Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effect of treatment in 42 patients

728

November 1980 The J o u r n a l o f P E D I A T R I C S

Endocrine and neurologic outcome in childhood craniopharyngioma." Review of effect of treatment in 42 patients Forty-two cases of craniopharyngioma in children are reviewed. Only 9.5% had sought medical attention because of symptoms suggesting hormonal deficit," however, growth retardation was present in 53% and growth hormone deficiency was documented in 72% before treatment. Multiple hypothalamic-pituitary hormone deficiencies were present in all patients after treatment. Eleven percent had normal skull radiographs at presentation; pneumoencephalograms and computed tomographic brain scans were abnormal on every occasion on which the); were performed Recurrence and mortality rates as well as the neurologic outcome o f survivors were similar in children treated by radical excision and those treated by limited excision plus radiotherapy. The neurologic prognosis was poorest in those children who had limited excision or drainage without radiotherapy. Additional hypothalamic-pituitary dysfunction following treatment was less common in children who had limited excision plus radiotherapy than in children who had either limited excision or attempted total removal. Unless gross total tumor excision can be readily achieved, limited excision by transsphenoidal microsurgery or craniotomy plus radiotherapy appears to be the treatment of choice for craniopharyngioma in childhood

M. J. Thomsett, M.B., F.R.A.C.P.,* F. A. Conte, M.D., S. L. Kaplan, M.D., a n d M . M . G r u m b a c h , M . D . , * * S a n F r a n c i s c o , Calif.

CRANIOPHARYNGIOMA is the most c o m m o n tumor involving the hypothalamic-pituitary area in childhood,' and represents about 9% of intracranial tumors in claildrenY Most reports on childhood craniopharyngioma have been concerned with the neurosurgical aspects, and the few detailed assessments of hypothalamic-pituitary function before and after treatment have been confined to small numbers of patients. 3-1~ We carried out a review of 42 cases of craniopharyngioma in children seen at the University of California San From the Department o f Pediatrics, University o f California San Francisco. Supported in part by grants from the National Institute o f Child Health and Human Development and the National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, USPHS," and was carried out in the Pediatric Clinical Research Center funded by a grant from the N I H 501-RR00079-17. *Recipient of a fellowship from the Queensland Children "s Hospital Research Foundation, Brisbane, Australia. **Reprint address: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143.

Vol. 97, No. 5, pp. 728-735

Francisco between 1966 and 1978 to document the prevalence and nature of hypothalamic-pituitary dysfunction before and after treatment, and to assess the effect of various therapeutic approaches on endocrine and neurologic prognosis. The results indicate that although symptoms of endocrine deficiency were infrequently the presenting cornAbbreviations used UCSF: University of California, San Francisco TSH: thyroid-stimulating hormone RIA radioimmunoassay T~: tri-iodothyronine T~: thyroxine TRF: thyrotropin-releasing factor 17-OHCS: 17-hydroxycorticosteroids GH: growth hormone LH: luteinizing hormone FSH: follicle-stimulating hormone LRF: luteinizing hormone-releasing factor ADH: anti-diuretic hormone PRL: prolactin PEG: pneumoencephalogram

0022-3476/80/110728+08500.80/0 9 1980 The C. V. Mosby Co.

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Endocrine and neurologic outcome in craniopharyngioma

plaint, hypothalamic-pituitary hormone deficiency is common at presentation and virtually universal after treatment. MATERIALS

AND M E T H O D S

Records were reviewed of all 42 patients with histologically proven craniopharyngioma who had been evaluated in the Pediatric Endocrine Unit at UCSF between 1966 and 1978. The surgical treatment was performed at UCSF in 21 cases. The latest post-treatment evaluation was performed from six to 132 months after surgery; the follow-up period after treatment ranged from six to 192 months. Measurements of heights and weight were compared to National Center for Health Statistics tablesl~; the standards for height velocity and weight velocity were those of Tanner and Whitehouse. 1~ Bone age was assessed according to the method of Greulich and Pyle? ~All of these data are expressed as standard deviations from the mean value for age. Recurrences after treatment were defined as progressive symptoms and signs that required surgicai intervention. The mere presence of residual tumor in symptomatically stable patients was not regarded as a recurrence. Radiation therapy was given to 17 children, of whom nine received this treatment at UCSF, where the techniques previously described by Lichter et aP ~ were used. Doses ranged from 4,500 to 5,700 rads (mean 5,100 rads), over four to 12 weeks (mean seven weeks) in these 17 patients. Neurologic outcome in surviving patients was defined as good if the patient was free from major neurologic handicap; fair if the patient could care for himself despite neurologic handicap; and poor if the patient was incapable of looking after himself. Endocrine assessment. Thyroid-stimulating hormone. Thyroid status was assessed by measurement of the serum concentration of protein-bound iodine 17 or T4TM and by T3 resin uptake estimations.TM The serum concentration of TSH was determined by RIA as previously described ~~ using WHO 68/38 as the TSH standard. TSH deficiency was diagnosed when hypothyroidism was associated with a low serum TSH and a low T3 resin uptake, and evidence of secondary or tertiary hypothyroidism was obtained by response to thyrotropin-releasing factor. ~~TSH deficiency was assumed to be present in patients with a low serum concentration of T~ and a low T~ resin uptake even though TSH measurements were not made and the response to TRF was not assessed. ACTH. A diagnosis of ACTH deficiency was made if there was either a deficient plasma cortisol response to

7 29

insulin-induced hypoglycemia, or a deficient plasma 11deoxycortisol or 24-hour urinary 17-hydroxycorticosteroid response to metyrapone. Plasma cortisol concentrations were estimated by competitive protein-binding assay'~1 or by RIA. 22 The reference range for plasma cortisol concentration in our laboratory is 10 to 25/~g/dl at 8 AM and the normal increment following insulin-induced hypoglycemia is > 7/~g/dl. Plasma 11-deoxycortisol was estimated by competitive protein-binding assay?' The 24-hour excretion of urinary 17-OHCS was determined as previously describedY:~ The reference range is 3.0 • 1.0 mg/m~/24 hours. The normal response to metyrapone is either a rise in plasma 11-deoxycortisol ___ 7 /~g/dl or a twofold or greater increase in 24-hour urinary 17-OHCS values from a normal baseline value. ~3 Growth hormone. The plasma concentration of GH was determined as previously reported 24using HS2160E as the standard. GH deficiency was established if plasma GH concentrations failed to reach a value of 7 ng/ml or higher, following stimulation by arginine, insulin-induced hypoglycemia and/or L-dopa. ~3 Luteinizing hormone~follicle-stimulating hormone. Plasma LH and FSH concentrations were measured by RIA as previously described~5; LER 960 was used as the LH standard and LER 869 as the FSH standard (1 ng LER 960 = 40 ng LER 907 or 7.8 mIU 2nd IRP HMG; 1 ng LER 869 = 100 ng LER 907 or 3 mIU 2nd IRP HMG). Gonadotropin deficiency was diagnosed if the plasma LH and FSH respor~se to luteinizing hormone-releasing factor was subnormal for age ~'~and signs of pubertal development were delayed. Anti-diuretic hormone. ADH deficiency was considered present if the patient did not concentrate urine during a water deprivation test ~ or if random urine specific gravities were persistently < 1.005 in the presence of polyuria and polydipsia. ADH function was regarded as normal if the urine volume was normal and the random urine specific gravity was > 1.018 in the absence of glucose, protein or contrast medium in the urine. Prolactin. The plasma concentration of PRL was determined by RIA as previously reported ~7 using Lewis 203-1 as the hPRL standard. The normal range in our laboratory is 6.6 _+ 0.8 ng/ml (mean • standard error) (range 1.6 to 18 ng/ml) and the normal peak plasma PRL concentration following TRF stimulation is 27.2 • 3.8 ng/ml (range 7 to 68 ng/ml). RESULTS Presenting features. Of the 42 children, 24 were boys and 18 girls. Age at diagnosis ranged from 1.8 to 17.2 years (mean 9.2 years) with a peak incidence between 8 and 10 years. Mean birth weight, gestational age, and

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The Journal of Pediatrics November 1980

Table 1. Hypothalamic-pituitary dysfunction before and after treatment

Before treatment

After treatment

13/18 4/17 7/29 3/8 4/24 2/10 1/3

39/39 30/38 35/41 20/28 29/41 5/31 9/14

GH + ACTH TSH LH/FSH Jr ADH ~r PRL* PRL (TRF)* *In euthyroidpatients.

Table II. Number of hypothalamic-pituitary hormone deficiencies in children who had data on four or more hormones

Deficiencies~patient 0 J 1 ] 2 [ 3 ] 4ormore Pretreatment (n = 18) Post-treatment (n = 38)

3

4

9

1

1

0

0

3

7

28

Note: In euthyroid patients, an increased basal concentrationof serum PRL or deficientPRL responseto TRF was regarded as a deficiency. midparental height were similar to those of the general population. A history of craniopharyngioma in a cousin was elicted from two patients. The primary symptom leading to medical evaluation was headache or vomiting in 18, visual disturbance in 15, growth failure in three, and polyuria, seizures, decreased school performance, or facial nerve palsy in one child each. These symptoms were present from one day to 48 months (mean 14.3 months) before diagnosis. A routine skull radiograph taken after an accidental fall led to the diagnosis of craniopharyngioma in two asymptomatic children. Thus, 36 children presented because of neurologic symptoms and only four because of symptoms suggesting hormone deficiency. Although retarded growth was the presenting complaint in only three children, height, height velocity, and bone age were more than --2.5 SD below the mean value for age in 14/3 l, 11 / 16, and 4/18, respectively. Individual height varied from - 5 to + 0.5 SD (mean --2.2 SD) from the mean value, and weight from -2.3 to + 1.3 SD (mean --1 SD) from the mean. All three boys > 14 years and both girls > 13 years had absent or arrested pubertal development. Decreased visual acuity was present in 14/33; visual field defect in 13/32; optic atrophy in 11/29; papilledema in 9/42; and cranial nerve palsy in 12/42. Radiologic studies. Of 36 patients in v~hom skull radiographs were available, an enlarged or eroded sella turcica

was reported in 18, and calcifications within or above the sella in 28. The skull radiograph was read as normal in four cases. Pneumoencephalograms subsequently revealed intracranial calcification in two additional children. PEG and computed axial tomographic brain scan were abnormal in 33/33 and 7/7 children, respectively. Carotid angiograms and radionuclide brain scans were normal in 3/21 and 2/5 patients, respectively, all of whom had an abnormal PEG. Fourteen of 37 children had ventricular dilatation. The tumor was confined to the sella in two children, extended superior to the sella in 40, and posterior!y in six. Hypothalamic-pituitary dysfunction. Table I details the results of endocrine studies before and after treatment. In euthyroid patients the random concentrations of plasma PRL was elevated in 2/10 before treatment and in 5/31 after treatment, and the plasma PRL response to T R F was deficient in 1/3 before and in 9/14 after treatment. Assessments of four or more pituitary hormones were performed in 18 children before treatment and in 38 after treatment. The extent of the hypothalamic pituitary dysfunction in these children is shown in Table II. Before treatment, only 3/18 children had no demonstrable endocrine deficiency. Four children had a single pituitary hormone deficiency (GH in 2, ACTH and L H / F S H in one each). Of nine children who had deficiencies of two hormones before treatment, deficiencies or abnormalities of GH/TSH, GH/PRL and GH/ACTH were present in two children each, and deficiencies of GH/ADH, GH/ LH-FSH and A C T H / A D H were present in one child each. When last reviewed after treatment, deficiencies or abnormalities of four or more pituitary hormones were found in 28/38 patients. Treatment and neurologic prognosis. Table III summarizes the various treatments used and the neurologic outcome from each. Surgery alone was the initial treatment in 25 children. Twenty-four had craniotomies, with radical tumor excision in 13, and partial excision or drainage in 11. One other child had total tumor excision via the transsphenoidal route. Surgery plus radiotherapy was performed in the other 17 children. Nine of these 17 patients had craniotomies (for partial tumor removal in seven and drainage only in two), and eight had partial removal of the craniopharyngioma by transsphenoidal microsurgery. The children treated with surgery plus radiotherapy have been followed for 52 _+ 10 months (mean _+SE). This is a significantly shorter period (P < 0.05 by analysis of variance for unequal sized groups) than the follow-up period either for all the children treated with surgery alone (87 _+ 11 months) or for the children treated with partial excision or drainage alone (98 _+ 19 months).

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Endocrine and neurologic outcome in craniopharyngioma

731

Table IlL Relationship of therapy to neurologic outcome

Recurrences

Mo

N (%)

Deaths

Poor

78 _+ 12 98 + 19

4 (29%) 10 (91%)

43 (11-72) 19 (1-60)

2 (14%)* 4 (36%)

2 (14%) 2 (18%)

1 (9%) 2 (18%)

8 (57%) 3 (27%)

87 + 11 52 _+ 10

14 (56%) 3 (18%)

26 (1-72) 19 (14-25)

6 (24%)* 0

4 (16%) 2 (12%)

3 (12%) 3 (18%)

11 (44%) 12 (70%)

17 (40%)

25 (1-72)

6 (14%)*

6 (14%)

6 (14%)

23 (55%)

N

Complete removal Partial removal or drainage

14 11

Surgery alone Partial removal or drainage, plus radiotherapy

25 17

Totals

42

Therapy

Outcome of survivors

Mo mean (range)

follow-up (mean +_SE)

y-----.------.~

]Fair[

Good

*One additionalpatient treated by total removal at 15.2 years of age committed suicide 10.7 years later and has not been included in the mortality statistics. However, it was not significantly shorter than for children treated with radical excision alone (78 • 12 months, e = NS). Recurrences occurred in 17 children (40%) (Table III). In the 11 children who had only partial excision or drainage, 10 had a recurrence, whereas of the 14 children in whom total excision was achieved, four had recurrences. Of the 17 children who had partial excision or drainage plus radiotherapy, three had recurrences between 14 and 25 months (mean 19 months) after surgery. No deaths occurred in the immediate post-operative period, but six deaths occurred 7 to 151 months (mean 78 months) post-treatment (Table III). Three deaths were from recurrence, one each was from respiratory failure (Pickwickian syndrome) and adrenocortical insufficiency, and one was from unknown causes. All deaths were in children treated with surgery alone. An additional patient treated by radical excision at 15.2 years of age committed suicide 10.7 years later but has not been included in these statistics. Of the surviving patients, 23 were judged tO have a good outcome, six a fair outcome, and six a poor outcome. When last reviewed, one of the patients with a poor outcome remained unconscious 26 months after attempted complete excision of the tumor. Although these data suggest that limited excision or drainage plus radiotherapy confers a better neurologic prognosis than does surgery alone, the patients who had surgery alone have been followed for a longer period. To obviate this difference in the duration of follow-up, the recurrences and deaths in each group occurring 36 months after surgery were analyzed. These data are shown in Table IV. During this 36-month period, the recurrence rates were similar for children treated with total tumor excision and for those treated with partial excision or drainage plus radiotherapy. However, a significantly higher recurrence rate within 36 months was Observed in children with

Table IV. Relationship of therapy to neurologic outcome 36 months after surgery

Therapy

I N

I Recurrences I Deaths

Complete removal Partial removal or drainage

13 10

2 (15%) 8* (80%)

0 2

Surgery alone Partial removal or drainage, plus radiation therapy

23 11

10 (43%) 2* (18%)

2 0

*P = 0.01 by two-tailed Fisherexact test. partial excision or drainage alone (P = 0.01 by the two-tailed Fisher exact test). No significant difference in mortality rate was apparent by 36 months in the various groups. However, two deaths occurred in the radical excision group and four deaths in the partial removal group after the initial 36-month follow-up period. Thus, when total excision is not achieved, subsequent radiotherapy appears to confer a better neurologic prognosis. Possible neurologic sequelae to radiotherapy (i.e., episodes occurring during radiotherapy in the absence of tumor or untreated pituitary hormone deficiency) occurred in six patients; these episodes included seizures in two patients, somnolence and apathy in two, and acute hydrocephalus and headaches in one child each. An additional patient developed a deficiency of recent memory in the first year after radiotherapy. Treatment and endocrine prognosis. The effect of therapy on subsequent hypothalamic-pituitary hormone function was examined in those patients in whom the posttreatment status of a hormone could be compared to the pretreatment status of the same hormone. None of these patients has experienced a recurrence. Reversal of previously abnormal hormone function to normal following treatment was not observed in any patient. As shown in Table V, the intervals between treatment and the latest endocrine studies are similar for all treatment groups. In children who had surgery alone,

73 2

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The Journal of Pediatrics November 1980

Table V. Effect of therapy on hypothalamic-pituitary hormone function assessed by comparing the post-treatment status of pituitary hormones which were known to have normal function before treatment

N

Before treatment

After treatment

Mo between treatment and latest endocrine studies (mean +_ SE)

7 6

24 15

1" 2

25 ___8 29 _+ 7

13 14

39 38

3~ 15*t

27 _+ 6 28 +_ 6

No. of normal hormone functions Therapy

Complete removal Partial removal or drainage Surgery alone Partial removal or drainage, plus radiation therapy *P < 0.05 by X2. ~-P < 0.005 by X~.

the effect of treatment on a previously normal hormone function could be assessed on 39 occasions in 13 children; on only three of these 39 occasions was normal function of that hormone retained after treatment. In children treated with surgery plus radiotherapy, this comparison could be made on 38 occasions in 14 children; normal function of the hormone was maintained after treatment in 15 of these 38 instances, a significantly better result (P < 0.005 by X~). These data suggest that partial excision plus radiotherapy is followed by less additional hypothalamicpituitary dysfunction than is surgery alone. Growth after treatment. Seven GH deficient children who were 3.5 to 13.5 years of age at surgery and who were not receiving GH or sex hormone replacement therapy, grew at a normal rate for bone age for at least two years after treatment. All seven had surgery via craniotomy and none received radiotherapy; total excision of the tumor was achieved in four and partial excision in three. Height velocities in these children ranged from -1.7 to + 3.6 SD (mean + 0.5 SD) from the mean value for bone age in the first year after treatment, and from -1.3 to +4.2 SD (mean + 1.3 SD) in the second year. Weight gain in these children was marked; the weight velocity averaged + 4.4 and + 1.2 SD above the mean value for bone age in the first and second years, respectively. Normal linear growth was maintained for five years after treatment in four of these seven children. Random plasma PRL concentrations during the period of normal growth were normal in four and elevated in one. DISCUSSION Craniopharyngioma is predominantly a disease of childhood. In reviewing 1,002 cases from the world's literature, Banna ~ found the greatest frequency.in fife first two decades of life. In patients less than 17 years of age, the peak occurrence was at eight years with smaller peaks at four and 13 years/ very similar to the age

distribution in the present series. The youngest patient in our series was 1.8 years of age at diagnosis; however, cases have been reported in neonates/'~ The male preponderance found in the present series has been previously reported? ~~ 3o but others have noted an equal sex ratio? 31 Although skull radiographs obtained following minor trauma led coincidentally to the diagnosis of craniopharyngioma in two asymptomatic children, normal skull radiographs were obtained in 11% of cases, which is similar to the findings of Banna et aP and Hoff and Patterson? ~ The high incidence of false-negative reports from radionuclide brain scans limit their usefulness in diagnosis. Computed tomographic brain scans were abnormal in every patient in which this study was performed, although a normal scan in patients with craniopharyngioma has been reported? 3 As in previous reports/. ~', 32 we noted that a long interval often occurs between onset of symptoms and diagnosis, and that few children with craniopharyngiomas seek medical care because of symptoms of hormonal deficiency. Despite this fact, 83% of the children in our series on whom extensive pretreatment endocrine data were available had at least one hypothalamic-pituitary hormone deficiency. Comparison of pretreatment endocrine data from previous reports with those from the present study indicates that GH deficiency has been the most frequently observed abnormality/, i0-1~ Additional hypothalamic-pituitary hormone deficiencies are to be expected following treatment of a tumor in the hypothalamic-pituitary areas?. ~ 7. ,,,. ~ In no patient was endocrine function improved by treatment, and multiple hormone deficiencies were present after treatment in most cases. Elevated random concentrations of plasma PRL were found in 16% of patients, suggesting that there is frequent hypothalamic involvement. The occurrence of normal growth in GH-deficient

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Endocrine and neurologic outcome in craniopharyngioma

children after treatment of intracranial lesions was first described by Matson, 34 and has since been the subject of several reports?. ~, ,2. :,~_:~,,A normal growth rate, usually associated with rapid weight gain, was noted in seven of our 42 patients for at least two years after treatment. The explanation for this p h e n o m e n o n is unclear. Numerous reports have documented normal somatomedin activity in these children? .... ~ ~ Normal 24-hour GH production with low random plasma GH concentrations, ~s an immunologically active but biologically inactive GH, :~6 hyperprolactinemia? ~ and hyperinsulinism~ have all been suggested as possible explanations. Hyperprolactinemia seems unlikely to be a significant growth factor in these children, as the prolactin concentrations were normal in four of our patients with normal growth and in reports by othersY. ~. ~ Costin et aW- found a correlation between post-treatment growth rate in obese children and plasma insulin concentration after stimulation, but found no such correlation in nonobese children who were growing normally after surgery. The factors responsible for the normal somatomedin activity in these children with a normal growth rate despite GH deficiency await further elucidation. The treatment of craniopharyngioma has been the subject of considerable debate. The location and size of the tumor as well as impingement o n or adherence to neighboring structures, and the presence of obstructive hydrocephalus, all influence prognosis and selection of the approach to therapy. Matson~ recommended radical excision as the treatment choice, and in reviewing patients who had total excision of their tumor by Matson, Katz ~~ reported a 74% recurrence-free survival rate four to 19 years following surgery, which is similar to the results of such treatment in the present study. However, recurrences as long as 20 years following total excision have been reported. 4~ The use of radiotherapy with less extensive surgery was first reported in 1937~'-'; more recently this approach has had a growing n u m b e r of advocates? ~, ~....... ~ The experience in the present study suggests that even when gross total excision can be achieved, the recurrence and mortality rates, and neurologic outcome among the surviving patients, are no better than when partial excision or drainage is followed by radiotherapy. However, the combined surgical/radiotherapeutic approach is associated with a better endocrinologic prognosis than is total removal alone. In children in whom total excision of the tumor cannot be achieved, subsequent irradiation is followed by fewer deaths and fewer recurrences. Wider use of the operating microscope with the greatly increased magnification it affords, for complete tumor removal by craniotomy, or partial removal by transsphenoidal micro-

733

surgery combined with radiotherapy, may lead to a lower morbidity and recurrence rate; this remains to be established by future studies. A n y benefits of the combined surgical and radiotherapeutic approach in terms of better neurologic and endocrine prognosis (and possibly lower mortality) must be balanced against the potential hazards of radiotherapy. These include radiation damage of the optic nerve, 47 additional endocrine morbidity2~. 3, malignancy) ...... emotional and social problems? 4 and diminished intellectual ability? ~ Seven patients in the present study developed neurologic complaints that could have been due to radiation therapy. In summary, this study demonstrates that although few children with craniopharyngioma seek medical.attention because of endocrine symptoms, hypothalamic-pituitary hormone deficiency is c o m m o n at diagnosis, and virtually universal after treatment. Partial tumor excision plus radiotherapy was associated with a better endocrine prognosis in our group of patients than either total or partial excision alone, and a better neurologic prognosis t h a n partial excision alone. Unless radical excision of tumor can be achieved without risk of serious neurologic sequelae or death, limited excision plus radiotherapy appears to be the treatment of choice for craniopharyngioma in children, despite the potential long-term hazards of radiation therapy.

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Endocrine and neurotogic outcome in craniopharyngioma

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