Pituitary adenomas in childhood and adolescence ISABELLE L. RICHMOND, M.D., PH.D., AND CHARLES B. WILSON, M.D.

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1 J Neurosurg 49: , 1978 Pituitary adenomas in childhood and adolescence ISABELLE L. RICHMOND, M.D., PH.D., AND CHARLES B. WILSON, M.D. Department of Neurological Surgery, University of California School of Medicine, San Francisco, California is This report describes a group of 25 children and adolescents with biopsy-proven pituitary adenomas. They were found in 33% of patients encountered in our recent study of 74 parasellar tumors detected in patients under 20 years old. Earlier detection accounts for this apparent increase in frequency. This interpretation is supported by the rarity of signs of intracranial hypertension at presentation, as well as decreased incidence and severity of visual failure. More than 70% of patients have evidence of pituitary hypersecretion at presentation. Increased awareness of these endocrinological signs as well as improved hormonal assays facilitate both diagnosis and management. Hypopituitarism is rare; the important exception is suppression of gonadotrophic function that is known to occur early in the natural history of intrasellar pituitary adenomas. The low incidence of suprasellar and extrasellar extension is documented by both radiographic and operative findings. Transsphenoidal resection was employed in 92% of patients, with an estimated total resection in 73% of cases. Follow-up studies show a high quality of survival; no patient has severe neurological deficit and less than half of them require replacement therapy. The recurrence rate is 8%. Our findings do not support a previous report that pituitary adenomas in this age group are frequently extrasellar and invasive. KEY WORDS 9 pediatric brain tumor 9 pituitary adenoma 9 transsphenoidal resection 9 pediatric pituitary tumor I N large series of intracranial tumors in the pediatric age group, pituitary adenomas account for only 1% to 10% of the total. 1'a'4 Little is known of the natural history of this disease in this age group, although Ortiz-Suarez and Erickso# suggest that pituitary adenomas in children tend to be extrasellar and invasive. This report describes the presentation, preoperative findings, surgical management, and follow-up results of 25 pediatric patients encountered in a series of 250 histologically verified pituitary adenomas. 9 Patient Selection Clinical Material The 25 children studied (16 females and nine males) were admitted to the Neurosurgical Service at the University of California School of Medicine, San Francisco, between 1968 and 1977; all operations were performed by one of us (C.B.W.). The series includes all patients who had pituita'ry adenomas with documented onset of symptoms before the age of 20 years. Data were abstracted from the hospital charts. J. Neurosurg. / Volume 49 / August,

2 I. L. Richmond and C. B. Wilson Age Incidence TABLE 1 Age distribution in 25 children with pituitary adenomas Age Onset of First (years) Symptoms Treatment Only one patient was less than 9 years of age (Table 1). The majority of these patients were being investigated for delayed puberty, and a group of seven late adolescents is included because a delay of investigation, rather than delayed onset, was responsible for their age at treatment. The lag between onset of symptoms and diagnosis is similar to that reported by Lucas. ~ Presenting Symptoms Headache and visual failure, although they are classically regarded as presenting symptoms of pituitary adenoma, were uncommon, probably because the tumors encountered were relatively small ones (Table 2). Growth failure and concomitant panhypopituitarism were also uncommon. Failure of sexual maturation, the most frequent presenting sign, was the reason for investigation in over half of the cases. More than 70% of these patients presented with signs of pituitary hypersecretion. The incidence of secreting adenomas was comparable to our adult series of 250 patients? Obesity, emphasized by Ortiz-Suarez and Erickson, 5 was seldom conspicuous. Endocrine Status Evaluation and management of endocrine function was undertaken in collaboration with the pediatric endocrinology service. Preoperative evaluation revealed few patients with pituitary hyposecretion except for gonadotrophins (Table 3). Growth hormone (STH), adrenocorticotrophic hormones (ACTH), and prolactin plasma levels were obtained in patients who presented with signs of hypersecretion of these hormones; postoperative serial determination of these hormone levels was especially helpful for following patients for resolution or recurrence. Visual Deficits Papilledema was not observed, although optic atrophy was seen in patients presenting with significant visual impairment. Temporal and homonymous visual field defects occurred only rarely (Table 4). All patients with preoperative visual field deficits were significantly improved following surgery. Ex- TABLE 2 Presenting symptoms in 25 children with pituitary adenomas Symptoms (7o) headache 8 visual failure 8 growth failure 0 failure of sexual maturation 52* pituitary hypersecretion 80 gigantism/acromegaly 20 Cushing's disease 8 Nelson's disease 8 galactorrhea 44 precocious puberty 0 diabetes insipidus 0 *78 7o of pubescent patients. TABLE 3 Preoperative endocrine status in 25 cases Hormone Decreased Increased (yo) (yo) growth hormone (STH) 0 16' adrenocorticotrophic hormones 0 16t thyroid stimulating hormone 8 0 gonadotrophins 72 0 prolactin -- 32~: anti-diuretic hormone 0 0 *STH levels for an additional patient with acromegaly were not available. ttwo patients required replacement corticosteroid therapy after bilateral adrenalectomy. SProlactin levels for three additional patients with galactorrhea were not available. 164 J. Neurosurg. / Volume 49 / August, 1978

3 Pituitary adenomas in childhood and adolescence TABLE 4 Visual deficits in 23 cases Visual Defects (~) papilledema 0 optic atrophy 12 field cut temporal unilateral 4 temporal bilateral 8 homonymous 4 traocular muscle function was normal in all patients except in one child with congenital ptosis. Radiological Findings Findings typical of long-standing intracranial hypertension were absent. Sellar abnormalities (asymmetry and erosion) seen on plain skull films (Table 5) were further evaluated using hypocycloidal polytomography. Angiography was used to investigate displacement of parasellar vessels. Pneumoencephalography, which continues to be the most informative preoperative study, was abnormal in all 25 patients. In 64% of the patients, the tumor was entirely intrasellar; the remaining 36% had suprasellar extension (Table 6). Early in this series, suprasellar extension was an indication for subfrontal exploration, but in retrospect these tumors could have been removed by a transsphenoidal approach. Hydrocephalus was not observed. Computerized tomographic brain scanning has not been performed on enough patients as yet to assess its usefulness. Surgical Management and Radiation Therapy Transsphenoidal removal was the procedure of choice and was employed in 22 patients (Table 7). One additional patient underwent transsphenoidal biopsy and cryoablation early in the study. Two patients who presented with visual failure and a large suprasellar extension underwent craniotomy with optic nerve decompression. There has been no operative mortality. Two patients have been explored for recurrence. One patient, who had previously undergone craniotomy, biopsy, and radiation therapy at another institution, developed a cerebrospinal fluid (CSF) fistula 1 month after transsphenoidal resection of residual tumor; this was successfully closed transsphenoidally. However, signs of recurrence of a sellar mass that developed 2 months later led to a subfrontal exploration, at which time a necrotic frontal lobe was encountered in the sella. The histological changes found in this cortical tissue were consistent with radiation necrosis. The patient died 51/2 years later of adrenal insufficiency in the setting of a brainstem abscess. Autopsy revealed gross liquification and softening of areas in the midbrain, parasellar region, and right temporal lobe. Microscopically, sulfur granules were found in areas of liquification that were infiltrated with significant numbers of polymorphonuclear cells. No organisms were found. Destruction of the floor of the sella by recurrent tumor, as well as invasion of the sphenoid and ethmoid sinuses, was documented. Despite the absence of clinically detectable CSF leak, there was clearly no anatomical barrier between the nasal sinuses and the subarachnoid space. Another patient (DK, see below) had persistent elevation of growth hormone following transsphenoidal gross total removal of an acidophilic adenoma. Eight months later, pneumoencephalography revealed a recurrent sellar mass with a 5-mm suprasellar extension that was not present in the original study. A second transsphenoidal exploration revealed an acidophilic adenoma. Following this operation, the boy received heavy particle irradiation. Presently he is doing well on replacement therapy and has had normal levels of growth hormone. Tumor Types Pathological study of the pituitary adenomas found in these children revealed a TABLE 5 Plain skull x-ray findings in 25 cases Findings (%) normal 4 split sutures 0 abnormal sella 96 calcification 0 J. Neurosurg. / Volume 49 / August,

4 I. L. Richmond and C. B. Wilson TABLE 6 Pneumoencephalographic findings in 25 cases Findings (%) normal study intrasellar lesion 0 64 suprasellar extension 3rd ventricle deformity hydrocephalus/foramen of Monro obstruction 0 TABLE 7 Surgical management in 25 cases Operation No. of craniotomy total resection 0 subtotal resection 2 transsphenoidal approach total resection 17 subtotal resection 5 biopsy and cryoablation 1 high incidence of secretory tumors that paralleled evidence of hormonal hypersecretion at presentation (Tables 2 and 3). Electron microscopy and immunohistochemical techniques provided an excellent correlation between tumor cell characteristics and hormone hypersecretion, although some mixed types were found. The two recurrent tumors were acidophilic. As in adults, many of the tumors encountered are microadenomas that can be removed selectively with preservation of normal pituitary function. Follow-up Review Although the period of follow-up review is rather short (average, 14 months), the quality of survival appears to be very good (Table 8). There has been one late death attributable to corticosteroid insufficiency in the setting of intracranial infection, and no operative mortality. Less than half of the survivors are on endocrine replacement therapy, and all are free of severe visual or neurological deficits. To date, there are two documented recurrences, and monitoring for elevation of appropriate hormone levels continues in all patients. Discussion Pituitary adenomas have been considered rare tumors in the pediatric age group. 1-4 Lucas z encountered nine cases with onset of symptoms before 15 years of age in a series of 50 prolactin-secreting pituitary adenomas (18%). The incidence in our series 9 and in that of Guiot as reported by Lucas 2 was approximately 10%. We encountered pituitary adenomas in 33% of pediatric patients with parasellar masses reviewed in our recent report. 7 Although this incidence reflects referral patterns to some extent, it appears that earlier detection of small tumors is a major factor in this apparent change in frequency, and is not surprising in view of the natural history of this disease. Findings that support this interpretation are the rarity of signs of intracranial hypertension and the decreased incidence of visual failure as presenting symptoms, as well as the relative sparing of pituitary function. An important exception is depression of gonadotrophic function, which is known to occur early in the evolution of intrasellar pituitary adenomas. The high incidence of secreting adenomas (> 70%) facilitates diagnosis, and serial determinations of hormone levels are important in the management of these patients. Plain skull films, tomography, and small volume pneumoencephalography are the key radiological examinations. Important features that help distinguish pituitary adenomas from TABLE 8 Follow-up results in 25 children with pituitary adenoma* Follow-up Quality of Survival~ Period mos mos-1 yr mos-5 yrs yrs *Average follow-up period was 14 months. tl = alive and well; 2 = endocrine replacement therapy; 3 = significant visual deficit; 4 = other severe neurological deficit, such as coma, hemiplegia; 5 = dead. 166 J. Neurosurg. / Volume 49 / August, 1978

5 Pituitary adenomas in childhood and adolescence craniopharyngiomas, the most common parasellar tumors in children, are lack.of calcification and a high incidence of focal sellar abnormality, which are best demonstrated with tomography. Significant suprasellar extension or invasiveness were encountered infrequently in this series (36%), in contrast to a previous report of pituitary adenomas in five adolescents, four of whom had extrasellar extension? Lucas 2 reported suprasellar extension in five of the 14 cases she reviewed (35%). Transsphenoidal resection is the procedure of choice for management of pituitary adenomas in children, and in most cases an excellent clinical response is obtained with minimal morbidity. Intraoperative infection was not encountered. Transient postoperative diabetes insipidus occurred in 10 patients, but only one patient (TN, see below) required long-term pitressin therapy. We feel that the indications for the transsphenoidal approach to pituitary adenomas in children and adolescents are the same as in adults. Preoperative hypocycloidal tomography is useful for evaluation of the pneumatization of the sphenoid sinuses. Incomplete pneumatization requires the surgeon to exercise greater caution in obtaining exposure by drilling through the sphenoid, but this can be accomplished adequately and safely with experience. We have encountered only one CSF leak postoperatively, and this was in a patient (TN) who had undergone craniotomy and radiation therapy before transsphenoidal reexploration. Postoperative tomograms show excellent remodeling of the sella after transsphenoidal resection of adenomas in this age group. Radiation therapy is rarely indicated as the initial treatment because of the good response to operative removal and the risk of radiation damage to the optic nerve and hypothalamic pituitary axis in patients with benign disease and expected long-term survival. 8,8 Radiation therapy is therefore reserved for patients with residual or recurrent lesions showing clinical progression. Four of seven patients with estimated subtotal resection have received radiation therapy postoperatively. One patient (DK, see above) has received radiation therapy after reexploration for a recurrent tumor. The indications for postoperative radiation therapy include persistent or recurrent hypersecretion, especially in patients in whom total resection was not surgically feasible, and mass effect, including progressive visual field defects from residual or recurrent tumor in the case of the large, generally non-secreting adenomas. The relative risks of reexploration and possible delayed effects of radiation therapy must be considered in the management of such patients. Although the period of follow-up study is limited, this group of patients shows a low recurrence rate and a generally high quality of survival. Less than half of these patients require hormone replacement therapy, and none has a significant visual field deficit. Early detection and treatment of small tumors whose presence is detected through their hypersecretion undoubtedly contribute to these favorable results. In addition, removal of hypersecreting adenomas has been followed by resolution of the resultant hypercortisolism in all four patients with Cushing's disease, and by return of growth hormone levels to the normal range in four of five patients with acromegaly/gigantism (one patient has been lost to follow-up review). Of the 13 patients investigated for amenorrhea, six have had spontaneous menses postoperatively (two patients have become pregnant). An additional four patients have menses on replacement therapy. The two male patients with prolactin-secreting adenomas have normal prolactin levels reported postoperatively. They have both developed normal secondary characteristics and galactorrhea has ceased postoperatively. Summary Pituitary adenomas are more common in childhood and adolescence than previously suspected. Although the most common presenting complaint is failure of sexual maturation, 80% of these patients have evidence of pituitary hypersecretion preoperatively. The most common type encountered in this series was the prolactin-secreting adenoma. The frequency and type of hypersecretion parallels the distribution found in our recent adult series. ~ Transsphenoidal resection is the procedure of choice in the management of these tumors. Radiation therapy is reserved for recurrent or residual lesions showing clinical progression. To date, response to surgical therapy has been excellent, with minimal morbidity. J. Neurosurg. / Volume 49 / August,

6 I. L. Richmond and C. B. Wilson Further follow-up study will be required to determine the effectiveness of alternative therapies in achieving long-term control and in maintaining endocrine function adequate to permit the processes of growth, sexual maturation, and reproductive activities to occur in these children and adolescents. References 1. Koos WT, Miller MH: Intracraniai Tumors of Infants and Children. Stuttgart: Georg Thieme Verlag (St. Louis: CV Mosby), Lucas C: Adenomes ~ Prolactine de I'Enfant. Faculte de Medicine de Marseille, 1977 (M.D. thesis) 3. Matson D: Neurosurgery of Infancy and Childhood, ed 2. Springfield, Ill: Charles C Thomas, Odom GL, Davis CH, Woodhall B: Brain tumors in children. Clinical analysis of 164 cases. Pediatrics 18: , Ortiz-Suarez H, Erickson DL: Pituitary adenomas in adolescents. J Neurosurg 43: , Richards GE, Wara WM, Grumbach MM, et al: Delayed onset of hypopituitarism: sequelae of therapeutic irradiation of central nervous system, eye and middle ear tumors. J Pediatrics 89: , Richmond IL, Wilson CB: Parasellar tumors in children. Presented at the American Association of Neurological Surgeons Meeting, Toronto, Canada, April 24-28, 1977 (Paper No. 55) 8. Shalet SM, Beardwell CG, Morris-Jones PH, et al: Pituitary function after treatment of intracranial tumours in children. Lancet 2: , Wilson CB, Dempsey LC: Transsphenoidal microsurgical removal of 250 pituitary adenomas. J Neurosurg 48:13-22, 1978 This work was supported in part by NINCDS Training Grant Address reprint requests to: Editorial Office, Department of Neurological Surgery, 350 Parnassus Avenue, Suite 807, University of California, San Francisco, California J. Neurosurg. / Volume 49 / August, 1978