Abstract
Background
Craniopharyngioma tumors and their treatment can lead to significant long-term morbidity due to their proximity to vital structures. The optimal treatment has been debated for many years. We aimed to review the long-term outcomes of children treated for craniopharyngioma in our institution over the past decade and describe trends in treatment and outcomes over the past 3 decades.
Methods
Charts of children with craniopharyngioma treated and followed at The Hospital for Sick Children between 2001 and 2011 were reviewed. Data regarding findings at diagnosis, treatment, and long-term outcomes were analyzed. Comparison was made with previously published data from our institution.
Results
Data from 33 patients are included; mean age at treatment, 10.7 ± 4.8 years. In 18 children (55%), the initial surgical approach was tumor cyst decompression with or without adjuvant therapy, compared with only 0–2% in the preceding decades (P < .01). Diabetes insipidus occurred in 55% of children and panhypopituitarism in 58% compared with 88% (P < .01) and 86% (P < .01), respectively, in the previous 10 years. Overall, there was a 36% reduction in the number of children who developed severe obesity compared with the preceding decade. Body mass index at follow-up was associated with body mass index at diagnosis (P = .004) and tumor resection as an initial treatment approach (P = .028).
Conclusions
A shift in surgical treatment approach away from gross total resection has led to improved endocrine outcomes. This may have beneficial implications for quality of life in survivors.
Keywords: craniopharyngioma, hypothalamic obesity, interferon alpha, intracystic chemotherapy, pediatrics
The optimal treatment approach for craniopharyngioma tumors has been subject to debate for many years. Benign tumor histology and high survival rates were the bases supporting complete resection as the method of choice in the past.1–5 This approach was targeted at achieving cure; however, the tumor's proximity to vital structures such as the optic chiasm and the hypothalamus poses a major challenge to achieving this goal. Extensive surgeries resulted in multiple long-term complications6–8 and significant recurrence rates.9,10 Neurocognitive, pituitary, and hypothalamic dysfunction are prevalent in series using primarily gross total resection (GTR).1,2,4 In recent years, less invasive surgical approaches have gained acceptance, along with wider use of adjuvant treatments. Advancements in radiation technology as well as in chemotherapy methods and medications have led to a number of potential adjuvant treatments, including instillation of chemotherapy via an Ommaya reservoir.11–13 This has led to a shift in treatment perspective with consideration of craniopharyngioma as a chronic condition, with primary goals being reduction of long-term morbidity and improvement in quality of life. At the same time, a more individualized treatment approach is being adopted in many centers, tailoring treatment to the specific characteristics of the patient and the tumor.14 This leads to the question of whether clinical outcomes have improved with shift of therapy. Accordingly, in this report we aim to (i) review the treatment modalities used and the long-term outcomes (pituitary hormone deficiencies, obesity, tumor regrowth) of pediatric patients with craniopharyngioma tumors treated in our institution over the last decade and (ii) compare these outcomes with results based on previously published data from our institution.1,15 We hypothesized that a decreased rate of pituitary hormone deficiencies and obesity will accompany the change in the treatment approach.
Materials and Methods
Data Collection
Charts of children with craniopharyngioma who had primary tumor treatment between October 2001 and October 2011 and who subsequently continued follow-up for at least 6 months at our institution were reviewed to ensure no overlap with previously published data.15 Patients for whom data regarding presentation, treatment, or follow-up were not available were excluded. The study was approved by the Research Board of Ethics at The Hospital for Sick Children, Toronto, Canada. All patients had histologically confirmed craniopharyngioma.
The following information was obtained from the medical record: gender, age at diagnosis, presenting symptoms and findings, anthropometrics at diagnosis, tumor characteristics, treatment modalities, and outcomes, including pituitary hormone deficiencies, obesity, recurrence, and survival.
Tumor Characteristics
Images of the brain were independently reviewed by a neuroradiologist (H.B.). Where possible, brain MR and CT images were reviewed; for 1 patient who had only CT, this was reviewed. Two imaging series were assessed for each patient: the series taken at diagnosis and the series taken at the last follow-up. From the former, data were collected for tumor size and appearance (solid or cystic), the presence of hydrocephalus and/or calcifications, and the grade of hypothalamic involvement. From the latter, the grade of hypothalamic involvement was assessed. Tumor size was classified based on the largest diameter present: small (≤2 cm), medium (2.1–4 cm), large (4.1–6 cm), and very large (>6 cm).10 Hypothalamic involvement was classified using the grading system suggested by Müller et al.16 Grade 0 included tumors with no hypothalamic involvement/lesion. Grade 1 included tumors with involvement of the anterior hypothalamus, the region posterior to the stalk and anterior to the mammillary bodies. Grade 2 included tumors with hypothalamic involvement of the anterior and posterior hypothalamic area, involving the mammillary bodies and the area beyond the mammillary bodies. Displacement of the mammillary bodies was not considered as involvement.
Pituitary Hormone Deficiencies
Outcome definitions of deficiencies of thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and antidiuretic hormone (ADH) were determined based on a specific diagnosis recorded in the chart or replacement treatment at the time of the review. Growth hormone (GH) deficiency was based on (i) GH replacement at any time, (ii) a combination of linear growth failure and a low level of insulin-like growth factor 1, or (iii) GH peak <8 μg/L on 2 provocative GH stimulation tests. Anterior panhypopituitarism was considered if there was deficiency of 5 anterior pituitary hormones (GH, TSH, ACTH, LH, and FSH) or deficiency of TSH, ACTH, and GH in a prepubertal child.
Obesity Definitions
Based on the World Health Organization growth references and definitions, overweight and obesity were defined as body mass index (BMI) >1 and 2 SD scores above the mean for age and gender (BMI z-score), respectively.17 Severe obesity was defined as a BMI z-score >4.
Craniopharyngioma Treatment
Surgical treatment was classified as GTR when resection resulted in no tumor residual on postoperative imaging, as partial resection (PR) for any smaller degree of resection, or as tumor decompression for a procedure that was aimed primarily at decompressing a cystic tumor, usually with biopsy. Adjuvant treatment options were radiation or intracystic chemotherapy (ICC). In order to simplify matters, as only a minority of children were treated with GTR, we referred to either tumor regrowth or recurrence as “regrowth.” Patients were considered to have tumor regrowth when they became symptomatic to require recurrent treatment that was not part of the original treatment protocol or when an increase in tumor size was detected.
Long-term Trends in a Single Institution
Data published in the past from our institution through 1975–19891 and 1990–200115 allowed review of treatment approaches and outcomes over time. The prevalence of the different treatment modalities and outcomes were compared among the 3 time periods of 1975–1989,1 1990–2001,15, and 2001–2011.
Statistical Analysis
Statistical analysis was performed using Statistical Package for Social Sciences version 19.0 software. Continuous variables are expressed as mean ± SD or mean (range). Categorical variables are expressed as frequencies and proportions. Linear regression analysis was performed to assess relations between BMI z-score at last follow-up and several exposure variables chosen based on the literature in order to identify specific risk factors. These included age at diagnosis, gender, BMI z-score at diagnosis, tumor size, hydrocephalus pre-op, hypothalamic involvement pre- and posttreatment, treatment modality, radiation at any time, GH deficiency, and tumor regrowth. t-Tests or chi-square tests were performed to evaluate associations between tumor regrowth and these specific risk factors. Results were considered statistically significant at P ≤ .05. The prevalences of treatment approaches and outcomes (pituitary hormone deficiencies, obesity, and tumor regrowth) among the 3 time periods were compared using chi-square tests.
Results
Patient Characteristics
Thirty-three pediatric patients (15 females) met the inclusion criteria and are presented in this analysis (see Table 1). Mean age at diagnosis was 10.7 years (range, 2–17.2), with a bimodal distribution of peaks noted between 5 and 15 years of age. Mean follow-up period was 4.0 years (range 0.7–9.3). Two patients were excluded from the study due to insufficient data regarding their clinical presentation and initial treatment and/or follow-up. Groups were similar in terms of age at diagnosis, duration of follow-up, or gender distribution.
Table 1.
Baseline patient and tumor characteristics
| 2001–2011 | 1990–2001 | 1975–1989 | |
|---|---|---|---|
| Patient number | 33 | 43 | 50 |
| Mean age, y (range) | 10.7 (2.0–17.2) | 8.5 (2.8–16.1) | 9.4 (1.8–17.6) |
| Mean follow-up duration, y (mean) | 4.0 (0.7–9.3) | 4.7 (0.25–10) | 4.9 (1–14) |
| Female n (%) | 15 (45) | 24 (56) | 22 (44) |
| Mean largest diameter | 4.9 (2.2,12.6) | ||
| Small | 0 (0) | 2 (5) | |
| Medium | 15 (45)c | 8 (21)c | |
| Large | 10 (30) | 29 (74) | |
| Very large | 8 (24) | ||
| Calcifications | 32 (97) | 50 (100) | |
| Hydrocephalus | 22 (67)b | 28/39 (72)a | 24 (48)ab |
| Cystic component | 32 (97)c | 15/39 (38)ac | 40 (80)a |
| Grade 0 | 2 (6) | 3/39 (8) | 2 (4) sellar |
| Grade 1 | 6 (18) | 36/39 (92) hypothalamic deformity | 25 (50%) prechiasmatic |
| Grade 2 | 25 (76) | 23 (46%) retrochiasmatic |
Continuous data are presented as mean (range), categorical variables are presented as number of patients (percent). Tumor grading methods differed among periods: 1990–2001, tumors were categorized based on whether any hypothalamic deformity was seen on imaging; 1975–1989, tumors were categorized as sellar, prechiasmatic, or retrochiasmatic.
aDifference between first and second time periods, P < .05.
bDifference between first and third time periods, P < .05.
cDifference between second and third time periods, P < .05.
Clinical Presentation and Tumor Characteristics at Diagnosis of Craniopharyngioma
Clinical presentation
The most prevalent presenting features were neurologic—of these, headaches were the most common, followed by visual disturbances (Table 2). Prior to treatment, 21% children were obese and none had a BMI z-score >4. Of the pituitary hormone deficiencies, the most prevalent at diagnosis were of GH, LH, and FSH, followed by diabetes insipidus (DI). No other pituitary hormone deficiencies were diagnosed at presentation. Obesity rates at tumor diagnosis did not differ significantly among time periods. The prevalences of DI and hypothyroidism at diagnosis were higher between 1975 and 1989 compared with the most recent decade.
Table 2.
Prevalence of clinical findings at tumor diagnosis
| Presenting finding n (%) | 2001–2011 | 1990–2001 | 1975–1989 |
|---|---|---|---|
| Neurologic | |||
| Headache | 28 (85) | 32 (74) | 34 (68) |
| Visual | 25 (76) | 34 (79)a | 29 (58)a |
| Nausea/vomiting | 14 (42) | 7 (16) | |
| Weight related | |||
| Obesity/weight gain | 7 (21) | 8 (19) | 9 (18) |
| Weight loss | 5 (15) | 5 (12) | |
| Pituitary hormonal deficiency/imbalance | |||
| Growth hormone/short stature | 8 (24) | 11 (26) | 20 (40) |
| LH, FSH | 7 (21) | 4 (9) | 7 (14) |
| ADH | 2 (6)b | 4 (9) | 12 (24)b |
| TSH | 0b | 4 (9) | 7 (14)b |
| Precocious puberty | 0 | 0 | 1 (2) |
| ACTH | 0 | 1 (2) | 0 |
| Any pituitary imbalance | 11 (37)b | 14 (33)a | 33 (66)a,b |
aDifference between first and second time periods, P < .05.
bDifference between first and third time periods, P < .05.
cDifference between second and third time periods, P < .05.
Tumor characteristics
Mean size at largest diameter was 4.9 cm (range, 2.2–12.6; Table 1). None of the tumors were classified as small, and over half were large or very large. The vast majority (97%) were cystic and had calcifications identified within the tumor. The majority (94%) demonstrated some degree of hypothalamic involvement. In the period 1975–1989, tumors were classified as sellar, prechiasmatic, or retrochiasmatic; and in the period 1990–2001, classification was based on whether any hypothalamic deformity was detected on imaging. There was no significant difference among the time periods in the proportion of tumors that were categorized as not involving the hypothalamus or as being sellar only.
Craniopharyngioma Treatment
Initial treatment
Eighteen children were treated with cyst decompression, without tumor resection (Table 3). Decompression options included insertion of a drain that was then connected to an Ommaya reservoir (n = 10), fenestration of the tumor cyst (n = 2), transsphenoidal aspiration (n = 1), or a combination of fenestration and either an Ommaya, an external ventricular drain, or a ventriculoperitoneal shunt (n = 7). Biopsies were taken at the time of decompression. Adjuvant treatment included radiation or ICC with either bleomycin or interferon-α. Both agents impair the function of the cyst cell lining to induce cyst shrinkage and potentially cyst wall collapse. Due to our experience of bleomycin-associated neurotoxicity,18 intracystic treatment with this medication was discontinued in 2005. Bleomycin was replaced with intracystic interferon-α, a nonneurotoxic agent, based on early reports by a Brazilian group.18 When used, radiation treatment included a total dose of 5400 cGy divided in 30 fractions. The choice of a treatment modality for individual patients was made by the neurosurgery and neuro-oncology specialists. Among the factors considered were the tumor size, location, and appearance, as well as the child's age, symptoms, and pituitary involvement. When possible, a minimally invasive surgical procedure was preferred and radiation was avoided, especially in children younger than 10 years and in patients with preserved pituitary function.
Table 3.
Craniopharyngioma treatment modality—data regarding initial treatment and treatment for tumor regrowth
| 2001–2011, |
1990–2001, | 1975–1989, | ||||
|---|---|---|---|---|---|---|
| Initial treatment |
n (%) | n (%) | n (%) | |||
| Cyst decompression (CD) | Decompression | 9 (27) | 0 | 0 | ||
| CD and radiation | 4 (12) | |||||
| CD and ICC | 7 (21)b,c | 1 (2)c | ||||
| PR | Partial resection | 6 (18) | 5 (12) | 5 (10) | ||
| PR and radiation | 3 (9) | 0 | 0 | |||
| GTR | 4 (12) | 37 (86) | 45 (90) | |||
| Regrowth/recurrence | 17 (52) | 13 (30) | 17 (34) | |||
| Treatment for regrowth | 1st | 2nd | 1st | 2nd | ||
| CD | Decompression | 5 (15) | 4 (12) | NA | ||
| CD and radiation | 0 | 1 (3) | ||||
| ICC | 0 | 1 (3) | ||||
| Partial resection | 5 (15) | 1 (3) | 5 | |||
| Radiation | 3 (9) | 1 (3) | 1 | 5 | ||
| PR and radiation | 2 (6) | 0 | 8 | |||
| GTR | 0 | 0 | 5 | 3 | ||
| Radiation at any time | 14 (42)c | 4 (9)a,c | 14 (28)a | |||
Cyst decompression (CD) options include insertion of a drain that was then connected to an Ommaya reservoir, cyst fenestration, transsphenoidal aspiration, or a combination of fenestration and either an Ommaya, an external ventricular drain, or a ventriculoperitoneal shunt.
ICC 2001–2011: of 8 patients, 4 received bleomycin and 4 interferon. In 1990–2001, intracystic bleomycin was given to 1 patient.
aDifference between first and second time periods, P < .05.
bDifference between first and third time periods, P < .05.
cDifference between second and third time periods, P < .05.
NA, data not available.
In total, 14 (42%) patients received radiation treatment and 8 (24%) received ICC at some time point during follow-up. ICC included bleomycin in 4 patients and interferon-α in 4. Interferon was given to 3 patients as part of the initial course of treatment. Of these patients, 2 did not experience recurrence during study follow-ups of 20 and 28 months. The third patient required cyst fluid drainage 2 months post–interferon treatment and then no further intervention during 41 months of study follow-up. These patients had a normal BMI z-score at the end of follow-up ranging between 0.2 and 0.5. The patient with recurrence was initially treated with cyst drainage alone, then received interferon for recurrence, with the last dose being 2 months before data collection ended.
Long-term Outcomes
Tumor regrowth
Regrowth occurred in 17 (52%) patients (Table 4). Median time from initial treatment to regrowth was 11.5 months (range, 1.9–46). Of the 4 patients initially presumed to have a GTR, 2 required a second surgery. Two out of 7 patients treated initially with radiation experienced regrowth that was treated by drainage in one case and partial resection in the other. Four out of 7 patients treated initially with ICC experienced regrowth that was treated by drainage in 3 cases and PR in another. Eight patients (24%) had >1 episode of regrowth requiring treatment; of these, 4 responded to cyst decompression as the sole intervention. Regrowth was associated with younger age at diagnosis—mean 8.7 years compared with 12.8 years (P = .007)—and with the degree of hypothalamic involvement at last follow-up (P = .005). All but 1 patient in this cohort had evidence of tumor residual at the last follow-up.
Table 4.
Long-term pituitary deficits and obesity at diagnosis and following craniopharyngioma treatment
| n (%) | 2001–2011 |
1990–2001 |
1975–1989 |
|||
|---|---|---|---|---|---|---|
| Diagnosis | Last follow-up | Diagnosis | Last follow-up | Diagnosis | Last follow-up | |
| Pituitary deficiency/abnormality | ||||||
| Growth hormone/short stature | 8 (24) | 28 (85) | 11 (26) | 14 (33) | 20 (40) | 9 (20) treated with GH |
| LH, FSH | 7 (21) | 20 (61) | 4 (9) | NA | 7 (14) | 14 (30) |
| ADH | 2 (6) | 18 (55) | 4 (9) | 38 (88) | 12 (24) | 43 (93) |
| TSH | 0 | 24 (73) | 4 (9) | NA | 7 (14) | 38 (83) |
| Precocious puberty | 0 | 0 | 0 | 0 | 1 (2) | 0 |
| ACTH | 0 | 21 (64) | 1 (2) | 41 (95) | 0 | 41 (89) |
| Any pituitary deficiency | 11 (37) | 29 (88) | 14 (33) | 41 (95) | 33 (66) | 46 (100) |
| Anterior panhypopituitarism | 19 (58) | 37 (86) | NA | |||
| Obesity/weight gain | 7 (21) | 19 (58) | 8 (19) | 28 (65) | 9 (18) | 24 (52) |
| Severe obesity | 4 (12) | 8 (19) | ||||
| Weight loss | 5 (15) | 5 (12) | ||||
Obesity, BMI z-score >2; severe obesity, BMI z-score >4; NA, data not available.
Survival
Survival rate in this series was 97%. One patient died 5.1 years after diagnosis. Autopsy failed to disclose a cause of death. The patient presented to the emergency department at another hospital with what appeared to be an acute infection and deteriorated rapidly, despite the use of stress steroid dosing at the onset of illness and upon arrival at the hospital.
Pituitary hormone deficiencies
Twenty-nine patients had at least 1 pituitary hormone deficiency at the last follow-up. The most prevalent deficiency was of GH, found in 28 (85%) patients; of which, 8 were preexisting deficiencies. This was followed by TSH deficiency in 24 (73%) and ACTH deficiency in 21 (64%), none of which existed prior to treatment. LH and FSH deficiencies were found in 20 (61%) patients; of which, 6 were preexisting, and 1 resolved after treatment. ADH deficiency was detected in 18 (55%) patients; of which, 2 were preexisting. The prevalence of anterior panhypopituitarism was 58%.
Obesity. At the last follow-up, obesity was detected in 19 patients—7 were obese at diagnosis, with severe obesity in 4; 2 cases were preexisting. Overall mean BMI z-score at diagnosis was 1.0 ± 1.2, and at last follow-up 2.3 ± 1.3. Of those with obesity at last follow-up, mean BMI z-score at diagnosis was 1.5 ± 0.9, and at last follow-up 3.2 ± 0.7. The most rapid weight gain was demonstrated in the first 9 months posttreatment (Fig. 1), and thereafter a milder increment in weight was evident. BMI z-score at the last follow-up was associated with the BMI z-score at diagnosis (r = 0.49, P = .004), and a weaker association was found with resection (either GTR or PR) as an initial treatment approach compared with decompression (r = 0.38, P = .028). Obesity or BMI z-score at last follow-up was not found to be associated with the grade of hypothalamic involvement either at diagnosis or at posttreatment.
Fig. 1.
BMI z-scores of all individuals at diagnosis and during up to 60 mo of follow-up, 2001–2011. A loess smoother is used to demonstrate the trend in BMI z-scores, increasing rapidly in the first 8.8 mo of treatment with later stabilization. A reference line demonstrates the change in trend.
Trends in Treatment Approach and Outcome, 1975–2011
Treatment approach
During the past decade, a significant reduction in the use of GTR has been accompanied by a small increment in the rate of PRs and a pronounced increment in the frequency of minimally invasive surgical approaches (Fig. 2, Table 3). The treatment strategy from 1975–1989 was extensive resection of tumors targeted at achieving cure, and disease recurrence/regrowth was treated by either another surgical procedure, radiation, or a combination of both. From 1990–2001, the approach shifted toward more conservative management, consisting of incomplete resections with or without radiation. ICC use has increased significantly from 0 in 1975–1990 to 1 patient receiving intracystic bleomycin in 1990–2001 and 8 patients receiving ICC either bleomycin or interferon-α in the most recent decade. Radiation treatment as part of the initial regimen increased from 0 in 1975–1990 and 1990–2001 to 7 patients (21%) in the most recent decade. Radiation as treatment for recurrence was used in 12/50 (24%) patients in 1975–1990, 4 patients (9%) in 1990–2001, and 7 patients (21%) in the most recent decade. Overall, use of any adjuvant treatment as part of the initial treatment regimen has increased from 0 to 2% and now 42%.
Fig. 2.
Prevalence of initial surgical treatment approach in the 3 time periods. Abbreviations: STR, subtotal resection; CD, cyst decompression. *significant difference between groups, P < .05; **significant difference between groups P < .01.
Fig. 3.
Prevalence of long-term pituitary deficiencies and obesity for the 3 time periods. Abbreviations: Ant panhypopit, anterior panhypopituitarism; obesity, BMI z-score >2; severe obesity, BMI z-score >4. **significant difference between groups, P < .01.
Regrowth/recurrence
Recurrence rates were not significantly different among the 3 time periods, shifting from 34% and 30% in the past to 52% in the last decade (P = .14).
Pituitary hormone deficiencies and obesity
Prevalence of pituitary hormone deficiency has decreased significantly, including both anterior panhypopituitarism and DI (Fig. 3). When comparing the change in prevalence of pituitary deficits between tumor diagnosis and last follow-up over the 3 time periods, the prevalence of DI and hypocortisolism increased more in the earlier groups (by 69% and 79% for DI, and 89% and 93% for ACTH deficiency) compared with the last decade (49% and 64%, respectively). The prevalence of obesity decreased by ∼10% and that of severe obesity by 36%; however, this is not statistically significant (P = .50 and P = .44, respectively). The change in prevalence of obesity from the time of diagnosis to last follow-up was 34% for the 1975–1989 cohort, 47% for the 1990–2001 cohort, and 37% for the last decade.
Discussion
Over the past 3 decades, in this tertiary care center, the treatment approach to craniopharyngioma has shifted from a goal of “curative” tumor resection to use of minimalistic surgery plus adjuvant treatment to reduce tumor symptoms. This change was accompanied by a decrease in pituitary hormone deficits at last follow-up without impairing survival rates or significantly increasing tumor progression rates.
First-line adjuvant therapies in our center have included radiation and ICC. Radiation has been reported to have favorable results in terms of tumor regrowth/recurrence; however, it may pose additional risk for significant long-term adverse effects such as decreased neurocognitive function and increased risk for secondary cancers.5,8,19 In contrast, intracystic instilled substances act locally and are targeted at destroying the secretive properties of the tumor cell lining to induce cyst shrinkage and wall collapse. This is a treatment option for patients with predominantly cystic tumors, as is often the case in pediatric craniopharyngioma. Intracystic bleomycin for the treatment of pediatric craniopharyngioma has been in use since 198520 and is usually well tolerated. However, it is a neurotoxic agent, and despite verification of appropriate catheter positioning, leakage into the brain parenchyma with associated morbidities and even mortality has been described.11,21,22 Due to this, in our practice, the use of intracystic bleomycin has been discontinued.18 Interferon-α presents a safer treatment option, with reduced complications and minimal side effects.12,23 While intrathecal and intraventricular administrations of interferon have been in use for many years for the treatment of infectious, inflammatory, and malignant conditions,24,25 intracystic treatment with this agent for craniopharyngioma is relatively new. The first report of its effectiveness in the pediatric population was published in 2005.26 Intraventricular interferon-α has been associated with transient arachnoiditis and chronic fatigue syndrome.25 Complications/toxicities described in pediatric craniopharyngioma patients are not common but include headaches, fever, fatigue, and arthralgias.12,26,27 Those symptoms are, however, mostly transient and wean off as therapy continues. Based on the reported experience, a standard of care protocol for intracystic interferon-α administration was developed at SickKids in Toronto.28 It is worthwhile noting that 3 patients were initially treated with decompression alone, with follow-up ranging between 8.5 and 38 months. This suggests that cyst drainage may postpone other treatments, potentially reducing hypothalamic and pituitary insufficiency rates during childhood, a critical time for growth and development.
Rates of tumor regrowth in this series are comparable to those reported in the literature, even with apparently complete tumor resection. Recurrence rates after GTR are reported to be around 36%29 and higher after incomplete resections, occurring in up to two thirds of patients.9,10 The present paper defined any reexpansion of the existing tumor cyst as recurrence. Therefore, the recurrence rate may seem higher, as different authors would not define increase in cyst sizes as recurrence. Those reexpansions of cyst can be treated by removal of cyst fluid using a preexisting drain. This can be done in the outpatient setting with fewer side effects and less interference with everyday routines compared with surgery or radiation. Pituitary hormone deficiencies after surgical treatment of craniopharyngioma have been reported to be present in 80–100% of patients, even with pituitary stalk preservation.2,9,30 We found a comparable rate of individual hormone deficiencies, with an encouraging finding being the significant reduction in the prevalence of panhypopituitarism at last follow-up.
Taking into consideration the great significance of morbidities such as hypopituitarism, hypothalamic dysfunction, and neurocognitive impairments that are prevalent in series using primarily GTR,2,4 and despite significant advancements in microsurgical techniques, a surgical approach individualized to the patient and tumor location is gaining acceptance. As seen in this series, the cystic nature of typical craniopharyngiomas in childhood facilitates cyst decompression with or without ICC as a less invasive treatment approach. Nevertheless, in cases where the tumor does not involve the hypothalamus and is located entirely within the sella or prechiasmatic area, an attempt for complete resection aimed at cure is reported to have beneficial results, particularly if panhypopituitarism is preexisting.10 For smaller, primarily intrasellar tumors, endoscopic transsphenoidal surgery can be performed.31 The endonasal approach provides good surgical access and visualization of the infrachiasmatic region and in recent years has been used in some centers for more complex supradiaphragmatic-infrachiasmatic tumors.32,33
Despite advancements in treatment and a reduction in pituitary complications, weight gain associated with craniopharyngioma, and particularly the rapid weight gain evidenced in the early posttreatment period, remains a major concern. This weight gain might be explained by extreme sensitivity of hypothalamic centers to any type of damage or manipulation, as well as a high prevalence of hypothalamic involvement at initial presentation. A nonsignificant reduction in obesity prevalence, particularly in the prevalence of severe obesity, was found among the time periods. Our ability to detect differences might be impaired by the relatively small number of patients, yet this could still represent a clinically important trend. Another noteworthy point is that the rates of obesity in the general pediatric population have been rapidly increasing over the past 3 decades—the prevalence of obesity in Canadian youth has tripled between 1978 and 2009.34 Given this background of increasing prevalence, a relatively stable prevalence of obesity in craniopharyngioma patients may actually represent a favorable trend over time.
Our study has several limitations. First, given the individualized approach to treatment, variables attributable to tumor and patient characteristics influence outcomes, making it difficult to separately analyze the effects of the treatment modality used. Second, given the rarity of the disease, we might have been underpowered to detect smaller differences in outcomes among the time periods. Lastly, due to the retrospective nature of this study, additional data not recorded in the medical record may have influenced our findings.
Optimal treatment strategies for pediatric craniopharyngioma patients have been unresolved for many years. Findings from this study provide support for a less aggressive surgical approach. Ongoing, prospective follow-up of larger patient populations will aid in determining differences among alternative treatment modalities. Standardization of definitions regarding tumor location and involvement of anatomical neighborhood structures as well as standardization of treatment approaches will enable more precise analysis and comparison of data between centers. Taken together, such approaches will enable further tailoring of treatment to reduce long-term adverse outcomes.
Conflict of interest statement. None declared.
References
- 1.Hoffman HJ, De Silva M, Humphreys RP, Drake JM, Smith ML, Blaser SI. Aggressive surgical management of craniopharyngiomas in children. J Neurosurg. 1992;76(1):47–52. doi: 10.3171/jns.1992.76.1.0047. [DOI] [PubMed] [Google Scholar]
- 2.De Vile CJ, Grant DB, Kendall BE, et al. Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted? J Neurosurg. 1996;85(1):73–81. doi: 10.3171/jns.1996.85.1.0073. [DOI] [PubMed] [Google Scholar]
- 3.Van Effenterre R, Boch AL. Craniopharyngioma in adults and children: a study of 122 surgical cases. J Neurosurg. 2002;97(1):3–11. doi: 10.3171/jns.2002.97.1.0003. [DOI] [PubMed] [Google Scholar]
- 4.Poretti A, Grotzer MA, Ribi K, Schonle E, Boltshauser E. Outcome of craniopharyngioma in children: long-term complications and quality of life. Dev Med Child Neurol. 2004;46(4):220–229. doi: 10.1017/s0012162204000374. [DOI] [PubMed] [Google Scholar]
- 5.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. Childs Nerv Syst. 2005;21(8–9):747–757. doi: 10.1007/s00381-005-1186-5. [DOI] [PubMed] [Google Scholar]
- 6.Crom DB, Smith D, Xiong Z, et al. Health status in long-term survivors of pediatric craniopharyngiomas. J Neurosci Nurs. 2010;42(6):323–328. doi: 10.1097/jnn.0b013e3181f8a59d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sughrue ME, Yang I, Kane AJ, et al. Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma. J Neurooncol. 2011;101(3):463–476. doi: 10.1007/s11060-010-0265-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Muller HL. Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. Horm Res. 2008;69(4):193–202. doi: 10.1159/000113019. [DOI] [PubMed] [Google Scholar]
- 9.Jung TY, Jung S, Moon KS, Kim IY, Kang SS, Kim JH. Endocrinological outcomes of pediatric craniopharyngiomas with anatomical pituitary stalk preservation: preliminary study. Pediatr Neurosurg. 2010;46(3):205–212. doi: 10.1159/000318426. [DOI] [PubMed] [Google Scholar]
- 10.Steno J, Bizik I, Steno A, Matejcik V. Craniopharyngiomas in children: how radical should the surgeon be? Childs Nerv Syst. 2011;27(1):41–54. doi: 10.1007/s00381-010-1330-8. [DOI] [PubMed] [Google Scholar]
- 11.Hukin J, Steinbok P, Lafay-Cousin L, et al. Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience. Cancer. 2007;109(10):2124–2131. doi: 10.1002/cncr.22633. [DOI] [PubMed] [Google Scholar]
- 12.Cavalheiro S, Di Rocco C, Valenzuela S, et al. Craniopharyngiomas: intratumoral chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases. Neurosurg Focus. 2010;28(4):E12. doi: 10.3171/2010.1.FOCUS09310. [DOI] [PubMed] [Google Scholar]
- 13.Stripp DC, Maity A, Janss AJ, et al. Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults. Int J Radiat Oncol Biol Phys. 2004;58(3):714–720. doi: 10.1016/S0360-3016(03)01570-0. [DOI] [PubMed] [Google Scholar]
- 14.Puget S, Garnett M, Wray A, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. 2007;106(1 Suppl):3–12. doi: 10.3171/ped.2007.106.1.3. [DOI] [PubMed] [Google Scholar]
- 15.Ahmet A, Blaser S, Stephens D, Guger S, Rutkas JT, Hamilton J. Weight gain in craniopharyngioma—a model for hypothalamic obesity. J Pediatr Endocrinol Metab. 2006;19(2):121–127. doi: 10.1515/jpem.2006.19.2.121. [DOI] [PubMed] [Google Scholar]
- 16.Müller HL, Gebhardt U, Teske C, et al. Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol. 2011;165(1):17–24. doi: 10.1530/EJE-11-0158. [DOI] [PubMed] [Google Scholar]
- 17.World Health Organization. Growth reference 5–19 years. 2012 http://www.who.int/growthref/who2007_bmi_for_age/en/index.html. Accessed February 5, 2013. [Google Scholar]
- 18.Lafay-Cousin L, Bartels U, Raybaud C, et al. Neuroradiological findings of bleomycin leakage in cystic craniopharyngioma. Report of three cases. J Neurosurg. 2007;107(4 Suppl):318–323. doi: 10.3171/PED-07/10/318. [DOI] [PubMed] [Google Scholar]
- 19.Kiehna EN, Merchant TE. Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus. 2010;28(4):E10. doi: 10.3171/2010.1.FOCUS09297. [DOI] [PubMed] [Google Scholar]
- 20.Takahashi H, Nakazawa S, Shimura T. Evaluation of postoperative intratumoral injection of bleomycin for craniopharyngioma in children. J Neurosurg. 1985;62(1):120–127. doi: 10.3171/jns.1985.62.1.0120. [DOI] [PubMed] [Google Scholar]
- 21.Jiang R, Liu Z, Zhu C. Preliminary exploration of the clinical effect of bleomycin on craniopharyngiomas. Stereotact Funct Neurosurg. 2002;78(2):84–94. doi: 10.1159/000068014. [DOI] [PubMed] [Google Scholar]
- 22.Park DH, Park JY, Kim JH, et al. Outcome of postoperative intratumoral bleomycin injection for cystic craniopharyngioma. J Korean Med Sci. 2002;17(2):254–259. doi: 10.3346/jkms.2002.17.2.254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Steinbok P, Hukin J. Intracystic treatments for craniopharyngioma. Neurosurg Focus. 2010;28(4):E13. doi: 10.3171/2010.1.FOCUS09315. [DOI] [PubMed] [Google Scholar]
- 24.Maimone D, Grimaldi LM, Incorpora G, et al. Intrathecal interferon in subacute sclerosing panencephalitis. Acta Neurol Scand. 1988;78(3):161–166. doi: 10.1111/j.1600-0404.1988.tb03639.x. [DOI] [PubMed] [Google Scholar]
- 25.Chamberlain MC. A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis. Cancer. 2002;94(10):2675–2680. doi: 10.1002/cncr.10547. [DOI] [PubMed] [Google Scholar]
- 26.Cavalheiro S, Dastoli PA, Silva NS, Toledo S, Lederman H, da Silva MC. Use of interferon alpha in intratumoral chemotherapy for cystic craniopharyngioma. Childs Nerv Syst. 2005;21(8–9):719–724. doi: 10.1007/s00381-005-1226-1. [DOI] [PubMed] [Google Scholar]
- 27.Ierardi DF, Fernandes MJ, Silva IR, et al. Apoptosis in alpha interferon (IFN-alpha) intratumoral chemotherapy for cystic craniopharyngiomas. Childs Nerv Syst. 2007;23(9):1041–1046. doi: 10.1007/s00381-007-0409-3. [DOI] [PubMed] [Google Scholar]
- 28.Bartels U, Laperriere N, Bouffet E, Drake J. Intracystic therapies for cystic craniopharyngioma in childhood. Front Endocrinol (Lausanne) 2012;3:39. doi: 10.3389/fendo.2012.00039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Elliott RE, Wisoff JH. Surgical management of giant pediatric craniopharyngiomas. J Neurosurg Pediatr. 2010;6(5):403–416. doi: 10.3171/2010.8.PEDS09385. [DOI] [PubMed] [Google Scholar]
- 30.Merchant TE, Kiehna EN, Sanford RA, et al. Craniopharyngioma: the St. Jude Children's Research Hospital experience 1984–2001. Int J Radiat Oncol Biol Phys. 2002;53(3):533–542. doi: 10.1016/s0360-3016(02)02799-2. [DOI] [PubMed] [Google Scholar]
- 31.Elliott RE, Jane JA, Jr., Wisoff JH. Surgical management of craniopharyngiomas in children: meta-analysis and comparison of transcranial and transsphenoidal approaches. Neurosurgery. 2011;69(3):630–643. doi: 10.1227/NEU.0b013e31821a872d. [DOI] [PubMed] [Google Scholar]
- 32.Flitsch J, Müller HL, Burkhardt T. Surgical strategies in childhood craniopharyngioma. Front Endocrinol (Lausanne) 2011;2:96. doi: 10.3389/fendo.2011.00096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Fernandez-Miranda JC, Gardner PA, Snyderman CH, et al. Craniopharyngioma: a pathologic, clinical, and surgical review. Head and Neck. 2012;34(7):1036–1044. doi: 10.1002/hed.21771. [DOI] [PubMed] [Google Scholar]
- 34.Obesity in Canada. Prevalence among children and youth. http://www.phac-aspc.gc.ca/hp-ps/hl-mvs/oic-oac/chi-jeu-eng.php. Accessed February 5, 2013. [Google Scholar]