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Original Studies |
Departments of Pediatrics (D.J.D., W.L.M., F.A.C., S.L.K., M.M.G., S.M.R., S.E.G.) and Neurosurgery (C.B.W.), University of California, San Francisco, California 94143
Address all correspondence and requests for reprints to: Dr. Stephen E. Gitelman, Department of Pediatrics, University of California, 500 Parnassus Avenue, MU 405E, Box 0136, San Francisco, California 94143-0136. E-mail: sgitelma{at}PEDS.UCSF.EDU
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Abstract |
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18 yr) who underwent transsphenoidal exploration for the primary
treatment of Cushing’s disease at University of California-San
Francisco from 1974–1993. Only 7 patients had persistent disease,
defined as evidence of Cushing’s disease within 6 months of surgery,
yielding an initial remission rate of 83%. We comprehensively
evaluated 26 of the 35 patients who experienced an initial remission,
including testing of the ACTH-adrenocortical axis. The mean duration of
follow-up is 7.2 yr (range, 1.5–13.6 yr). Seven experienced a relapse
of Cushing’s disease, yielding a net remission rate of 73%. Relapses
occurred an average of 4.2 yr postoperatively (range, 0.75–6.2 yr).
Five patients experienced relapse within 5 yr of surgery, whereas 2
relapsed more than 5 yr postoperatively. Repeat transsphenoidal surgery
was performed in 8 patients with persistent or recurrent disease, and 6
of these remain in remission. Low serum or urinary cortisol
measurements within the first post-operative week predicted remission
of Cushing’s disease, but were not necessarily predictive of long-term
cure. Hypercortisolism had significant effects on bone metabolism, as
reflected by both diminished bone density in the majority of patients
examined and decreased growth rate. Both parameters improved after
surgical care, although they did not fully normalize. We conclude that
transsphenoidal surgery is a safe and effective treatment for pediatric
Cushing’s disease, but long-term surveillance is necessary to detect
possible recurrences. |
Introduction |
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Transsphenoidal pituitary microsurgery has emerged as the treatment of choice for Cushing’s disease in children and adults (10, 11), but success rates have been variable. Initial remission rates of 70–98% of patients and long term success rates of 50–98% have been reported (2, 6, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). These discrepancies may relate to neurosurgical skill and to the length and methods of the follow-up studies; furthermore, recurrence rates appear to be higher when the patients are followed for more than 5 yr (12, 14, 15). Most studies have reported results with adult patients, often with a small number of pediatric patients mixed in, and some reports suggest that children and adolescents may be at higher risk for recurrence than adults (11, 14). We now report the surgical results and long term follow-up of 42 children and adolescents with Cushing’s disease who underwent transsphenoidal adenomectomy at our institution between 1974–1993.
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Subjects and Methods |
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Forty-two consecutive children or adolescents underwent transsphenoidal adenomectomy at the University of California-San Francisco (UCSF) as primary treatment for Cushing’s disease between 1974–1993. There were 25 girls and 17 boys; the average age at surgery was 13.1 yr, the median age was 13.4 yr, and the range was 6.5–18 yr. The majority of the patients were admitted to the pediatric endocrine service before surgery. Transsphenoidal microsurgery and selective adenomectomy were performed at UCSF, and all but one operation were performed by the same neurosurgeon (C.B.W.). Surgical remission was confirmed by finding very low or unmeasurable 24-h urinary free cortisol (<20 µg/m2·24 h) and 17-hydroxycorticosteroids (17OHCS; <2 mg/m2·24 h) and/or low plasma cortisol measurements (<8 µg/dL) during the postoperative period as well as clinical resolution of symptoms.
Follow-up information was obtained through chart review followed by a 3-day comprehensive endocrinological evaluation at the Pediatric Clinical Research Center. The 3-day in-patient protocol was approved by the UCSF institutional review board, and all subjects or their parents gave informed consent for the studies. Subjects who were unable to come to San Francisco were asked to provide medical information via their physicians. Specific measurements of urinary free cortisol and plasma cortisol and ACTH were requested to confirm remission.
Pre- and post-operative laboratory evaluations
Blood samples for determination of cortisol and ACTH were obtained at 0700, 0720, 0740, 1900, 1920 and 1940 h to assess the diurnal variation. Two baseline 24-h urine samples were collected for free cortisol and 17OHCS determinations. Baseline 24-h urinary free cortisol was considered elevated if it was above 80 µg/m2·day, and urinary 17OHCS was considered elevated if it was above 5 mg/m2·day (2, 4, 5, 22). Low and high dose dexamethasone suppression tests (20 and 80 µg/kg·day, respectively, divided into four equal doses per day for 2 days each) (2, 3, 4, 5) were performed, and urinary free cortisol and urinary 17OHCS were determined on each day.
In some patients, ovine CRH (Ferring Laboratories, Suffern, NY) was administered (1 µg/kg, iv), and blood samples for cortisol and ACTH determinations were obtained 15 min before and 0, 15, 30, 60, 90, and 120 min after treatment (23). When baseline urinary steroid excretion was elevated, a CRF response was considered to be indicative of Cushing’s disease if the plasma ACTH or cortisol values increased above the mean baseline value by at least 34% or 20%, respectively (23).
GH secretion in response to arginine (0.5 g/kg, iv; maximum dose, 20 g) and levodopa (75–250 mg, orally, depending on weight) was measured after pretreatment with propranolol (0.75 mg/kg, orally) when there was no history of reactive airways disease, congenital heart disease, or hypoglycemia. Normal stimulated GH responses in our clinic were considered to be peak GH levels of 7 ng/mL or more. GHRH (1µg/kg, iv), TRH (200 µg, iv), and GnRH (100 µg, iv) were given simultaneously to measure GH, TSH, PRL, and gonadotropin reserves.
Radiological evaluation
Brain imaging was performed using magnetic resonance imaging (MRI) with gadolinium in 17 patients, computed tomography (CT) in 22 patients, and pneumoencephalography in 2 patients, depending on their years of diagnosis. Bone age was obtained at the initial evaluation and at follow-up visits. Plain spine films or bone mineral density determined by dual energy x-ray absorptiometry or quantitative CT was measured pre- and postoperatively.
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Results |
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The presenting signs and symptoms in our patients are summarized
in Table 1
. The most common findings were
weight gain, growth failure, fatigue, hypertension, and either pubertal
delay or irregular menses. Heights at diagnosis ranged from +0.3 to
-3.5 SD from the patients’ age- and sex-adjusted means,
with an average height at diagnosis of -1.8 SD. The
mid-parental target height for this group of patients was +0.4
SD (range, -1.5 to +2.5 SD), so that the mean
height at diagnosis was even more retarded than -1.8 SD.
The boys tended to be older at diagnosis (male mean, 13.7 yr; female
mean, 12.7 yr), with a greater impairment in height (boys, -2.2
SD; girls, -1.6 SD) and a greater duration of
their disease (as reported by their parents) before diagnosis (2.5
vs. 1.9 yr). Pubertal delay, bruising, and headache were
more commonly reported in children with long-standing disease. Bone
demineralization, detected by plain films or densitometry, was found in
74% of the cases, but did not appear to correlate with a longer
duration of illness and was not associated with fractures.
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Preoperative diagnostic studies
Of our 42 patients, 32 had preoperative diagnostic studies
performed at UCSF (Table 2). Absent
diurnal rhythms of plasma cortisol and ACTH and increased urinary
excretion of 17OHCS were seen in all 32 of these patients. Increased
urinary excretion of 17OHCS was seen in 24 of 24 patients evaluated,
and increased urinary excretion of free cortisol was seen in 25 of 29
patients (86%). Four patients had normal urinary excretion of free
cortisol (<80 µg/m2·day) despite increased urinary
excretion of 17OHCS (>5 mg/m2·day). Thus in our
population, increased urinary excretion of 17OHCS appeared to be a more
reliable indicator of Cushing’s disease than urinary free cortisol.
Suppression of urinary steroid excretion by high doses of dexamethasone
was seen in 92% of the subjects. Urinary free cortisol was suppressed
by an average of 80% from the control value (range, 33–99%), whereas
17OHCS was suppressed by an average of 71% (range, 26–97%).
Three patients were able to suppress their urinary steroid
excretion with low dose dexamethasone.
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In 13 of 18 patients who underwent MRI brain imaging with gadolinium, the MRI correctly predicted a pituitary adenoma. Surgical exploration was negative in 4 patients with positive MRI studies, and exploration was positive in 1 patient with a negative study. Only 5 of 22 patients had pituitary adenomas seen by CT scanning, although all had surgically demonstrable pituitary adenomas. Thus, MRI with gadolinium had a 72% sensitivity and CT had a 23% sensitivity in identifying pituitary adenomas.
Preoperative pituitary assessment
Thirty patients presented with diminished growth velocity. Of 17 who had provocative testing of GH secretion, 3 had blunted responses. Of 11 patients who had GHRH testing, 6 had blunted GH responses, but only 1 of these 6 had an abnormal GH response to provocative testing. Five of 27 patients had hypothyroidism with low free T4 levels, and 3 of 15 patients who had TRH testing had subnormal responses, reflecting secondary or tertiary hypothyroidism. Twenty-two patients had presenting signs or symptoms of arrested pubertal development. Of 14 who underwent a GnRH test, 7 had a subnormal gonadotropin response.
Transsphenoidal surgery
The outcomes of the 42 patients who underwent transsphenoidal
surgery are summarized in Fig. 1. An
adenoma was found in 36 patients, and the surgical impression was
confirmed histologically. The surgically estimated sizes of the
adenomas ranged from 1–20 mm, with a mean of 3.8 mm. Of the 6 patients
who had a negative exploration, 4 had persistent disease
postoperatively, and 2 experienced a remission even though no tumor was
seen. Of the 2 patients in remission, 1 has remained free of disease
for 6.5 yr, and 1 had a recurrence after 4 yr. Perioperative
complications included 8 cases of transient diabetes insipidus that did
not require medication at discharge.
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Seven of the 42 patients had persistent disease, defined as
evidence of Cushing’s disease within 6 months of surgery. The 4 in
whom no tumor was found underwent bilateral adrenalectomy, 2 had repeat
transsphenoidal surgery, and 1 continues to have evidence of Cushing’s
disease. Nine of 42 patients were not seen following the initial
6-month post-operative period. We have comprehensively evaluated 26 of
the remaining 35 patients (Fig. 2). This
follow-up ranges from 1.5–13.6 yr, with a mean of 7.2 yr. Nineteen
patients remain in remission, giving an overall remission rate of
73%.
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Eight patients had repeat transsphenoidal surgery for either recurrent or persistent Cushing’s disease. Of those eight, six are in remission 0.5–12 yr later (mean, 4.6 yr). Thus, the remission rate for repeat transsphenoidal surgery was similar (75%) to that for the initial surgery.
Predictors of outcome
Early morning plasma cortisol or 24-h urinary free cortisol
measurements performed approximately 1 week postoperatively provided a
good index of surgical outcome (Table 3).
Among the 7 patients who failed their initial surgery, all 5 who were
tested had normal or high plasma cortisol or urinary free cortisol
concentrations during the first postoperative week. Thirty-four of the
36 patients who experienced an initial remission had early morning
plasma cortisol or 24-h urinary free cortisol measurements performed
approximately 1 week postoperatively. Twenty-five of these 34 patients
had unmeasurable or low plasma cortisol or urinary free cortisol
values. Fourteen of these 25 patients are in remission, 10 for more
than 5 yr. Four of the 25 patients have had a recurrence of their
Cushing’s disease, and 7 remain without follow-up. None of these
patients had persistent disease. Five patients had normal plasma or
urinary free cortisol values in the early postoperative period; of
these, 2 had persistent disease, 1 had a recurrence 9 months after
surgery, and 2 continue to be in remission, 1 of whom is more than 9 yr
from surgery. Thus, a normal plasma or urinary cortisol measurement in
the immediate postoperative period was not necessarily predictive of
recurrence or persistence.
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CRF testing
All three patients who had pre- and postoperative CRF tests had supranormal preoperative cortisol and ACTH responses. One patient had unmeasurable CRF-induced ACTH and cortisol values after surgery. Subsequent CRF tests of this patient showed a gradual recovery of the cortisol response, and he continues in remission 2.3 yr postoperatively. One patient had persistent disease, confirmed by high postoperative cortisol and ACTH responses to CRF. Two years after a second transsphenoidal surgery, this patient had a suppressed cortisol response to CRF and a normal ACTH response. The third patient had suppressed cortisol values but supranormal ACTH concentrations in response to CRF in the immediate postoperative period. At 3.2 yr follow-up, the CRF test shows elevated cortisol values and a clearly supranormal ACTH response, with concomitantly elevated urinary steroid values and clinical evidence of a recurrence.
Five additional patients underwent CRF testing at various intervals postoperatively. In three patients who have been in remission for 1.9, 6.4, and 9 yr, CRF tests show normal ACTH and cortisol responses. In one case, the CRF test confirmed a recurrence 4.7 yr after the original surgery. The fifth patient had a 22-mm macroadenoma that was only partially resected, but she has had normal diurnal variation of plasma cortisol and normal urinary steroid excretion since the immediate postoperative period. Her CRF test has shown a normal cortisol response but high ACTH levels; she has been in remission for 2.5 yr.
Growth
Nineteen of our patients have completed their growth and are not GH deficient. Preoperative height measurements averaged -1.7 SD from their age- and sex-adjusted means (range, -3.5 to +0.3 SD), and final height was -1.14 SD from the mean (range, -2.5 to +0.7 SD). We compared individual final height with midparental target height in 13 patients for whom the parents’ heights were available. There was no correlation between degree of compromised final height and duration of disease before diagnosis. However, 4 patients whose final heights were more than -2 SD from their midparental target heights had the onset or a recurrence of their disease during puberty. By contrast, the remaining 9 patients were between -0.5 and -2.0 SD from their midparental target height. Three of these had onset of disease after menarche, 2 had diagnosis and surgery before the onset of puberty, and 4 had the onset and diagnosis during puberty. Thus, it appears that the onset of Cushing’s disease during puberty may be associated with greater compromised final adult height.
Anterior pituitary testing
Fifteen of 20 patients who were screened for anterior pituitary hormone deficiencies had normal anterior pituitary function and 5 patients had an isolated pituitary hormone deficiency. One of these 5 has secondary hypothyroidism, and the other 4 have isolated GH deficiency. Two of these 4 require hydrocortisone replacement 2.5–3 yr after surgery. One had a normal ACTH response to CRF, but blunted plasma cortisol secretion; the other had a sluggish response to an ACTH stimulation test.
Bone density
Preoperative plain films of the spine in 11 of 15 patients studied revealed varying degrees of demineralization, as interpreted by different radiologists. In 3 patients, preoperative bone densitometry revealed severe osteopenia, ranging from 3.9–7.0 SD below age- and sex-matched control values. One of these patients has had a follow-up study, with dramatic improvement from -7.0 to -1.8 SD within 2.5 yr of surgery. Four additional patients have had dual energy x-ray absorptiometry scans of the spine performed as part of their long term follow-up evaluation. One has a normal bone density after 10 yr in remission. The child with GH deficiency and absent cortisol response to CRF had severe osteopenia on preoperative plain films, and follow-up bone density 3 yr after surgery and 2 yr after starting GH replacement was 4.6 SD below the mean for his age and sex. Two additional patients had recurrences at the time of their bone density studies, with densities -1.7 and -1.4 SD from the mean, respectively. Of the 4 patients studied who were in remission, 3 had bone densitometry within 2 SD of normal. Thus, it appears that there is a dramatic improvement of bone mineral density with remission of Cushing’s disease.
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Discussion |
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Compulsive behavior and overachievement in school were notable psychological changes in our patients. The grades of many of the A students decreased after surgery, which we found to be an intriguing unofficial measure of surgical success. These personality changes have been noted anecdotally in previous case reports (5, 25) and are in contrast to the typical adult psychological disturbances of emotional lability, irritability, decreased concentration, and depression (1, 10, 24) .
The endocrine abnormalities in childhood Cushing’s disease are similar to those in adults, namely hypersecretion and absence of diurnal rhythmicity of secretion of cortisol and ACTH; abnormal negative feedback regulation of ACTH secretion by glucocorticoids, as shown by abnormal suppressibility with dexamethasone; and subnormal responsiveness of GH, TSH, and gonadotropins to stimulation (1, 26). In the pediatric population, the diagnostic criteria for urinary steroid excretion and the doses of dexamethasone should be adjusted for body surface area and weight, respectively (4, 5, 22). Even with these adjustments, we found three children who suppressed their glucocorticoid secretion with low dose dexamethasone treatment, reiterating the need to interpret the dexamethasone tests in the context of baseline excretion of urinary free cortisol and 17OHCS, the results of CRF testing, and pituitary imaging. The excretion of urinary free cortisol was not as reliable an indicator of Cushing’s disease as were the urinary 17OHCS measurements in our patients (2), but at least one of these measurements was increased in 100% of our patients.
In our series of 42 patients who underwent selective adenomectomy, the initial surgical success rate was 83%. The definition for surgical success is similar to that used in other recent studies (12, 14), i.e. remission of signs and symptoms of disease for at least 6 months postoperatively accompanied by normalization of endocrine values. Our initial success rate compares favorably with other published results. However, with an average follow-up of 7.2 yr (range, 1.5–13.6 yr), our recurrence rate of 27% is higher than those of some other published studies that had mean follow-up periods of 2–4 yr (6, 12, 16). It is likely that longer follow-up in those series would increase the recurrence rate, as we witnessed two recurrences more than 5 yr after surgery. Our recurrence rate is similar to those in two reports from Europe (13, 18), which had overall success rates of 75% and 78%, respectively, and is substantially better than that in another report from the United States, which found a 42% recurrence rate after a mean follow-up period of 5.5 yr (14). Of our 8 patients who had repeat transsphenoidal surgery for either persistent or recurrent disease, 75% are in remission, with a mean follow-up of 4.2 yr. Thus, our experience remains optimistic, with a long term remission rate of 73%, a low incidence of long term pituitary deficiency, and few perioperative complications. Furthermore, repeat transsphenoidal surgery for recurrent or persistent disease has been a successful secondary therapy and avoids the potential problems of Nelson’s syndrome after bilateral adrenalectomy and side-effects from medical or radiation therapy.
Several groups have attempted to predict outcome based on early postoperative hormonal evaluation (12, 18, 20, 27, 28). The European Cushing’s Disease Survey Group found a high correlation between recurrence rate and higher postoperative serum or urinary cortisol concentrations among nearly 700 patients (12). Pieters et al. (18) suggested that patients with postoperative cortisol concentrations above 3.6 µg/dL have a higher chance of recurrence. Trainer et al. (28) recommended early reoperation or radiotherapy in patients with detectable steroid levels after surgery. All of these studies appear to include significant numbers of patients who did not have recurrences but who had normal postoperative basal or CRF-stimulated cortisol values. Our results were similar. Low or unmeasurable urinary steroids predicted long term remission in 78% of our cases. However, low postoperative cortisol values were not a specific predictor of success, as 40% of the patients who did experience recurrences had low or unmeasurable postoperative values. Furthermore, only 60% of our patients who had normal or high postoperative cortisol values experienced a relapse. Because 40% of our patients who had normal or elevated postoperative values are still in remission, we cannot recommend early reoperation or radiotherapy in these patients.
Bone demineralization is a widely described sign of Cushing’s disease, but accurate quantitation was not possible until the advent of objective and sensitive densitometry measures. The osteoporosis in pediatric Cushing’s disease is multifactorial, including the combination of a direct steroid effect on new bone formation, and the hypogonadism and GH deficiency that are often seen in affected children. Significant skeletal acquisition occurs during the pubertal growth spurt (29); delayed puberty and hypogonadism are associated with decreased bone density (30, 31). Bone demineralization was found in 74% of our patients studied by any measure (including plain films) and in all of those who underwent formal bone densitometry. As in other studies (7, 9), our data indicate that some recovery of bone density occurs postoperatively, but it is not yet clear whether this recovery will be complete or if adult bone mineralization will be compromised. Because bone mineralization will correlate with further risk for fractures, bone densitometry should be a part of the initial and long term evaluation in Cushing’s disease.
Compromised growth is a key feature of pediatric Cushing’s disease. GH secretion in response to provocative testing was blunted in only 3 of the 17 patients who were tested and had growth arrest, although a higher number had blunted responses to tropic stimulation by GHRH. Bone age was delayed in only 3 of 23 patients evaluated. Compromised GH secretion may play a part in the short stature of Cushing’s disease, but the direct effects of cortisol on target tissues are probably more important. Our data suggest that final height is indeed compromised compared to midparental target height, and this is consistent with earlier reports (2, 8). We found that height was most severely compromised in patients who had the disease during puberty, suggesting that missing the pubertal growth spurt may be responsible for what we see as an inadequate catch-up growth after remission. Thus, even early aggressive treatment of pediatric Cushing’s disease may not guarantee normal growth.
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Acknowledgments |
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Footnotes |
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Received March 10, 1997.
Revised May 16, 1997.
Accepted May 21, 1997.
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References |
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