweight patients were more prevalent with third ventricle floor tumors than with intrasellar tumors (4.2% vs 27.0%, p = 0.038, Table 4). We divided these patients into four subgroups based on treatment (only surgery, surgery plus radiation, surgery plus gamma knife radiation, and surgery plus radi-
Table 1 Characteristics of patients by the location of the craniopharyngioma
Table 3 Pituitary hormone replacement in children by location of the craniopharyngioma
Characteristic
Hormone replace
Intrasellar
Third ventricular
Total
Patients All Valuable
32 (43.8%) 27 (40.9%)
41 (56.1%) 39 (59.1%)
73 66
Age (years) Mean (SD)
7.35 (3.56)
8.35 (4.73)
8.02 (4.28)
Gender Male Female
17 (63.0%) 10 (37.0%)
23 (59.0%) 16 (41.0%)
40 26
At puberty
3 (11.1%)
10 (25.6%)
13
Growth hormone Sex hormone Thyroxin Cortisone Vasopressin
Intrasellar (%)
Third ventricular (%)
Pre
Post
Last
Pre
Post
Last
38.5 7.7 38.5a 15.4 23.1
46.2 7.7 96.3b 86.4 88.5
29.2 16.7 95.8 79.2c 70.8
31.4 8.6 14.3a 5.7 14.3
28.2 12.9 76.9b 69.2 84.6
27.0 10.8 81.1 45.9c 64.9
Pre, preoperative; Post, postoperative; Last, last visit. a p = 0.039. b p = 0.009. c p = 0.016
Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194 Table 4 Overweight status and obesity in children by location of the craniopharyngioma Intrasellar (%) Pre Overweight Obese a
11.1 7.4
Post 11.1 7.4
Third ventricular (%) Last a
4.2 4.2a
Pre
Post
Last
15.4 5.1
17.9 23.1
27.0a 27.0a
p = 0.038; p < 0.05.
ation and gamma knife radiosurgery). However, no statistical differences in treatment and recurrence rates were found between the two locations. 3.3. Other complications Some patients had other complications that persisted during long-term follow-up. Five cases had hepatic disorder including fatty liver, ALT elevation, common biliary duct stone and gallstone, and liver cirrhosis. One female died of hepatopulmonary syndrome with hypoxia 11 years later. She had liver cirrhosis and esophageal varices. One boy had diabetes mellitus during the follow-up period (10 years). All of these were Group Two patients. Twelve children suffered from hyperlipidemia, eight of whom were in the third ventricle floor tumor group. In the same group, one patient suffered from intracranial hemorrhage and another had a transient infarction accident. The results revealed that Group Two patients were at risk of long-term complications. Two patients had severe neurological sequelae which became cerebral palsy with epilepsy. One girl revealed an anaplastic astrocytoma after 7 years of treatment. Two boys were diagnosed as having moyamoya syndrome 3 and 4 years after radiotherapy, respectively. 4. Discussion The presentation of a craniopharyngioma varies with the size, location, and extension of the tumor [7]. Our review report also revealed the same results. Significant differences were found in non-endocrine symptoms between the two groups in our study. The complaints were usually non-endocrine-related, with headaches and vomiting with third ventricle floor tumors and visual disturbances with intrasellar tumors being the most common. The reason that our subjects had higher rates of hypothyroidism postoperatively and more intrasellar location patients required cortisone replacement was also associated with these patients having more prevalent hypopituitarism. Group One patients required three forms and Group Two required two forms of hormone supplements. These results are compatible with the anatomy of the sellar region.
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Dysfunction of the hypothalamic–pituitary system can be due either to the tumor itself or to the type of treatment [8,9]. The choice of treatment should depend on various aspects: the volume and location of the mass, the adjacent structures, and quality of life considerations. Gonc et al. [10] observed that neither radiotherapy nor extent of tumor removal – either total or subtotal – influenced the endocrinological outcome. In our series, we observed no change in the frequency of hypothalamopituitary axis dysfunction with regard to the treatment. Thus, these data suggest that different tumor locations may affect the endocrinological presentation and outcome. Approximately one-third (33.4%) of Group Two (third ventricle floor tumors) patients were morbidly overweight and obese. This occurred after injury to the ventromedial area (the so-called ‘‘satiety center’’), leading to hyperphagia [11]. Pathological studies have demonstrated that on a microscopic level, there is interdigitation of the tumor capsule with parenchyma in the wall of the third ventricle [12,13]. It is possible that a craniopharyngioma in the third ventricle floor can more easily injure the hypothalamus. A recent study [14] reported an increased prevalence of features of metabolic syndrome in childhood craniopharyngiomas. This might be a result of hypothalamic damage causing obesity and GH deficiency [14]. We had five cases which suffered from hepatic disorder, and one female died due to hepatopulmonary syndrome. Eight patients had hyperlipidemia, nine had uric acid elevation, and one boy had diabetes mellitus during the follow-up period. Patients with hypothalamic and/or pituitary disease are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of nonalcoholic fatty liver disease (NAFLD) [15]. NAFLD is determined by a liver biopsy or by fatty infiltration on image studies in association with abnormal liver enzymes [15]. Patients were excluded if they had a secondary cause of NAFLD [15]. Four of five patients in this study were compatible with that diagnosis. It is essential to identify these patients as they are at risk of metabolic syndromes and increased morbidity or mortality. Our study was limited by having an insufficiently long follow-up duration to compare the incidence of metabolic syndrome with the general population. These observations imply that dedicated long-term follow-up of these patients especially in Group Two is required. There were two boys in our series who presented with excessive growth after treatment. Deficiencies in thyrotropin, corticotropin, gonadotropins, and growth hormone were confirmed in these boys. Both of them were given cortisone, thyroxine, and desmopressin replacement therapy. One of them had used growth hormone for 4 months, but tumor recurrence was found. So he received no growth hormone supplementation after the second surgery. These patients presented an interest-
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ing combination of hypopituitarism and excessive growth. The condition between the absence of growth hormone in the patients’ serum and clinical presentation of a tall stature is difficult to explain. Normal statural growth in the absence of a growth hormone secretory response to stimuli has been demonstrated in children after surgically induced hypopituitarism for a craniopharyngioma [16,17]. It is possible that his growth hormone reserve was insufficient to be detected by our assay but was large enough to allow him to grow. So the question arises: Does the serum growth hormone which we detect truly represent the biologically active hormone [18]? Another possible explanation of this situation is there are other factors which we do not know about which influence growth. The growth factor may be secreted by the tumor or by ectopic neurohypophysis. 5. Conclusions We concluded that different tumor locations seem to influence the behavior of craniopharyngiomas in children. At presentation, the prevalence of complaints in craniopharyngiomas differed between Group One (intrasellar tumors) and Group Two (third ventricle floor tumors) patients. Children with intrasellar craniopharyngiomas reported more prevalent visual complaints and endocrinopathies before surgery. Endocrine complications, particularly hypothyroidism postoperatively and long-term cortisone replacement, were more prevalent among patients with intrasellar tumors. Our observations also indicate that third ventricle floor craniopharyngiomas are more prevalent in raising intracranial pressure at presentation and in weight gain during long-term follow-up. Damage to the hypothalamus should be considered in these patients. The presence of obesity and hepatic disorders in patients with third ventricle floor craniopharyngiomas is associated with increased morbidity and mortality. Prospective studies are necessary to determine better management practices for those patients likely to be at risk of metabolic syndromes and nonalcoholic fatty liver disease.
Acknowledgment We thank the research program of Taipei Veterans General Hospital (V95A-064) for support of this study.
References [1] Wong TT, Ho DM, Chang KP, Yen SH, Guo WY, Chang FC, et al. Primary pediatric brain tumors: statistics of Taipei VGH, Taiwan (1975–2004). Cancer 2005;104:2156–67. [2] Brunel H, Raybaud C, Peretti-Viton P, Lena G, Girard N, PazParedes A, et al. Craniopharyngioma in children: MRI study of 43 cases. Neurochirurgie 2002;48:309–18. [3] Huang YC, Kao YH. Secular trends in the height and weight of Taiwanese children and adolescents 1964–1992 academic years. Public Health Quarterly 1999;25:247–56. [4] Chen W, Wu KW, Mi LL, Liu JL. Weight-for-length index in evaluation of children’s body weight status: a simple and accurate method. J Formos Med Assoc 1993;92:S128–34. [5] Huang YC, Wu JY, Yang MJ. Weight-for-height reference and the prevalence of obesity for school children and adolescents in Taiwan and Fuchien areas. J Chin Med Assoc 2003;66:599–606. [6] Khafaga Y, Jenkin D, Kanaan I, Hassounah M, Al-Shabanah M, Gray A. Craniopharyngioma in children. Int J Radiat Oncol Biol Phys 1998;42:601–6. [7] Chen C, Okera S, Davies PE, Selva D, Crompton JL. Craniopharyngioma: a review of long-term visual outcome. Clin Experiment Ophthalmol 2003;31:220–8. [8] Paja M, Lucas T, Garcia-Uria J, Salame F, Barcelo B, Estrada J. Hypothalamic–pituitary dysfunction in patients with craniopharyngioma. Clin Endocrinol 1995;42:467–73. [9] Barreca T, Perria C, Francaviglia N, Rolandi E. Evaluation of anterior pituitary function in adult patients with craniopharyngiomas. Acta Neurochir 1984;71:263–72. [10] Gonc EN, Yordam N, Ozon A, Alikasifoglu A, Kandemir N. Endocrinological outcome of different treatment options in children with craniopharyngioma: a retrospective analysis of 66 cases. Pediatr Neurosurg 2004;40:112–9. [11] Brazis PW, Masdeu JC, Biller J, editors. Localization in clinical neurology. Boston: Little, Brown and Company; 1996. [12] Sorva R. Children with craniopharyngioma. Early growth failure and rapid postoperative weight gain. Acta Paediatr Scand 1988;77:587–92. [13] Curtis J, Daneman D, Hoffman HJ, Ehrlich RM. The endocrine outcome after surgical removal of craniopharyngiomas. Pediatr Neurosurg 1994;21:24–7. [14] Srinivasan S, Ogle GD, Garnett SP, Briody JN, Lee JW, Cowell CT. Features of the metabolic syndrome after childhood craniopharyngioma. J Clin Endocrinol Metab 2004;89:81–6. [15] Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 2004;39:909–14. [16] Holmes LB, Frantz AG, Rabkin MT, Soeldner JS, Crawford JD. Normal growth with subnormal growth hormone levels. New Engl J Med 1968;279:559–66. [17] Kenny FM, Iturzaeta NF, Mintz D, Drash A, Garces LY, Susen A, et al. Iatrogenic hypopituitarism in craniopharyngioma: unexplained catch-up growth in three children. J Pediatr 1968;72:766–75. [18] Baumann G, Cain JP, Dingman JF. Gigantism with hypopituitarism. Am J Med 1972;53:805–10.
Original article
Comparison of hypothalamopituitary axis dysfunction of intrasellar and third ventricular craniopharyngiomas in children Yi-Yen Lee a, Tai-Tong Wong b,c, Yi-Ting Fang d, Kai-Ping Chang Yi-Wei Chen e,c, Dau-Ming Niu a,c
a,*
,
a
Department of Pediatrics, Taipei City Hospital, Renai Branch, NO.10, Sec. 4, Renai Road, Taipei 106, Taiwan, ROC Department of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC c National Yang-Ming University, School of Medicine, Taipei, Taiwan, ROC Institute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC e Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC b
d
Received 9 January 2007; received in revised form 22 June 2007; accepted 25 July 2007
Abstract In this study, we attempted to determine if different locations of a tumor influence the hypothalamopituitary axis function and outcomes with childhood craniopharyngiomas. The preoperative, postoperative, and long-term follow-up endocrinological disturbances of 66 children with a craniopharyngioma were retrospectively studied. The patients were divided into two subgroups according to the location of the tumor (intrasellar and third ventricle floor). The mean age at onset was 8.02 (range, 1.42–17.58) years. These patients were followed-up for a median duration of 7.2 (range, 2–22) years. Vision problems as the first symptom were more common in Group One (with intrasellar tumors) compared to Group Two (55.6% vs 15.4%; p = 0.001; Fisher’s exact test). Increased intracranial pressure was the most common initial symptom in patients in Group Two (51.3%) and the second most common symptom in Group One (37%). The majority of patients in both Group One and Group Two required some forms of pituitary hormone supplements (96% vs 84%). At the last follow-up, more patients with intrasellar craniopharyngiomas needed cortisone supplements (79.2% in Group One vs 45.9% in Group Two; p = 0.016; Fisher’s exact test); however, children with third ventricle floor tumors had more prevalent weight gain (4.2% in Group One vs 27.0% in Group Two; p = 0.038; Fisher’s exact test). There were different initial presentations and endocrinological outcomes between children with intrasellar and third ventricle floor craniopharyngiomas. The intrasellar tumors had greater pituitary hormone disturbance. However, at the long-term follow-up, children with third ventricle floor tumors had a greater prevalence of being overweight and obese, which was associated with hypothalamic dysfunction. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Craniopharyngioma; Hypothalamic–pituitary axis function; Endocrine; Location; Children
1. Introduction Craniopharyngiomas constitute of 5.6–12% of primary pediatric brain tumors in children [1]. These benign epithelial tumors arise and are located in the sellar–suprasellar region, involve the sellar turcica *
Corresponding author. Tel.: +886 2 2875 7128; fax: +886 2 2873 9019. E-mail address: [email protected] (K.-P. Chang). 0387-7604/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2007.07.011
and/or third ventricular floor, and commonly cause hypothalamic–pituitary dysfunction and endocrinopathies at diagnosis. Modalities of treatment include extensive surgical resection, limited resection along with radiation therapy, and sometimes additional intracystic injections of a radioisotope/bleomycin. These types of treatment may cause further injury to the hypothalamic–pituitary function. Because of the various endocrinological presentations in patients with craniopharyngiomas under similar treatments, we
190
Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194
hypothesized that different craniopharyngioma locations might be prone to developing different phenotypes. Therefore in this retrospective study, we sought to examine the clinical associations between intrasellar and third ventricle floor craniopharyngiomas, as well as to determine the long-term outcomes of these patients. 2. Materials and methods There were 84 patients with craniopharyngioma treated at our center from May 1977 through May 2004. The medical records of 73 children were reviewed. All patients underwent neurosurgery. Two children who were older than 18 years old, one male who died of cardiac arrhythmia in the early postoperative period (within 1 month), three cases for whom much of the data of were lost, and another one who received only gamma knife radiosurgery were excluded. The data collected included age, gender, body weight, body height, presenting symptoms, duration of presenting symptoms to the diagnosis, complications, modalities, and recurrences. 2.1. Classification of craniopharyngiomas according to emergence and extension We followed Choux–Raybaud’s [2] classification to differentiate these tumors into intrasellar tumors and third ventricular (infundibulum and tuber cinereum) tumors through MRI/CT or operative findings (Figs. 1,2). Various extensions of the craniopharyngiomas were observed from tumors arising in these two locations. In our series, 27 cases (40.9%) were in Group One (intrasellar tumors) and 39 cases (59.1%) were in Group Two (third ventricular tumors).
2.2. Endocrine evaluation Preoperative, postoperative (within 3 months after surgery, except for seven patients within 1 year), and long-term follow-ups (with a mean duration of 7.2 years, and range of 2–22 years) for hypothalamopituitary function were assessed. Patients received hormonal therapy according to their endocrine insufficiency and the period (every 1–3 months) followed-up at the endocrinology clinic. The follow-up endocrinological data were taken from our own charts. Basal hormonal measurements were obtained. A provocation test was not performed preoperatively. Cortisol insufficiency was defined as a low serum level (baseline <5 lg/dl, peak <18 lg/dl), and/or synthetic adrenocorticotropic hormone (ACTH, 250 lg of Tetracosactrin Synathen)-stimulated cortisol levels with an increment of <7 lg/dl. Hypothyroidism was assessed by the total, free thyroxin (FT4), triiodothyronine (T3), and thyrotropin (TSH) levels. A precocious puberty study was selectively performed on patients (girls younger than 8 and boys younger than 9 years old) who were not of pubertal age but had pubertal findings on physical examination. On the other hand, when patients were at a puberty age (girls older than 13 and boys older than 14 years) and had no pubertal development, the hypothalamopituitary gonadal axis function was evaluated. The serum levels of testosterone in males and estradiol in females, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. A luteinizing hormone-releasing hormone (LHRH) test was performed. A peak LH/FSH ratio of >1 and a peak LH level of >10 IU/l were consider indicative of puberty. The growth hormone status was assessed by two pharmacological growth hormone provocation tests
Fig. 1. MRI (left) and CT (right) of intrasellar craniopharyngiomas.
Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194
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Fig. 2. MRI (left) and CT (right) of third ventricular (infundibulum and tuber cinereum) craniopharyngiomas.
(clonidine, insulin tolerance, or levodopa test) during the follow-up period. GH deficiency was diagnosed when its peak level was <10 ng/ml during the provocation test. Central diabetes insipidus was diagnosed as follows: clinical presentation (polyuria/polydipsia), urine output of >5 ml/kg/h with a urine specific gravity of <1.010 or urine osmolality of <200 nmol/L and increased urine osmolality (>450 m Osm/kg) after nasal desamino-Darginine vasopressin (DDAVP) was used (DDAVP test). 2.3. Perioperative evaluation of CSWS and SIADH We diagnosed patients with electrolyte imbalance as having cerebral salt wasting syndrome (CSWS) or secretion of inappropriate antidiuretic hormone (SIADH) according to the above data. CSWS is characterized by polyuria, hyponatremia, and high urine sodium. SIADH is manifested as dehydration, hyponatremia (serum sodium <135 mEg/L), low serum osmolarity (<280 m Osm/kg), high urine osmolarity (usually greater than that of the serum), and urine sodium of >25 mEq/L. 2.4. Growth retardation, the overweight status, and obesity We reviewed the growth charts of these patients. The body mass index (BMI) was defined as the ratio of body weight in kilograms to the square of body height in meters (kg/m2). Thus, each child’s BMI value was calculated and compared with age- and gender-specific reference values currently used in Taiwan [3–5]. Growth retardation was manifested as heights more than 3 standard deviations (SDs) below the mean for the age and gender. Being overweight was defined as a BMI between the 85th and 95th percentiles, and obesity as a BMI
above the 95th percentile. The body weight and height and BMI data preoperatively, postoperatively (1–3 years after surgery), and at the last visit were recorded. 2.5. Surgery and radiotherapy The treatment policy employed at our hospital is total resection whenever possible, and repeats resection, total if possible, for disease progression, as long as this is practical. The decision to perform a total resection was made based on the surgeon’s operative report and a negative postoperative CT/MRI [6]. If a total resection was not possible, therapeutic alternatives included subtotal resection with postoperative radiotherapy or gamma knife radiation surgery, except in children younger than 3 years. Cyst aspiration and/or a bleomycin injection followed by radiotherapy were used if necessary. We treated craniopharyngioma cases with megavoltage irradiation using 6–10 MV linear accelerators. A three-dimensional (3D) conformational technique was initiated in 1997. Before 1997, we used a 2D technique with bilateral opposing portals. At that time, no accurate dose distribution plot was available before we began treatment. The 3D conformational technique was used for most patients to ensure that the treatment dose was well distributed. The treatment fields were arranged so that they encompassed the entire tumor locally plus margins of 0.5–1.0 cm. Treatment doses ranged from 50 to 60 (median, 54) Gy. 2.6. Statistical analysis Statistical analyzes were performed with the Statistical Package for Social Sciences (vers. 11.0, SPSS, Chicago, IL, USA). The Pearson chi-squared test and Student’s t-test were used to compare the data. Pearson
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correlation analysis or two-tailed Fisher’s exact test was applied. Differences were considered statistically significant at the p < 0.05 level. 3. Results 3.1. Patient characteristics Characteristics of the craniopharyngioma subjects are shown in Table 1. Patients consisted of 26 females (39.4%) and 40 males (60.6%). The mean age at onset was 8.02 (standard deviation (SD), 4.28; median, 7.0; range, 1.42–17.58) years. Tumor location included 27 patients (40.9%) in Group One and 39 patients (59.1%) in Group Two. Thirteen patients were at the age of puberty (P13 years in girls and P14 years in boys). There were no statistical differences in patient characteristics between groups one and two. 3.2. Clinical features There were 15 patients (55.6%) in Group One (intrasellar tumors) who presented with vision problems as the first symptom. There was a significant difference in the two locations (p = 0.001, Table 2). However, 20 patients (51.3%) in Group Two (third ventricle floor tumors) presented with increased intracranial pressure as the first symptom (p = 0.318). Fifteen cases (22.7%) had variable degrees of hyponatremia in the early postoperative period. Serum sodium levels were below 130 mEq/l during 1–8 days after the operation, lasting 3–5 days. Nine patients (13.6%) were diagnosed as having cerebral salt wasting syndrome. There was no significant difference in early postoperative hyponatremia between the different tumor locations. In the pituitary endocrine evaluation, patients were labeled with a number from 1 to 5, which indicated how many kinds of hormone deficiency they experienced. The results of the two groups were compared. Group One patients required more forms of hormone replacement than in the Group Two patients postoperatively (3.27 vs 2.72, p = 0.018, t-test) and at the last visit
Table 2 Initial presentation (first or major symptom) by the location of the craniopharyngioma First symptom
Intrasellar Number
Percentage
Number
Third ventricular Percentage
p value
Vision Endocrine IICP Othersb Total
15 2 10 0 27
55.6 7.4 37.0 0 100
6 8 20 5 39
15.4 20.5 51.3 12.8 100
0.001a 0.180 0.318 0.073
IICP, increased intracranial pressure (headache, nausea, vomiting). a p < 0.05. b Others including unsteady gait, facial palsy, hemiparesis, incontinence and hand tremor.
(2.92 vs 2.3, p = 0.020, t-test). Furthermore, we not only compared the two groups in terms of preoperative, postoperative, and last follow-up hormone (growth hormone, corticotrophin, thyrotrophin, gonadotrophin, and vasopressin) deficiencies (Table 3) but also compared the two groups in terms of changes in the hormone deficiencies postoperatively and preoperatively, and of the last visit with preoperative and postoperative levels. There were no significant differences between these two groups in terms of changes in hormone insufficiency. Hypothyroidism was more prevalent in Group One patients than in Group Two patients pre- and postoperatively (p = 0.039 and p = 0.009, respectively). And more Group One patients needed cortisone supplements than did Group Two patients at the last visit (p = 0.016). There were no significant differences between the anterior and posterior pituitary functions in these two groups. The two groups showed no differences in body weight, body height, or the body mass index preoperatively and postoperatively. In the longterm follow-up, obese and overweight patients were more prevalent with third ventricle floor tumors than with intrasellar tumors (4.2% vs 27.0%, p = 0.038, Table 4). We divided these patients into four subgroups based on treatment (only surgery, surgery plus radiation, surgery plus gamma knife radiation, and surgery plus radi-
Table 1 Characteristics of patients by the location of the craniopharyngioma
Table 3 Pituitary hormone replacement in children by location of the craniopharyngioma
Characteristic
Hormone replace
Intrasellar
Third ventricular
Total
Patients All Valuable
32 (43.8%) 27 (40.9%)
41 (56.1%) 39 (59.1%)
73 66
Age (years) Mean (SD)
7.35 (3.56)
8.35 (4.73)
8.02 (4.28)
Gender Male Female
17 (63.0%) 10 (37.0%)
23 (59.0%) 16 (41.0%)
40 26
At puberty
3 (11.1%)
10 (25.6%)
13
Growth hormone Sex hormone Thyroxin Cortisone Vasopressin
Intrasellar (%)
Third ventricular (%)
Pre
Post
Last
Pre
Post
Last
38.5 7.7 38.5a 15.4 23.1
46.2 7.7 96.3b 86.4 88.5
29.2 16.7 95.8 79.2c 70.8
31.4 8.6 14.3a 5.7 14.3
28.2 12.9 76.9b 69.2 84.6
27.0 10.8 81.1 45.9c 64.9
Pre, preoperative; Post, postoperative; Last, last visit. a p = 0.039. b p = 0.009. c p = 0.016
Y.-Y. Lee et al. / Brain & Development 30 (2008) 189–194 Table 4 Overweight status and obesity in children by location of the craniopharyngioma Intrasellar (%) Pre Overweight Obese a
11.1 7.4
Post 11.1 7.4
Third ventricular (%) Last a
4.2 4.2a
Pre
Post
Last
15.4 5.1
17.9 23.1
27.0a 27.0a
p = 0.038; p < 0.05.
ation and gamma knife radiosurgery). However, no statistical differences in treatment and recurrence rates were found between the two locations. 3.3. Other complications Some patients had other complications that persisted during long-term follow-up. Five cases had hepatic disorder including fatty liver, ALT elevation, common biliary duct stone and gallstone, and liver cirrhosis. One female died of hepatopulmonary syndrome with hypoxia 11 years later. She had liver cirrhosis and esophageal varices. One boy had diabetes mellitus during the follow-up period (10 years). All of these were Group Two patients. Twelve children suffered from hyperlipidemia, eight of whom were in the third ventricle floor tumor group. In the same group, one patient suffered from intracranial hemorrhage and another had a transient infarction accident. The results revealed that Group Two patients were at risk of long-term complications. Two patients had severe neurological sequelae which became cerebral palsy with epilepsy. One girl revealed an anaplastic astrocytoma after 7 years of treatment. Two boys were diagnosed as having moyamoya syndrome 3 and 4 years after radiotherapy, respectively. 4. Discussion The presentation of a craniopharyngioma varies with the size, location, and extension of the tumor [7]. Our review report also revealed the same results. Significant differences were found in non-endocrine symptoms between the two groups in our study. The complaints were usually non-endocrine-related, with headaches and vomiting with third ventricle floor tumors and visual disturbances with intrasellar tumors being the most common. The reason that our subjects had higher rates of hypothyroidism postoperatively and more intrasellar location patients required cortisone replacement was also associated with these patients having more prevalent hypopituitarism. Group One patients required three forms and Group Two required two forms of hormone supplements. These results are compatible with the anatomy of the sellar region.
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Dysfunction of the hypothalamic–pituitary system can be due either to the tumor itself or to the type of treatment [8,9]. The choice of treatment should depend on various aspects: the volume and location of the mass, the adjacent structures, and quality of life considerations. Gonc et al. [10] observed that neither radiotherapy nor extent of tumor removal – either total or subtotal – influenced the endocrinological outcome. In our series, we observed no change in the frequency of hypothalamopituitary axis dysfunction with regard to the treatment. Thus, these data suggest that different tumor locations may affect the endocrinological presentation and outcome. Approximately one-third (33.4%) of Group Two (third ventricle floor tumors) patients were morbidly overweight and obese. This occurred after injury to the ventromedial area (the so-called ‘‘satiety center’’), leading to hyperphagia [11]. Pathological studies have demonstrated that on a microscopic level, there is interdigitation of the tumor capsule with parenchyma in the wall of the third ventricle [12,13]. It is possible that a craniopharyngioma in the third ventricle floor can more easily injure the hypothalamus. A recent study [14] reported an increased prevalence of features of metabolic syndrome in childhood craniopharyngiomas. This might be a result of hypothalamic damage causing obesity and GH deficiency [14]. We had five cases which suffered from hepatic disorder, and one female died due to hepatopulmonary syndrome. Eight patients had hyperlipidemia, nine had uric acid elevation, and one boy had diabetes mellitus during the follow-up period. Patients with hypothalamic and/or pituitary disease are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of nonalcoholic fatty liver disease (NAFLD) [15]. NAFLD is determined by a liver biopsy or by fatty infiltration on image studies in association with abnormal liver enzymes [15]. Patients were excluded if they had a secondary cause of NAFLD [15]. Four of five patients in this study were compatible with that diagnosis. It is essential to identify these patients as they are at risk of metabolic syndromes and increased morbidity or mortality. Our study was limited by having an insufficiently long follow-up duration to compare the incidence of metabolic syndrome with the general population. These observations imply that dedicated long-term follow-up of these patients especially in Group Two is required. There were two boys in our series who presented with excessive growth after treatment. Deficiencies in thyrotropin, corticotropin, gonadotropins, and growth hormone were confirmed in these boys. Both of them were given cortisone, thyroxine, and desmopressin replacement therapy. One of them had used growth hormone for 4 months, but tumor recurrence was found. So he received no growth hormone supplementation after the second surgery. These patients presented an interest-
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ing combination of hypopituitarism and excessive growth. The condition between the absence of growth hormone in the patients’ serum and clinical presentation of a tall stature is difficult to explain. Normal statural growth in the absence of a growth hormone secretory response to stimuli has been demonstrated in children after surgically induced hypopituitarism for a craniopharyngioma [16,17]. It is possible that his growth hormone reserve was insufficient to be detected by our assay but was large enough to allow him to grow. So the question arises: Does the serum growth hormone which we detect truly represent the biologically active hormone [18]? Another possible explanation of this situation is there are other factors which we do not know about which influence growth. The growth factor may be secreted by the tumor or by ectopic neurohypophysis. 5. Conclusions We concluded that different tumor locations seem to influence the behavior of craniopharyngiomas in children. At presentation, the prevalence of complaints in craniopharyngiomas differed between Group One (intrasellar tumors) and Group Two (third ventricle floor tumors) patients. Children with intrasellar craniopharyngiomas reported more prevalent visual complaints and endocrinopathies before surgery. Endocrine complications, particularly hypothyroidism postoperatively and long-term cortisone replacement, were more prevalent among patients with intrasellar tumors. Our observations also indicate that third ventricle floor craniopharyngiomas are more prevalent in raising intracranial pressure at presentation and in weight gain during long-term follow-up. Damage to the hypothalamus should be considered in these patients. The presence of obesity and hepatic disorders in patients with third ventricle floor craniopharyngiomas is associated with increased morbidity and mortality. Prospective studies are necessary to determine better management practices for those patients likely to be at risk of metabolic syndromes and nonalcoholic fatty liver disease.
Acknowledgment We thank the research program of Taipei Veterans General Hospital (V95A-064) for support of this study.
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